piperidines and Hypertension

This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.

Topics: Carcinoma, Neuroendocrine; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Thyroid Neoplasms

The development of Brutons Tyrosine Kinase (BTK) inhibitors has transformed the treatment of B-cell malignancies and other non-malignant conditions. Management of the unique cardiotoxic profile of these agents requires prompt recognition and a multi-disciplinary approach.. The increasing indications and addition of newer agents to clinical practice and emergence of BTK inhibitor-related cardiac adverse events have complicated the management decisions for utilization of this class of therapy. We review the incidence, mechanisms, and management approaches for BTK inhibitor-related atrial fibrillation, hypertension, and ventricular arrhythmias.. The newer BTK inhibitor acalabrutinib represents a new standard of care in front-line chronic lymphocytic leukemia (CLL) given the results of the ELEVATE-RR trial demonstrating comparable efficacy and a more favorable toxicity profile especially with regard to cardiac adverse events as compared to ibrutinib. Often not recognized by clinicians, BTK inhibitor-induced hypertension is common and can be severe, requiring prompt recognition and initiation or adjustment of anti-hypertensive medications to prevent major adverse cardiac outcomes. Novel BTK inhibitors in development are being designed to overcome the patterns of resistance from first-generation agents and to minimize off-target kinase activity, with promising toxicity profiles in early trials.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Cardiotoxicity; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Pyrimidines

The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).. In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension.. Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.

Topics: Blood Pressure; Chlorthalidone; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Piperidines; Potassium; Pyrazoles; Quinolines; Renal Insufficiency, Chronic; Spironolactone

This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect.. Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction.. For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work.. Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity.. This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension.. In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Bias; Blood Pressure; Body Weight; Bupropion; Diet, Reducing; Drug Combinations; Female; Fructose; Humans; Hypertension; Lactones; Male; Middle Aged; Naltrexone; Orlistat; Phentermine; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Time; Topiramate

The purpose of this review is to summarize the epidemiology, mechanisms, and management of cardiovascular complications of Bruton's Tyrosine Kinase inhibitors (BTKIs).. Ibrutinib increases the risk of atrial fibrillation, bleeding, and hypertension compared with non-BTKI therapies. The evidence to support an association between ibrutinib and other cardiovascular complications including ventricular tachyarrhythmias or cardiomyopathy is limited. Ibrutinib metabolism can be inhibited by some medications used to treat cardiovascular complications. The cardiovascular effects of more selective BTKIs, such as acalabrutinib, remain to be determined. Future research should address the mechanisms underlying the cardiovascular complications of BTKIs and how best to manage them. The risks and benefits of more selective BTKIs as compared with ibrutinib require further evaluation.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Atrial Fibrillation; Cardiotoxicity; Heart Failure; Hemorrhage; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Tachycardia, Ventricular

Ibrutinib is a new first-line drug for treating chronic lymphocytic leukemia (CLL), and could change frontline treatment of CLL from traditional IV chemotherapy to oral targeted therapy. Lymphocytosis often worsens with initiation of ibrutinib, but typically resolves over 6 to 18 months. Though patients generally tolerate ibrutinib well, the drug can cause adverse reactions including hypertension, atrial fibrillation, bleeding, and infections such as fungal pneumonia.

Topics: Adenine; Administration, Oral; Antineoplastic Agents; Atrial Fibrillation; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Diseases, Fungal; Lymphocytosis; Piperidines; Warfarin

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's. As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.. Lower levels of total T3 were strongly correlated with in-hospital mortality in patients with SCMP. A low T3 level might suggest poor prognosis in patients with SCMP.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Bacterial; Anxiety Disorders; Arecaceae; Arrhythmias, Cardiac; Autonomic Nervous System; Bacterial Proteins; Behavior Therapy; Burkholderia pseudomallei; Caco-2 Cells; Campylobacter; Campylobacter Infections; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chickens; Computer Simulation; Coumarins; COVID-19; Cross-Sectional Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diabetes Mellitus, Type 1; Diarrhea; Dietary Supplements; Echocardiography; Educational Measurement; Electrocardiography, Ambulatory; Endoribonucleases; Exercise; Exercise Therapy; Faculty, Dental; Farms; Fear; Female; Flame Retardants; Florida; Gene Expression Regulation, Plant; Halogenated Diphenyl Ethers; Hearing Loss, Sudden; Heart Rate; HIV Infections; Hospital Mortality; Humans; Hypertension; Hypoglycemia; Immunity; In Situ Hybridization; Japan; Kinetics; Kuwait; Lung Neoplasms; Macaca mulatta; Macrophages; Male; Masked Hypertension; Melioidosis; Methyltransferases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocardium; Oryza; Patient Education as Topic; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Piperidines; Plant Extracts; Plant Proteins; Platelet Count; Poultry Diseases; Prevalence; Protease Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Resistance Training; Retrospective Studies; Risk Factors; SARS-CoV-2; Saudi Arabia; Severe acute respiratory syndrome-related coronavirus; Students; Substance-Related Disorders; Surveys and Questionnaires; Swine; Tachycardia, Ventricular; Takotsubo Cardiomyopathy; Thyroid Gland; Transcriptome; Transfection; Tropism; United Arab Emirates; Virulence; Virulence Factors; Writing

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Arrhythmias, Cardiac; Arthralgia; Benzamides; Diarrhea; Hemorrhage; Humans; Hypertension; Infection Control; Infections; Male; Piperidines; Protein Kinase Inhibitors; Pyrazines

Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm's macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.. We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.. There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52-5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17-7.64) with high quality evidence.. Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

Topics: Adenine; Atrial Fibrillation; Databases, Factual; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk

Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections.

Topics: Adenine; Aged; Aged, 80 and over; Atrial Fibrillation; Autoimmunity; Communicable Diseases; Disease Management; Drug Interactions; Exanthema; Female; Hemorrhage; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings. Practical management recommendations are given for treating patients with ibrutinib and clinical considerations for the management of adverse events (AEs) that can be associated with ibrutinib treatment are addressed. This article highlights that patients should be monitored for treatment emergent adverse events, most of which are mild, transient and generally occur early in therapy and that, even with more challenging AEs, patients can often be maintained on therapy with minimal disruption through careful management. The necessity to use the correct ibrutinib dose, along with increased awareness, vigilance, mitigation and management of AEs, are all recommended to maximise outcomes for CLL patients treated with ibrutinib.

Topics: Adenine; Anticoagulants; Antineoplastic Agents; Arthralgia; Atrial Fibrillation; Diabetes Mellitus, Type 1; Diarrhea; Drug Eruptions; Drug Interactions; Exanthema; Fatigue; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytosis; Medication Adherence; Myalgia; Piperidines; Platelet Aggregation Inhibitors; Pyrazoles; Pyrimidines; Treatment Outcome

Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented.

Topics: Anilides; Carcinoma, Neuroendocrine; Cardiotoxicity; Humans; Hypertension; Indazoles; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sulfonamides; Thyroid Neoplasms

All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect.. To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction.. We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015).. Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo. . Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity.. After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure.. In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Blood Pressure; Cyclobutanes; Diet, Reducing; Female; Fructose; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Phentermine; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Safety-Based Drug Withdrawals; Time; Topiramate; Weight Loss

A meta-analysis of published data was conducted to investigate the overall risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer (NSCLC) who were receiving vandetanib.. A computerized search through electronic databases, including PubMed and Embase (until Dec 2014), was performed to obtain eligible randomized controlled trials (RCTs) that compared hypertension and/or QTc prolongation profile of vandetanib alone or plus chemotherapy with control groups (placebo, single targeted therapy, chemotherapy, or a combination of them) in patients with advanced NSCLC. The outcome measures were the overall risks of hypertension and QTc prolongation. Relative risk (RR) and 95% confidence interval (CI) were calculated and pooled using a random effects model.. A total of nine RCTs, which involved 4813 patients, were enrolled in the present study. A significant increase in risk was observed for all-grade hypertension (RR 5.58; 95% CI 4.16 to 7.48; P < 0.00001) and grade ≥3 hypertension (RR 4.79; 95% CI 2.31 to 9.93; P < 0.0001) in advanced NSCLC patients who were receiving vandetanib compared with the controls. Moreover, vandetanib significantly prolonged all-grade QTc interval (RR 7.90; 95% CI 4.03 to 15.50; P < 0.00001) and grade ≥3 QTc interval (RR 3.12; 95% CI 1.01 to 9.63; P = 0.05).. Current evidence showed that significant risks in developing hypertension and QTc prolongation exist in advanced NSCLC patients who were receiving vandetanib. Thus, appropriate monitoring and management of these events are recommended.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Hypertension; Long QT Syndrome; Lung Neoplasms; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Risk

All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option.. To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events. - changes in systolic and/or diastolic blood pressure - body weight reduction even though sibutramine and rimonabant have been withdrawn from the market.. Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews (status as of 17(th) August, 2012).. Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo.. Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity.. After the updated literature search, the number of studies remained the same, with eight studies comparing orlistat or sibutramine to placebo fulfilling our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg.. In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are lacking. Rimonabant and sibutramine have been withdrawn from the market for the time being.

Topics: Adult; Anti-Obesity Agents; Blood Pressure; Cyclobutanes; Diet, Reducing; Female; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Safety-Based Drug Withdrawals; Time; Weight Loss

To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients.. A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.. A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1-30.2%] and 6.4% (95% CI, 3.3-9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15-30.5%] and 7.6% (95% CI, 2.8-18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3-37.3%) and 8.8% (5.9%-12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2-33.7%) and 3.4% (95% CI: 1%-11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76-6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41-19.04, P = 0.000) in comparison with controls.. There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Hypertension; Incidence; Neoplasms; Piperidines; Publication Bias; Quinazolines; Risk

Reactive oxygen species (ROS) play an important role in physiological and pathological processes. In recent years, a feed-forward regulation of the ROS sources has been reported. The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidases, however, remain obscure. This work summarizes the latest findings on the role of cross talk between mitochondria and NADPH oxidases in pathophysiological processes. Mitochondria have the highest levels of antioxidants in the cell and play an important role in the maintenance of cellular redox status, thereby acting as an ROS and redox sink and limiting NADPH oxidase activity. Mitochondria, however, are not only a target for ROS produced by NADPH oxidase but also a significant source of ROS, which under certain conditions may stimulate NADPH oxidases. This cross talk between mitochondria and NADPH oxidases, therefore, may represent a feed-forward vicious cycle of ROS production, which can be pharmacologically targeted under conditions of oxidative stress. It has been demonstrated that mitochondria-targeted antioxidants break this vicious cycle, inhibiting ROS production by mitochondria and reducing NADPH oxidase activity. This may provide a novel strategy for treatment of many pathological conditions including aging, atherosclerosis, diabetes, hypertension, and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role. It is conceivable that the use of mitochondria-targeted treatments would be effective in these conditions.

Topics: Aging; Angiotensin II; Animals; Antioxidants; Atherosclerosis; Diabetes Mellitus; Humans; Hypertension; Mice; Mitochondria; NADPH Oxidases; Neurodegenerative Diseases; Nitric Oxide Synthase Type III; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Piperidines; Rabbits; Rats; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase; Xanthine Oxidase

Topics: Animals; Antihypertensive Agents; Binding Sites; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Humans; Hypertension; Models, Molecular; Molecular Structure; Peptidomimetics; Piperidines; Prorenin Receptor; Receptors, Cell Surface; Renin; Structure-Activity Relationship

All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option.. To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events. - changes in systolic and/or diastolic blood pressure - body weight reduction. Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews.. Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo.. Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity.. Eight studies comparing orlistat or sibutramine to placebo fulfilled our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg.. In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are needed.

Topics: Adult; Anti-Obesity Agents; Blood Pressure; Cyclobutanes; Female; Humans; Hypertension; Lactones; Male; Middle Aged; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time; Weight Loss

Obesity-related hypertension represents a common clinical condition characterised by complex pathophysiological and therapeutic features. From a pathophysiological view point, results of experimental and animal studies have led to the hypothesis that neurogenic mechanisms participate in the development and progression of the disease. The hypothesis is based on the evidence that metabolic (i.e. insulin-resistance) and neural (sympathetic activation) alterations frequently co-exist in the obese hypertensive patient and that they reciprocally potentiate each other. From a therapeutic view point, the 2007 European Society of Hypertension/European Society of Cardiology emphasised the importance in this clinical condition of treatment not only through antihypertensive drugs but also via lifestyle changes and drug-induced interventions that reduce body weight. The four Rimonabant In Obesity (RIO) studies have shown that rimonabant can decrease body weight. A recent meta-analysis, based on the RIO results, showed that rimonabant, particularly in obese hypertensive patients, can also decrease - although modestly (2.8 mmHg for systolic and 2.2 mmHg for diastolic) - blood pressure. These effects, which appear to be triggered by the weight reduction induced by the drug, are clinically relevant because they contribute favourably to lower the elevated cardiovascular risk profile of the obese hypertensive patient.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cannabinoids; Down-Regulation; Humans; Hypertension; Obesity; Piperidines; Pyrazoles; Rimonabant; Sympathetic Nervous System

Topics: Adrenal Gland Neoplasms; Bradykinin; Carotid Stenosis; Clinical Trials as Topic; Contrast Media; Endarterectomy, Carotid; Esophageal and Gastric Varices; Female; Heart Failure; Humans; Hyperglycemia; Hypertension; Hyperthyroidism; Internal Medicine; Male; Middle Aged; Osteitis Deformans; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Renal Insufficiency; Rimonabant; Risk Factors; Stents; Stethoscopes; Weight Loss

Angiogenesis does not initiate malignancy but promotes tumor progression and metastasis. Inhibiting angiogenesis is now a validated strategy for treatment of cancer. In order to do it, different ways are under investigation from cellular therapy to oral agents. Nowadays targeting angiogenesis with small molecules mainly concern inhibition of the VEGF receptors tyrosine kinase activity. Five molecules are currently in phase III trials and two of them (sunitinib and sorafenib) have been approved by the FDA for the treatment of advanced renal cancer. Despite those encouraging results, numerous points remain unclear. The toxicity profile seems to be favourable but long term effects could be problematic. Indeed, clinical trials have pointed out the role of VEGF pathway in the maintenance of numerous physiological functions. Moreover, none of the agents are specifically anti-angiogenic and the respective parts of the "off target" effects are difficult to evaluate. Simple and reliable surrogate markers of toxicity and efficacy are still lacking.

Topics: Administration, Oral; Angiogenesis Inhibitors; Animals; Asthenia; Axitinib; Benzenesulfonates; Humans; Hypertension; Imidazoles; Indazoles; Indoles; Neoplasms; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Phthalazines; Piperidines; Proteinuria; Pyridines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sunitinib; Vascular Endothelial Growth Factor A

The obesity pandemic will likely have a significant impact on the global incidence of cardiovascular disease. Although the mechanisms linking obesity and cardiovascular disease are unclear, recent studies have implicated the adipocyte as a potentially important mediator of vascular complications. The adipocyte is no longer considered a passive storage depot for triglycerides and fatty acids, but rather an active metabolic organ capable of producing several factors, commonly referred to as adipokines, that may have effects on many physiological and pathophysiological processes. With increasing fat mass, several adipose-related factors are upregulated that may affect local and distant inflammatory processes, including atherothrombosis. Other factors, such as adiponectin, are downregulated with increasing fat mass. Although most adipokines are thought to promote vascular disease, several studies over the past few years indicate adiponectin is actually protective against both diabetes and vascular disease. There are now available pharmacologic agents capable of altering the adipocyte transcription profile. This review will focus on the potential impact of adipocyte-derived factors towards vascular disease and emerging therapeutic strategies that may alter these effects.

Topics: Adiponectin; Anti-Obesity Agents; Cardiovascular Diseases; Cyclobutanes; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Rimonabant; Risk Factors

Diabetes mellitus and cognitive decline are major public health concerns among the elderly. In diabetic subjects without dementia, certain cognitive domains are impaired, such as memory, attention, and executive/frontal lobe function (diabetic cognitive dysfunction). Recent epidemiological studies have suggested that diabetes increases the risks for vascular dementia as well as Alzheimer's disease. There are accumulating evidences that indicate biological linkage between impaired brain glucose metabolism homeostasis and cognitive decline. Diabetes may cause serious brain damages through several mechanisms and induce a variety of cognitive decline. Most critical issue to be resolved is to identify the mechanism of dementia leading from diabetic cognitive dysfunction. Once elderly diabetics had severe cognitive decline, effective treatment of diabetes were hardly obtained. Thus, diabetic cognitive decline should be considered as an important comorbidity of the elderly diabetes and long-term management of hyperglycemia is required from a view point to sustain healthy brain function. In this short review, we are summarizing the clinical features and current biological findings of diabetic cognitive decline. Also, we introduce the comprehensive treatment of demented diabetic elderly, including therapeutic strategy, nursing and care.

Topics: Aged; Antihypertensive Agents; Brain; Cognition Disorders; Dementia; Diabetes Mellitus, Type 2; Donepezil; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Hyperlipidemias; Hypertension; Indans; Piperidines; Risk; Risk Factors

We describe characteristics of a selective endothelin (ET) ET(B) receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], which is widely used to demonstrate the role of endogenous or exogenous ETs in vitro and in vivo. In vitro, BQ-788 potently and competitively inhibited (125)I-labeled ET-1 binding to ET(B) receptors in human Girrardi heart cells (hGH) with an IC(50) of 1.2 nM, but only poorly inhibited the binding to ET A receptors in human neuroblastoma cell line SK-N-MC cells (IC(50), 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 showed no agonistic activity up to 10 microM and competitively inhibited the vasoconstriction induced by an ET(B)-selective agonist (pA(2), 8.4). BQ-788 also inhibited several bioactivities of ET-1, such as bronchoconstriction, cell proliferation, and clearance of perfused ET-1. Thus, it is confirmed that BQ-788 is a potent, selective ET(B) receptor antagonist. In vivo, in conscious rats, BQ-788, 3 mg/kg/h, i.v., completely inhibited a pharmacological dose of ET-1- or sarafotoxin6c (S6c) (0.5 nmol/kg, i.v.)-induced ET(B) receptor-mediated depressor, but not pressor responses. Furthermore, BQ-788 markedly increased the plasma concentration of ET-1, which is considered an index of potential ET(B) receptor blockade in vivo. In Dahl salt-sensitive hypertensive (DS) rats, BQ-788, 3 mg/kg/h, i.v., increased blood pressure by about 20 mm Hg. It is reported that BQ-788 also inhibited ET-1-induced bronchoconstriction, tumor growth and lipopolysaccharide-induced organ failure. These data suggest that BQ-788 is a good tool for demonstrating the role of ET-1 and ET(B) receptor subtypes in physiological and/or pathophysiological conditions.

Topics: Animals; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelins; Hemodynamics; Humans; Hypertension; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Receptor, Endothelin B

The new pharmacological developments in antidepressants are reviewed with particular reference to MAOIs. Combining an MAOI with amitriptyline reduces the risk of a tyramine-induced rise of blood pressure but does not eliminate the risk which is comparable to that of one of the new reversible MAO-A inhibitors (CGP 11305A).

Topics: Amitriptyline; Drug Interactions; Humans; Hypertension; Monoamine Oxidase Inhibitors; Piperidines; Tyramine

Serotonin (5-hydroxytryptamine) causes contraction of most large blood vessels and of venules. This is due mainly to direct activation of the smooth muscle or to amplification of the response to other neurohumoral mediators. Vasodilator responses to serotonin are seen mainly at the arteriolar level. They can be due to the release of other endogenous vasodilators, direct relaxation of vascular smooth muscle, inhibition of adrenergic neurotransmission, or release of an endothelium-dependent relaxing factor(s). Aggregating platelets release enough serotonin to evoke both constrictor and dilator responses. Hence the absence of endothelial cells or of adrenergic nerve activity may change the response to platelets from dilatation to constriction. Vasoconstrictor responses to serotonin released from aggregating platelets may play a role in the maintenance of the augmented peripheral resistance in hypertension. Such an involvement of serotonin is suggested by the following observations in humans and animals: the turnover rate of platelets is accelerated; the uptake of serotonin by platelets is reduced; the metabolism of serotonin by the endothelial cells is decreased; the vascular smooth muscles are hyperresponsive to the constrictor effects of serotonin and other serotonergic agonists; the S2-serotonergic antagonist ketanserin, which is devoid of agonistic properties, lowers arterial blood pressure in hypertensive humans. Whether the alpha-adrenergic blocking properties of ketanserin contribute to its antihypertensive properties in humans is still a matter of discussion.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Humans; Hypertension; Ketanserin; Methoxamine; Phenylephrine; Piperidines; Receptors, Adrenergic, alpha; Receptors, Serotonin; Regional Blood Flow; Serotonin; Serotonin Antagonists; Vasoconstriction; Vasodilation

Topics: Animals; Humans; Hypertension; Ketanserin; Muscle, Smooth, Vascular; Piperidines; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vascular Resistance

Recent plethysmographic experiments suggest that both postsynaptic alpha 1 and alpha 2 adrenoceptors in human resistance vessels play an important role in the maintenance and regulation of vascular tone. Central alpha 2 adrenoceptors are assumed to be involved in the central regulation of blood pressure. Radioligand binding studies on the density and characteristics of alpha adrenoceptors have not revealed consistent differences between normotensive and hypertensive subjects, with the exception of pheochromocytoma, in which a consistent down regulation of alpha 2 adrenoceptors in thrombocytes has been demonstrated. The radioligand binding studies are limited, since they cannot be performed on vascular tissues. Alpha adrenoceptors are vitally important as targets of several antihypertensive drugs; the activities of these agents and the principles and clinical relevance of mechanisms involving alpha adrenoceptors are reviewed.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Azepines; Blood Pressure; Calcium Channel Blockers; Clonidine; Guanfacine; Guanidines; Humans; Hypertension; Ketanserin; Methyldopa; Muscle, Smooth, Vascular; Phenylacetates; Piperazines; Piperidines; Prazosin; Radioligand Assay; Receptors, Adrenergic, alpha; Vascular Resistance

The realisation that serotonin plays a role not only in the carcinoid syndrome but also in migraine, nociception, dumping syndrome, vascular disease and hypertension, has led to an enormous amount of activity in search of serotonin antagonists. Numerous such pharmacological agents have been identified but only few have found their way into clinical use. All of them are competitive serotonin inhibitors, in that they vie for the same receptor as the amine itself and are thus able to block its action as well as imitate its effects. By far the widest use of such inhibitors is in the prevention of migraine, where they have effectively eliminated the dread of an attack from the life of the majority of patients. Whilst useful in the control of diarrhea in patients with carcinoid and dumping syndromes, their role in these diseases is limited. However, the possible role of serotonin in hypertension and nociception opens new avenues in the use of existing serotonin antagonists and calls for the discovery of a new generation of such pharmacological agents for the control of these conditions.

Topics: Cyproheptadine; Depression; Ergotamine; Humans; Hypertension; Ketanserin; Lisuride; Methysergide; Mianserin; Migraine Disorders; Piperidines; Pizotyline; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Vascular Diseases

Establishing alternatives to lifelong chemotherapy for patients with advanced pancreatic cancer has been proposed to address chemotherapy resistance and cumulative toxicity. Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in this setting, and concurrent immune checkpoint blockade could offer synergistic tumour control. The aim of this study was to test the safety and antitumour activity of maintenance with PARP inhibition combined with immune checkpoint blockade in patients with advanced pancreatic cancer who had a stable response to platinum-based chemotherapy.. We conducted an open-label, randomised, phase 1b/2 study of niraparib plus anti-PD-1 (nivolumab) or anti-CTLA-4 (ipilimumab) therapy for patients with advanced pancreatic cancer whose cancer had not progressed after at least 16 weeks of platinum-based therapy. Patients were randomly assigned (1:1) via permuted block randomisation (block sizes 2 and 4) to niraparib 200 mg orally per day plus either nivolumab 240 mg intravenously every 2 weeks (later changed to 480 mg intravenously every 4 weeks based on manufacturer update) or ipilimumab 3 mg/kg intravenously every 4 weeks for four doses. The primary endpoints were safety and progression-free survival at 6 months. Treatment groups were not compared for activity, which was assessed in each group against a clinically meaningful progression-free survival at 6 months of 44% (null hypothesis). Superiority of a treatment regimen could be declared if 6-month progression-free survival was 60%, and inferiority if 6-month progression-free survival was 27%. All patients who received at least one dose of study treatment and had at least one post-treatment assessment of response according to Response Evaluation Criteria in Solid Tumours version 1.1 were included in the efficacy population. The safety population consisted of all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03404960, and enrolment is completed and follow-up is ongoing.. 91 patients were enrolled between Feb 7, 2018, and Oct 5, 2021 and were randomly assigned to niraparib plus nivolumab (n=46) or niraparib plus ipilimumab (n=45). Of these patients, 84 were evaluable for the progression-free survival endpoint (niraparib plus nivolumab=44; niraparib plus ipilimumab=40). Median follow-up was 23·0 months (IQR 15·0-31·5). 6-month progression-free survival was 20·6% (95% CI 8·3-32·9; p=0·0002 vs the null hypothesis of 44%) in the niraparib plus nivolumab group; and 59·6% (44·3-74·9; p=0·045) in the niraparib plus ipilimumab group. Ten (22%) of 46 patients in the niraparib plus nivolumab group and 23 (50%) of 45 patients in the niraparib plus ipilimumab group had a grade 3 or worse treatment-related adverse event. The most common grade 3 or worse adverse events in the niraparib plus nivolumab group were hypertension (in four [8%] patients), anaemia (two [4%]), and thrombocytopenia (two [4%]) whereas in the niraparib plus ipilimumab group these were fatigue (in six [14%]), anaemia (five [11%]), and hypertension (four [9%]). There were no treatment-related deaths.. The primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer.. Bristol Myers Squibb, GlaxoSmithKline, the Basser Center Young Leadership Council, The Konner Foundation, The Pearl and Philip Basser Innovation Research Award, the Anonymous Foundation, and the US National Institutes of Health.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hypertension; Immune Checkpoint Inhibitors; Indazoles; Ipilimumab; Nivolumab; Pancreatic Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors

[Figure: see text].

Topics: Aged; Blood Pressure; Double-Blind Method; Female; Humans; Hyperkalemia; Hypertension; Male; Middle Aged; Outcome Assessment, Health Care; Piperidines; Pyrazoles; Quinolines; Renal Insufficiency, Chronic

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bendamustine Hydrochloride; Female; Follow-Up Studies; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prognosis; Rituximab; Survival Rate

The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.. Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.. With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Piperidines; Pneumonia; Progression-Free Survival; Remission Induction; Survival Rate

The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy.. This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety.. The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed.. The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; CD4 Lymphocyte Count; Cognition; Female; Follow-Up Studies; Humans; Hypertension; Hyponatremia; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Neutropenia; Piperidines; Progression-Free Survival; Quality of Life; Remission Induction; Retreatment; Sulfonamides; Survival Rate; Thrombocytopenia; Young Adult

Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer.. This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131.. Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred.. The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned.. Nordic Society of Gynaecological Oncology and Tesaro.

Topics: Aged; Anemia, Aplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Endometrioid; Disease Progression; Female; Humans; Hypertension; Indazoles; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Progression-Free Survival; Proteinuria; Thrombocytopenia

Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.

Topics: Adenine; Aged; Antihypertensive Agents; Female; Heart Diseases; Hematologic Neoplasms; Humans; Hypertension; Incidence; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Stroke

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Anemia; Atrial Fibrillation; Diarrhea; Drug Tolerance; Fatigue; Female; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Prevalence; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Safety

Background Blood pressure ( BP ) treatment goals in patients with diabetes mellitus and increased cardiovascular risk remain controversial. Our study objective was to determine cardiovascular outcomes according to achieved BP s over the average follow-up period in the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) trial. Methods and Results EXAMINE was a cardiovascular outcomes trial in 5380 patients with type 2 diabetes mellitus and recent acute coronary syndromes. Risks of major adverse cardiac events and cardiovascular death or heart failure were analyzed using a Cox proportional hazards model with adjustment for baseline covariates in 10-mm Hg increments of clinician-measured systolic BP from ≤100 to >160 mm Hg and diastolic BP from ≤60 to >100 mm Hg averaged during the 24 months after randomization. Based on 2015 guidelines from the American College of Cardiology, the American Heart Association and the American Society of Hypertension and 2017 American Diabetes Association guidelines, systolic BP s of 131 to 140 mm Hg and diastolic BP s of 81 to 90 mm Hg were the reference groups. A U-shaped relationship between cardiovascular outcomes and BP s was observed. Importantly, compared with the systolic BP reference group, adjusted hazard ratios for major adverse cardiac events and cardiovascular death or heart failure were significantly higher in patients with systolic BP s <130 mm Hg. Similarly, compared with the diastolic BP reference group, adjusted hazard ratios for major adverse cardiac events and for cardiovascular death or heart failure were significantly higher for diastolic BP s <80 mm Hg. Conclusions In patients with type 2 diabetes mellitus and recent acute coronary syndrome, average BP s <130/80 mm Hg were associated with worsened cardiovascular outcomes. These data suggest that intensive control of BP in patients with type 2 diabetes mellitus and ischemic heart disease should be evaluated in a prospective randomized trial. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00968708.

Topics: Aged; Analysis of Variance; Blood Pressure Determination; Cause of Death; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Hypertension; Hypoglycemic Agents; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prognosis; Prospective Studies; United States; Uracil

To explore the feasibility of different doses of dexmedetomidine for quiet extubation during anesthesia recovery in hypertensive patients monitored with Narcotrend.. A total of 120 hypertensive patients scheduled for thyroid surgery from August 2012 to June 2014 in the Second Affiliated Hospital of Wenzhou Medical University, were randomly divided into 6 groups (n=20 each). Dexmedetomidine 0.4 (group M1), 0.6 (group M2), 0.8 (group M3) or 1.0 (group M4) µg·kg(-1)·h(-1), remifentanil 0.1 µg·kg(-1)·min(-1) (group R) and normal saline (group S) were infused for half an hour before the end of surgery, and extubation was carried out when Narcotrend index (NI) values were ≥80 in each group. Data of heart rate (HR), systolic blood pressure (SBP) and minimal alveolar concentration (MAC) of sevoflurane were observed and recorded at the time of baseline (T0), half an hour (T1) and 15 min (T2) before the end of surgery, stopping sevoflurane (T3), before extubation (T4), 1 min (T5), 5 min (T6) and 10 min (T7) after extubation. Extubation time, recovery time and related adverse reactions were also recorded.. Compared with T0, SBP and HR at T4 to T7 in four M groups were significantly lower (all P<0.05). SBP and HR at T6, T7 in group R were significantly lower than at T0 (all P<0.05). SBP at T6, T7 and HR at T4 to T7 in group R were significantly lower than that of group S (all P<0.05). SBP and HR at T4 to T7 in four M groups were significantly lower than that of group S and group R (all P<0.05). The values of MAC of sevoflurane at T2 and T3 in group R and M2-4 were significantly lower than at T1 and that of group S (all P<0.05). Recovery time in group M3 [(19.1±2.8) min] and group M4 [(20.6±4.1) min] were significantly longer compared with other four groups (all P<0.05). The percentage of cough grade at level I and II in each M group and group R during extubation was significantly higher than that in group S (85%, 85%, 90%, 95%, 80% vs 45%, all P<0.05).. Dexmedetomidine could be safely used in hypertensive patients monitored with Narcotrend for quiet extubation during anesthesia recovery, but larger doses of dexmedetomidine may prolong the recovery time.

Topics: Airway Extubation; Anesthesia Recovery Period; Blood Pressure; Dexmedetomidine; Heart Rate; Humans; Hypertension; Methyl Ethers; Piperidines; Remifentanil; Sevoflurane

Remifentanil is known to attenuate the cardiovascular responses to tracheal intubation. We determined effective doses (ED(50)/ED(95)) of remifentanil to prevent the pressor response to tracheal intubation in patients with severe preeclampsia.. Seventy-five women with severe preeclampsia were randomly allocated to one of five remifentanil dose groups (0.25, 0.50, 0.75, 1.0, or 1.25 μg/kg) given before induction of anaesthesia using thiopental 5 mg/kg and suxamethonium 1.5 mg/kg. Systolic arterial pressure, heart rate and plasma catecholamine concentrations were measured. Neonatal effects were assessed by Apgar scores and umbilical cord blood gas analysis. A dose was considered effective when systolic arterial pressure did not exceed 160 mmHg for more than 1 min following tracheal intubation.. Baseline systolic blood pressure and heart rate did not differ among the groups. The intubation-induced increases of heart rate and blood pressure were attenuated in a dose-dependent manner by remifentanil. ED(50) and ED(95) were 0.59 (95% CI 0.47-0.70) μg/kg and 1.34 (1.04-2.19)μg/kg, respectively. Norepinephrine concentrations remained unaltered following intubation but increased significantly at delivery, with no differences between the groups. Apgar scores and umbilical arterial and venous pH and blood gas values were comparable among the groups. Two women each in the 1.0 and 1.25 μg/kg groups received ephedrine for hypotension defined as systolic arterial pressure <90 mmHg.. The ED(95) of remifentanil for attenuating the hypertensive response to tracheal intubation during induction of anaesthesia in severely preeclamptic patients undergoing caesarean delivery under general anaesthesia was 1.34 μg/kg.

Topics: Adult; Analgesics, Opioid; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Cesarean Section; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Intubation, Intratracheal; Laryngoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Piperidines; Pre-Eclampsia; Pregnancy; Remifentanil; Severity of Illness Index; Succinylcholine; Thiopental; Young Adult

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Topics: Aged; Antiparkinson Agents; Carbidopa; Drug Combinations; Female; Humans; Hypertension; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Piperidines; Pyrimidines; Receptors, N-Methyl-D-Aspartate

Patients with hypertension may be more prone to develop hypotension as a consequence of opioid administration under general anesthesia. The hemodynamic and bispectral index responses to a remifentanil bolus in neurosurgical hypertensive patients under target-controlled infusion with propofol and remifentanil are addressed.. Ten healthy patients and 10 patients with diagnosed hypertension under pharmacological treatment were studied. A 2 microg/kg remifentanil bolus was administered to all patients before skin incision under target-controlled infusion with propofol and remifentanil. Mean arterial pressure, heart rate, and the area under the curve for the bispectral index of the electroencephalogram were analyzed within the groups and compared between them every 30 seconds for two minutes following the bolus.. Two minutes after the remifentanil bolus, remifentanil predicted effect-site concentrations reached maximum values of 8.46+/-0.91 ng/ml and 9.74+/-1.29 ng/ml in the healthy and hypertensive patients, respectively. Both groups showed a significant decrease in mean arterial pressure, heart rate, and in the area under the curve for the bispectral index. Mean arterial pressure decreased by 17.3+/-10% and 24+/-9%, heart rate by 11.1+/-8% and 12+/-8%, and the bispectral index by 13+/-9.2% and 8.6+/-8.4% in the healthy and hypertensive patients, respectively, 120 seconds after the remifentanil bolus.. In a clinical situation in which high remifentanil doses may be required, hypertensive patients are expected to have hemodynamic and bispectral index responses similar to those observed in healthy patients.

Topics: Adult; Analgesics, Opioid; Area Under Curve; Consciousness Monitors; Demography; Dose-Response Relationship, Drug; Electroencephalography; Female; Humans; Hypertension; Male; Middle Aged; Neurosurgical Procedures; Physical Stimulation; Piperidines; Propofol; Remifentanil

Rimonabant, the first selective cannabinoid type 1 (CB1) receptor blocker, has been shown to improve multiple cardiometabolic risk factors in overweight/obese patients. This analysis assessed the impact of rimonabant on blood pressure in the pooled population from four large trials with similar design - the Rimonabant-In-Obesity (RIO) programme.. RIO-Europe (n = 1507) and RIO-North America (n = 3040) recruited overweight/obese patients, and RIO-Lipids (n = 1033) and RIO-Diabetes (n = 1045) recruited overweight/obese patients with untreated dyslipidaemia or type 2 diabetes, respectively. At study entry (screening), 37.2% (n = 2463) of patients had hypertension, 71.4% (n = 1757) of whom were taking an antihypertensive treatment.. After 1 year of treatment, mean change in systolic blood pressure (SBP) from baseline was -0.8 mmHg for rimonabant 20 mg versus +0.3 mmHg for placebo (P = 0.007); diastolic blood pressure (DBP) decreased by -0.8 versus -0.3 mmHg (P = 0.029) respectively. In the subgroup of patients with high blood pressure at baseline, SBP change was -7.5 mmHg for rimonabant 20 mg versus -4.7 mmHg for placebo (P = 0.005); DBP change was -5.2 versus -3.0 mmHg (P < 0.001). Reductions were more pronounced in patients with dyslipidaemia and type 2 diabetes. There was no effect of rimonabant 20 mg on blood pressure beyond that expected from weight loss alone. Overall, there was a similar incidence of adverse events (AEs) at 1 year in the placebo (81.8%) and rimonabant 20 mg (86.0%). The most common AEs occurring with rimonabant were nausea, dizziness, arthralgia and diarrhoea. A slightly higher proportion of patients in the rimonabant 20 mg group discontinued as a result of AEs (13.8%) versus placebo (7.2%).. Rimonabant 20 mg led to modest, but significant SBP and DBP reductions in overweight/obese patients. The effect of rimonabant on blood pressure appears to be mediated by weight loss.

Topics: Adult; Blood Pressure; Cannabinoid Receptor Antagonists; Diabetes Mellitus, Type 2; Double-Blind Method; Dyslipidemias; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pyrazoles; Rimonabant; Weight Loss

To compare 4 different anesthesia induction protocols, in a simulated model of rapid-sequence induction, in controlled hypertensive patients.. Prospective, randomized, double-blind, clinical investigation.. Large metropolitan university hospital.. 120 ASA II-III adult hypertensive patients.. Patients were allocated to 4 groups at random. After preoxygenation for 3 minutes, induction and tracheal intubation was performed in a 30 degrees head-up position. Thiopental (5-7 mg/kg) was the induction agent. Study groups were as follows: group LS (n = 30), lidocaine (1.5 mg/kg) and succinylcholine (1 mg/kg); group LR (n = 30), lidocaine (1.5 mg/kg) and rocuronium (1 mg/kg); group RS (n = 30), remifentanil (1 microg/kg) and succinylcholine (1 mg/kg); group RR (n = 30), remifentanil (1 microg/kg) and rocuronium (1 mg/kg). Patients were intubated 60 seconds after administration of muscle relaxant.. Hemodynamic data were obtained before induction (baseline), after induction, at intubation, and at 1, 3, 5, and 10 minutes after intubation. More than 20% change in blood pressure and heart rate was considered significant.. Systolic and mean arterial blood pressures at intubation and 1 and 3 minutes after intubation were higher in group LS compared with groups RS and RR (P < 0.01). Mean arterial blood pressure decreased after induction in groups LS, LR, and RR, but increased at intubation and 1 minute after intubation in groups LS and LR (P < 0.01). Mean arterial blood pressure was similar at all measurement intervals in group RS. The median area under the systolic, mean, and diastolic blood pressure time curves was higher in groups LS and LR compared with groups RS and RR (P < 0.05 and P < 0.01).. Remifentanil is a better adjunct for attenuation of the response to laryngoscopy and intubation compared with lidocaine, whereas remifentanil-succinylcholine combination appears to be more beneficial in terms of hemodynamic stability in hypertensive patients.

Topics: Analgesics, Opioid; Androstanols; Anesthesia; Anesthetics, Local; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Hypnotics and Sedatives; Intubation, Intratracheal; Laryngoscopy; Lidocaine; Male; Middle Aged; Neuromuscular Depolarizing Agents; Neuromuscular Nondepolarizing Agents; Piperidines; Remifentanil; Rocuronium; Succinylcholine; Thiopental

In a prospective randomised trial we studied haemodynamic stability during induction of anaesthesia for CABG surgery in patients receiving remifentanil-propofol or fentanyl-propofol anaesthesia.. Fifty-four patients scheduled for elective CABG surgery were studied. Anaesthesia was induced with propofol and pancuronium. The patients were randomly assigned to two groups according to the opioid used during the induction. The remifentanil group received 0.5 microg kg(-1) min(-1) of the drug and the fentanyl group received 5 microg kg(-1). We measured blood pressure, central venous pressure and heart rate continuously for 15 min before and 30 min after orotracheal intubation. We also recorded use of rescue medication for maintaining the mean arterial pressure between 65 and 85 mmHg.. After induction of anaesthesia the mean arterial pressure and heart rate decreased significantly in both groups (P<0.05). After orotracheal intubation the mean arterial pressure and heart rate increased significantly in the fentanyl group but not in the remifentanil group (P<0.05). The incidence of hypertonic events necessitating the use of rescue medication was significantly higher in the fentanyl group (P<0.05).. Our results show more stable haemodynamics after induction of anaesthesia in CABG surgery in patients receiving remifentanil-propofol than in patients receiving fentanyl-propofol.

Topics: Analgesics, Opioid; Anesthesia; Anesthetics, Intravenous; Blood Pressure; Central Venous Pressure; Coronary Artery Bypass; Female; Fentanyl; Heart Rate; Humans; Hypertension; Infusions, Intravenous; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Remifentanil; Risk Assessment; Risk Factors; Treatment Outcome

To compare the efficacy of different bolus doses of remifentanil, alfentanil, and saline at controlling the hemodynamic responses to day-case rigid bronchoscopy under general anesthesia.. Prospective, randomized, double-blind, placebo-controlled study.. Tertiary referral cardiothoracic hospital, single center.. Eighty consenting adults scheduled for elective day-case rigid bronchoscopy under general anesthesia.. Patients were randomized to receive a bolus of 10 micro g/kg of alfentanil, 1 micro g/kg of remifentanil, 2 micro g/kg of remifentanil or saline. After this, anesthesia was induced and maintained with a target-controlled propofol infusion (TCI) and succinylcholine was used for muscle relaxation. Heart rate and noninvasive arterial pressure were measured at 1-minute intervals throughout.. Patients' characteristics were similar in all 4 groups. There were no differences in time to return of spontaneous ventilation, wake-up times, or use of rescue vasopressors, and no patients complained of postoperative nausea. Remifentanil provided greater hemodynamic stability than alfentanil and a bolus of remifentanil of 2 micro g/kg significantly attenuated the rise in heart rate and was the most effective in preventing a rise in blood pressure.. A bolus of 2 micro g/kg of remifentanil successfully attenuated the hemodynamic response to rigid bronchoscopy without delaying recovery.

Topics: Aged; Alfentanil; Analgesics, Opioid; Area Under Curve; Blood Pressure; Bronchoscopy; Diastole; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Incidence; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prospective Studies; Remifentanil; Systole; Tachycardia; Time Factors; Treatment Outcome; Vasoconstrictor Agents

To evaluate the efficacy and tolerability of donepezil in patients with vascular dementia (VaD).. Patients (n = 616; mean age, 75.0 years) with probable or possible VaD, according to National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences criteria, were randomized to receive donepezil 5 mg/day (n = 208), donepezil 10 mg/day (after 5 mg/day for the first 28 days) (n = 215), or placebo (n = 193) for 24 weeks.. Seventy-six percent of the patients enrolled had probable VaD. A total of 75.3% of the 10 mg donepezil group and 80.8% of the 5 mg group completed the study compared with 83.4% of the placebo group. Both donepezil-treated groups showed improvements in cognitive function on the Alzheimer's Disease Assessment Scale-cognitive subscale compared with placebo, with a mean endpoint treatment difference, as measured by the change from baseline score, of approximately 2 points (donepezil 5 mg, -1.65 [p = 0.003]; 10 mg, -2.09 [p = 0.0002]). Greater improvements on the Clinician's Interview-Based Impression of Change-plus version were observed with both donepezil groups than with the placebo group (overall donepezil treatment vs placebo p = 0.008); 25% of the placebo group showed improvement compared with 39% (p = 0.004) of the 5 mg group and 32% (p = 0.047) of the 10 mg group. Withdrawal rates due to adverse events were low (placebo, 8.8%; donepezil 5 mg, 10.1%; 10 mg, 16.3%).. Donepezil-treated patients demonstrated significant improvements in cognition and global function compared with placebo-treated patients, and donepezil was well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Double-Blind Method; Female; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Risk Factors; Smoking; Stroke; Treatment Outcome

Hypertensive patients have both impaired endothelium-dependent vasodilation and increased activity of the endothelin (ET-1) system, which participate in their increased vascular tone and may predispose them to atherosclerosis. This study investigated the contribution of increased ET-1 activity to the impaired endothelium-dependent vasodilator function of hypertensive patients.. Forearm blood flow (FBF) responses to intraarterial infusion of acetylcholine (ACh; 7.5, 15, and 30 microg/min) and sodium nitroprusside (SNP; 0.8,1.6, and 3.2 microg/min) were assessed by strain-gauge plethysmography before and after nonselective blockade of ET(A) and ET(B) receptors by combined infusion of BQ-123 (ET(A) blocker; 100 nmol/min) and BQ-788 (ET(B) blocker; 50 nmol/min). During saline administration, the vasodilator response to ACh was significantly blunted in hypertensive patients compared with controls (P<0.001), whereas the vasodilator effect of SNP was not different between groups (P=0.74). Blockade of ET-1 receptors resulted in a significant increase in FBF from baseline in hypertensive patients (P<0.008) but not in controls (P=0.15). In hypertensive patients, a combined ET(A/B) blockade resulted in a significant potentiation of the vasodilator response to ACh compared with saline (P=0.01), whereas the response to SNP was unchanged (P=0.44). In contrast, the response to ACh was not significantly modified by ET-1 receptor antagonism in healthy subjects (P=0.14 compared with saline).. These findings indicate that blockade of ET-1 receptors improves endothelium-dependent vasodilator function in hypertensive patients, thereby suggesting that an increased ET-1 activity may play a role in the pathophysiology of this abnormality.

Topics: Acetylcholine; Endothelin Receptor Antagonists; Endothelium, Vascular; Female; Forearm; Humans; Hypertension; Infusions, Intra-Arterial; Male; Middle Aged; Nitroprusside; Oligopeptides; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Regional Blood Flow; Vasodilation; Vasodilator Agents

In a randomized double-blind study, we compared the effect of remifentanil and alfentanil on the cardiovascular response to laryngoscopy and tracheal intubation in patients on long-term treatment for hypertension. Forty ASA II-III patients were allocated to receive (i) remifentanil 0.5 microg kg(-1) followed by an infusion of 0.1 microg kg min(-1) or (ii) alfentanil 10 microg kg(-1) followed by an infusion of saline; all patients received glycopyrrolate 200 microg before the study drug. Anaesthesia was induced with propofol and rocuronium and maintained with 1% isoflurane and 66% nitrous oxide in oxygen. Laryngoscopy and tracheal intubation were performed after establishment of neuromuscular block. Arterial pressure and heart rate (HR) were measured non-invasively at 1 min intervals from 3 min before induction until 5 min after intubation. Systolic (SAP), diastolic and mean arterial pressure decreased significantly after induction in both groups (P<0.05). Maximum increases in mean SAP after laryngoscopy and intubation were 35 and 41 mm Hg in the remifentanil and alfentanil groups, respectively. After intubation, arterial pressure did not increase above baseline values in either group. HR remained stable after induction of anaesthesia, but increased above baseline values after intubation. Mean maximum HR was 87 beats min(-1) for the remifentanil group (12 beats min(-1) above baseline; P=0.065) and 89 beats min(-1) for the alfentanil group (15 beats min(-1) above baseline; P<0.05). There were no significant differences between groups in HR or arterial pressure at any time. There were no incidences of bradycardia. Seven patients in the remifentanil group and four in the alfentanil group received ephedrine for hypotension (i.e. SAP<100 mm Hg).

Topics: Adult; Aged; Alfentanil; Analgesics, Opioid; Anesthesia, General; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Intubation, Intratracheal; Laryngoscopy; Male; Middle Aged; Piperidines; Remifentanil

To compare in a prospective, randomized study the effects on cardiovascular changes after tracheal intubation produced by small doses of either remifentanil or fentanyl.. With Ethical Committee approval, after intravenous midazolam premedication (0.05 mg.kg-1), 30 normotensive, ASA physical status I-II patients, without cardiovascular or respiratory diseases, and with a Mallampati score < 2, were randomly allocated to receive an intravenous bolus of either 3 micrograms.kg-1 fentanyl (n = 15) or 1 microgram.kg-1 remifentanil (n = 15) infused over 60 sec and followed by a 0.15 microgram.kg-1.min-1 continuous intravenous infusion. General anesthesia was then induced with propofol (2 mg.kg-1), followed by atracurium besilate (0.5 mg.kg-1) to facilitate tracheal intubation. Following intubation, the lungs were ventilated mechanically using a 60% nitrous oxide in oxygen mixture with a 1% inspired fraction of sevoflurane. Arterial blood pressure and heart rate were recorded before anesthesia induction (baseline), one minute after induction of anesthesia, immediately after tracheal intubation and every minute for the first five minutes after intubation.. Systolic arterial blood pressure values were significantly higher in the Fentanyl than in the Remifentanil group patients from 2 to 5 min after tracheal intubation (p < 0.01), while no differences were observed between the two groups in either diastolic arterial blood pressure or heart rate values. Four patients in the Remifentanil group (26%) but only one patient in the Fentanyl group (7%) showed systolic blood pressure values < 90 mmHg during the study period (p = not significant); however, the observed decreases in systolic arterial blood pressure values were transient and did not require treatment for any subject.. We conclude that in healthy normotensive patients, the control of cardiovascular responses to tracheal intubation obtained with a 1 microgram.kg-1 loading dose of remifentanil is more effective than that provided by a 3 micrograms.kg-1 bolus of fentanyl, with the advantage of no risks for postoperative respiratory depression.

Topics: Anesthesia, General; Anesthetics, Intravenous; Atracurium; Blood Pressure; Female; Fentanyl; Heart Rate; Humans; Hypertension; Intubation, Intratracheal; Male; Middle Aged; Narcotics; Piperidines; Propofol; Prospective Studies; Remifentanil

Patients with unstable coronary syndromes are a heterogeneous group with varying degrees of ischemia and prognosis. The present study compares the prognostic value of a standard electrocardiogram (ECG) obtained at admission to the hospital with the information from 24-hour continuous electrocardiographic monitoring obtained immediately after admission. The admission ECGs and 24 hours of vectorcardiographic (VCG) monitoring from 308 patients admitted with unstable coronary artery disease were analyzed centrally regarding standard electrocardiographic ST-T changes, ST-vector magnitude (ST-VM), and ST change vector magnitude episodes. End points were death, acute myocardial infarction, and refractory angina pectoris within a 30-day follow-up period. ST-VM episodes (> or = 50 microV for > or = 1 minute) during VCG monitoring was the only independent predictor of death or acute myocardial infarction by multivariate analysis. ST-VM episodes during vectorcardiography was associated with a relative risk of 12.7 for having a cardiac event, hypertension was associated with a relative risk of 1.7, and ST depression on the admission ECG was associated with a relative risk of 5.7. Patients with ST depression at admission had an event rate (death or acute myocardial infarction) of 17% at 30-day follow-up. Patients without ST depression could further be risk stratified by 24 hours of VCG monitoring into a subgroup with ST-VM episodes at similar (8%) risk and a subgroup without ST-VM episodes at low (1%) risk (p = 0.00005). Continuous VCG monitoring provides important information for evaluating patients with unstable coronary artery disease. It is recommended that patients not initially estimated at high risk based on the admission ECG are referred for 24 hours of VCG monitoring for further risk stratification.

Topics: Aged; Angina Pectoris; Angina, Unstable; Anticoagulants; Antithrombins; Coronary Disease; Electrocardiography; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Glycine; Heparin; Humans; Hypertension; Male; Multivariate Analysis; Myocardial Infarction; Myocardial Ischemia; Patient Admission; Piperidines; Prognosis; Recurrence; Risk Assessment; Risk Factors; Survival Rate; Vectorcardiography

To study the role of vasopressin (VP) in essential hypertension, we examined plasma levels of VP and blood pressure (BP) response to an orally active V1 receptor antagonist, OPC-21268, in hypertensive patients on diets with different sodium contents. Plasma VP was determined in 12 normotensive subjects and 12 patients with mild essential hypertension on a regular sodium diet, and in eight hypertensive patients on a high sodium (250 mmol/day) and a low sodium (25 mmol/day) diet. BP response was examined for 4 h after single oral administration of OPC-21268 (100 mg) or placebo in eight patients on the regular diet, and in six patients on the high and low sodium diets. In four patients on the regular diet, the effects of OPC-21268 on the baroreflex control of heart rate were also examined with intravenous injections of methoxamine. Plasma VP did not differ between the normotensive and hypertensive subjects. Levels of VP in the plasma was higher in the high sodium than in the low sodium period, but the difference was not significant. BP and heart rate did not change significantly after administration of OPC-21268 or placebo under either condition. OPC-21268 also failed to lower BP in salt-sensitive patients on the high sodium diet. The baroreceptor reflex sensitivity was not modified by the administration of OPC-21268. Our results suggest that VP does not play an important role in mild essential hypertension through its action on the V1 receptors regardless of dietary sodium intake.

Topics: Adult; Aged; Antidiuretic Hormone Receptor Antagonists; Baroreflex; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Piperidines; Quinolones; Sodium, Dietary; Vasopressins

The effects of ketanserin (40 mg p.o.) on blood pressure and brachial haemodynamics (brachial artery diameter, brachial blood velocity and blood flow) have been compared in a double-blind study with those of ritanserin (10 mg p.o.) and placebo. Haemodynamic parameters were measured before and 1 h after treatment. Patients with mild to moderate essential hypertension participated in this study, 6 each on ketanserin, ritanserin and placebo. Placebo significantly reduced heart rate and did not modify the other parameters. Compared to placebo, ketanserin significantly reduced systolic and diastolic blood pressure, increased brachial blood velocity and flow, and decreased forearm vascular resistance. Compared to placebo, ritanserin slightly decreased blood pressure and slightly increased blood flow, but neither effect was significant. When blood circulation to the hand was excluded, neither ketanserin nor ritanserin modified the proximal arterial resistance or blood flow. It is concluded that the actions of ketanserin and ritanserin essentially occurred in the distal part of the upper limb, and alpha 1-receptor blockade is probably involved.

Topics: Arm; Blood Pressure; Brachial Artery; Double-Blind Method; Hand; Humans; Hypertension; Ketanserin; Middle Aged; Piperidines; Regional Blood Flow; Rheology; Ritanserin; Serotonin Antagonists; Vascular Resistance

In patients with essential hypertension, ketanserin (40 mg once or twice daily) reduces the blood pressure in mono- and combination therapy. Despite evidence of peripheral vasodilation, the heart rate is reduced. This would suggest that ketanserin has an additional sympathoinhibitory effect. However, the influence of ketanserin on plasma catecholamine levels at rest and during exercise or stress was small, and to date there is little evidence for a central sympathoinhibitory effect of ketanserin in humans. The antihypertensive effects of ritanserin, a selective 5-HT2-receptor antagonist, were investigated in a double-blind, placebo-controlled crossover study (4 weeks). Treatment with ritanserin, 10 mg twice daily, was ineffective in hypertensive patients, which indirectly suggests that the 5-HT2-blocking properties of ketanserin cannot alone be responsible for its antihypertensive effects.

Topics: Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Ritanserin

We have given the selective 5 HT2 antagonist ritanserin in a dose of 10 mg twice daily for 4 weeks in a double-blind, randomized, placebo-controlled, parallel group study of 18 patients with untreated essential hypertension. The fall in single platelet count due to 5 HT-induced platelet aggregation was significantly reduced by ritanserin compared with placebo (p less than 0.05). There were no significant changes in supine or erect blood pressure or heart rate after ritanserin compared to placebo. Forearm blood flow, measured by mercury-in-strain gauge venous occlusion plethysmography, was not significantly altered by ritanserin. Ritanserin caused prolongation of the QTc interval by 41 (SEM 11) ms (p less than 0.05 compared to placebo) but had no detectable effect on QRS duration, features suggestive of Class III antiarrhythmic activity. These findings do not support an independent role of the 5 HT2 receptor in maintaining raised arterial pressure in essential hypertension.

Topics: Aged; Blood Pressure; Double-Blind Method; Electrocardiography; Female; Forearm; Heart Rate; Humans; Hypertension; Male; Middle Aged; Piperidines; Platelet Aggregation; Random Allocation; Regional Blood Flow; Ritanserin; Serotonin; Serotonin Antagonists

We have studied the acute effects of the serotonergic type-2 (5-HT2) antagonists ketanserin and ritanserin given as single oral doses to patients with essential hypertension. Ketanserin has alpha 1-antagonist properties, whereas ritanserin is largely devoid of alpha 1-receptor binding affinity. Ketanserin (40 mg orally) caused a significant reduction (p less than 0.03) of sitting mean arterial pressure over the 8-h period following drug administration by an average of 15.4 +/- 3.2 mm Hg (mean +/- SEM) as compared to a reduction of 8.5 +/- 2.2 following placebo. In contrast, ritanserin had no significant effect on blood pressure compared to placebo; sitting mean arterial pressure was reduced by 9.0 +/- 2.6 and 10.8 +/- 1.8 mm Hg after administration of 10 and 20 mg, respectively, of ritanserin. There were no significant differences in pulse rate among placebo, ketanserin, or ritanserin phases. Ritanserin caused a reduction in the hostility score (p less than 0.05) as measured by the Multiple Affect Adjective Check List; ketanserin had no significant effects. The highly selective 5-HT2 antagonist ritanserin, given in a dose which caused measurable alteration of psychological function tests, had no acute effects on blood pressure. The acute antihypertensive effects of ketanserin are not caused by 5-HT2 antagonism alone, but are likely to be dependent on its alpha 1-antagonistic properties.

Topics: Adult; Affect; Aged; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Receptors, Serotonin; Ritanserin

The selective 5-HT2-receptor-blocking agent ritanserin is an analogue of the antihypertensive agent ketanserin. By evaluating the antihypertensive effects of ritanserin the aim of this investigation was to indirectly elucidate the mechanism of action of ketanserin. Thirteen patients with essential hypertension were treated with placebo and ritanserin, 10 mg b.i.d., in a double-blind, cross-over design (4-week periods). At the end of the treatment periods blood pressure as well as plasma concentrations of ritanserin were evaluated for 24 hours. Despite high steady state and peak plasma concentrations of ritanserin the compound did not lower the blood pressure compared with placebo. Since chronic selective 5-HT2-receptor blockade by means of ritanserin did not lower the blood pressure, it is concluded that the 5-HT2 blocking properties of ketanserin cannot alone be responsible for the antihypertensive effects of ketanserin.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Female; Histamine H2 Antagonists; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Ritanserin; Time Factors

Topics: Adrenergic beta-Antagonists; Clinical Trials as Topic; Diuretics; Dose-Response Relationship, Drug; Humans; Hypertension; Ketanserin; Piperidines; Placebos

The haemodynamic effects of ketanserin, a compound with S2-serotonergic receptor and alpha 1-adrenoceptor blocking properties, are reviewed in patients with essential hypertension. The drug has a definite antihypertensive action, both acutely and chronically, and its haemodynamic profile is similar to that of a vasodilator acting on both arterioles and veins but with its main action on arterioles. Its vasodilator action is associated with little reflex cardiostimulation. Pressor responses to i.v. phenylephrine are not altered by therapeutic i.v. doses of ketanserin but pressor responses to methoxamine, a compound that is more specific for vascular alpha 1-receptors than phenylephrine, have been reported to be reduced after chronic oral treatment with ketanserin. However, chronic ketanserin, unlike the alpha 1-adrenoceptor antagonist, prazosin in therapeutic doses, caused no parallel shift of the dose-pressor response curve of methoxamine and the shift was very small compared with prazosin. Studies in patients with autonomic failure and virtually no endogenous alpha 1-adrenergic tone have substantiated that ketanserin is capable of lowering blood pressure independently of alpha 1-adrenoceptor blockade.

Topics: Adrenergic beta-Antagonists; Clinical Trials as Topic; Double-Blind Method; Heart Rate; Humans; Hypertension; Ketanserin; Piperidines; Placebos; Pressoreceptors; Random Allocation; Receptors, Serotonin; Reflex

The purpose of this study was to compare the effects of the serotonin antagonist ketanserin and the post-synaptic alpha-blocker prazosin on blood pressure in patients with essential hypertension. Both drugs lower blood pressure by a reduction in total peripheral vascular resistance and by reducing the pre- and afterload, apparently achieving these haemodynamic effects through different mechanisms. Ketanserin appears to have a greater effect on afterload. Six men and four women (mean age 47.2 years) with diastolic blood pressure greater than or equal to 100 mmHg were treated for 4 weeks with placebo and then randomized and treated for 8 weeks double-blind with either ketanserin or prazosin. A 4-week wash-out phase with placebo was then instituted followed by another 8 weeks of treatment in a crossover fashion with either ketanserin or prazosin. Blood pressure was measured on each occasion in the supine, sitting and standing positions. The results showed that both medications significantly lowered blood pressure (computed sitting values for all patients: ketanserin from 177/104 +/- 5/7 to 158/89 +/- 8/5 mmHg; prazosin from 176/103 +/- 11/8 to 156/88 +/- 6/4 mmHg). The data in this study show that ketanserin as an antihypertensive agent is as effective as prazosin, but in contrast requires no titration of dosage and better compliance can be expected with twice daily rather than three times daily dosing.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Prazosin; Serotonin Antagonists

Ketanserin, an antagonist highly selective for 5-hydroxytryptamine (serotonin) type 2 (S2) receptors, was given as monotherapy in a dose of 40 mg b.i.d. to 24 subjects with mild to moderate essential hypertension. Its effects were evaluated in a placebo-controlled double-blind crossover study. The effect on blood pressure in 18 subjects was monitored by 24-hour ambulatory intra-arterial measurements. Systolic and diastolic intra-arterial pressures were significantly lowered by ketanserin both during the day and at night, whereas heart rate was unchanged. Cuff pressure readings (triplicate measurements) with the London School of Hygiene sphygmomanometer and an automatic device (12 measurements in 1 hour) in the outpatient clinic also showed a significant effect on both supine and standing pressures. No postural hypotension was noted. Ketanserin had no effect on endogenous creatinine clearance, serum cholesterol levels, and the plasma levels of norepinephrine, renin, and aldosterone. The only side effect that was significantly more common with ketanserin than with placebo treatment was an increase in body weight. Ketanserin may have a place in the treatment of mild to moderate essential hypertension.

Topics: Adult; Aged; Blood Pressure; Circadian Rhythm; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Posture; Random Allocation

Ketanserin is a new potent antiserotonergic drug which, unlike previous ones, is selective for S2-serotoninergic receptors and does not have an agonist action. A trial was carried out on medium-term treatment with ketanserin or propranolol in subjects suffering from mild to moderate hypertension. The trial was designed as a double-blind crossover randomized study comparing either ketanserin or propranolol with placebo. Thirteen patients completed the study, which was divided into two groups (A and B). Systolic (SBP), diastolic (DBP) and mean (MBP) blood pressures were measured by non-invasive, intermittent ambulatory monitoring performed using a Pressurometer II, from Del Mar Avionics. Heart rate was measured using a continuous electrocardiogram monitoring. Systolic blood pressure was significantly reduced both after ketanserin (A:11.1%; B:10.8%) and propranolol (A:11.7%; B:11.8%) but in group A its decrease was more pronounced after propranolol (P less than 0.01). Diastolic blood pressure was significantly reduced both after ketanserin (A:11.5%; B:11.1%) and propranolol (A:11.4%; B:11.9%), as was MBP (A:11.9%; B:11.8% for ketanserin and A:11.9%; B:11.9% for propranolol). The heart rate diminished significantly only after propranolol administration (P less than 0.01). Ambulatory monitoring showed a significant 24-h reduction of SBP after administration of propranolol (P less than 0.0025) and ketanserin (A:P less than 0.0025, B: P less than 0.005). Diastolic blood pressure was also significantly reduced after ketanserin (P less than 0.0005) and propranolol (A: P less than 0.0025, B: P less than 0.0005). The heart rate obtained by continuous electrocardiogram monitoring diminished significantly only after propranolol administration (P less than 0.0005). No significant changes of circadian behaviour of blood pressure were observed.

Topics: Adult; Ambulatory Care; Blood Pressure Determination; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Placebos; Propranolol

The antihypertensive effects of ketanserin (40 mg twice daily) and pindolol (5 mg twice daily) as monotherapy were compared in a crossover, double-blind trial in 17 patients with essential hypertension. Both ketanserin and pindolol decreased supine systolic and diastolic blood pressure significantly (P less than 0.01 for systolic and P less than 0.001 for diastolic) when evaluated at the end of the 2-month treatment periods. There was no significant difference between the two drugs. No significant changes in heart rate were observed on either drug. Both drugs were well tolerated.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Pindolol; Piperidines; Random Allocation

The efficacy and tolerability of ketanserin was compared with metoprolol in a double-blind parallel group study. After a 4-week placebo run-in on no treatment patients with a diastolic blood pressure (BP) of 95 mmHg or more received ketanserin 40 mg (n = 16) or metoprolol 100 mg (n = 17) twice daily. Blood pressure was measured in duplicate using a Hawksley random zero sphygmomanometer. Both blood pressure and heart rate were recorded after 5 min supine and 1 min standing. Patients visited after 2, 4, 8 and 12 weeks of treatment. Systolic, diastolic and mean arterial BPs, both supine and standing, were significantly reduced from week 2 by both treatments (P less than 0.05, Student's t-test). The mean (+/- s.e.m.) changes in supine BP at 3 months compared with baseline were -15.7 (3.6) mmHg systolic and -13.9 (2.7) mmHg diastolic in the ketanserin group and -26.6 (7.9) mmHg systolic and -15.2 (2.7) mmHg diastolic in the metoprolol group. There was a tendency for the fall in systolic BP to be greater in the metoprolol group, but this did not reach statistical significance except for the standing systolic BP at 1 month. Metoprolol caused a significant fall in heart rate compared with baseline values throughout the study, and the metoprolol group was significantly different from the ketanserin group at 2 months for the supine heart rate and at all time points for standing heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Metoprolol; Middle Aged; Piperidines; Placebos

The long-term safety and efficacy of ketanserin in the treatment of essential hypertension was assessed in monotherapy or in combination with the beta-blocker, metoprolol. In an initial double-blind phase, 40 patients were randomized and treated for 12 weeks with either ketanserin or metoprolol. When compared with baseline placebo values, both drugs were significantly effective in reducing blood pressure levels. The antihypertensive action of ketanserin was more gradual than that of metoprolol. The incidence of side-effects was lower with ketanserin: six cases of mild bradycardia were noted with the beta-blocker. Following this phase, all patients received ketanserin therapy during a 12-month period in an open study. Those patients not controlled by monotherapy [i.e. diastolic blood pressure (DBP) greater than 90 mmHg] were treated by a combination of both drugs. Twenty-two patients receiving ketanserin monotherapy were successfully controlled for all of the period of observation [mean supine systolic blood pressure (SBP)/DBP = 142/88]. Side-effects were minimal, with no significant changes observed in biochemical or haematological measurements during the year-long open phase. The results of this study document the efficacy and safety of long-term treatment of essential hypertension with ketanserin.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Ketanserin; Male; Metoprolol; Middle Aged; Piperidines; Random Allocation

This study was designed to compare the antihypertensive effectiveness of ketanserin (K) and metoprolol (M) in a 3-month double-blind treatment, and to assess the long-term efficacy of K in a 1-year open trial. Twenty-four patients with mild to moderate hypertension were randomly placed in two groups: group 1 (n = 11) received K, 40 mg/day, and group 2 (n = 13) received M, 200 mg/day. In the double-blind phase of treatment both K and M significantly lowered blood pressure (BP) (P less than 0.01). The heart rate was significantly decreased by M (P less than 0.01). In the 1-year follow-up, patients were divided into three groups: group I (n = 7) had been previously treated with K and maintained on K; group II (n = 4) was given K plus M (these patients had previously been treated with K, but K had failed to decrease diastolic BP to less than or equal to 90 mmHg); and group III (n = 13) was given K (previously these patients had been treated with M). In group I, the BP lowering effect remained constant throughout the 1-year follow-up. In group III, supine and standing diastolic BP decreased significantly after treatment with K (P less than 0.05). Side effects from K were minimal. Ketanserin appears to be a new alternative approach in the treatment of mild and moderate essential hypertension.

Topics: Adult; Aged; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Ketanserin; Male; Metoprolol; Middle Aged; Piperidines; Placebos

Ketanserin (K), a selective and specific S2-receptor antagonist, has been compared with metoprolol (M), a cardioselective beta-blocker, in a double-blind study in order to assess its efficacy and safety in the treatment of essential hypertension. After a placebo run-in period of 4 weeks, hypertensive patients [supine diastolic blood pressure (DBP) greater than or equal to 100 mmHg] were treated with K, 40 mg twice daily (n = 18), or with M, 100 mg twice daily (n = 14). Systolic pressure (SBP) and DBP, both supine and standing, were significantly reduced from the first month of treatment by both drugs and remained stable for the whole study period (12 weeks). About two-thirds of the patients treated with K responded to the therapy (drop in DBP of at least 10%) and half were normalized (DBP less than or equal to 90 mmHg). In the M group, 50% of patients responded and 30% were normalized. A significant decrease in the heart rate was observed with M, but not with K. Ten patients treated with K were followed for 1 year. The antihypertensive effect of K was maintained throughout the study with evidence of tolerance. No serious adverse reaction was observed.

Topics: Double-Blind Method; Heart Rate; Humans; Hypertension; Ketanserin; Metoprolol; Piperidines

Thirty elderly patients (mean age 77.5 years) with mild hypertension were considered for a double-blind trial comparing the effects of ketanserin and propranolol. After 28 days of placebo, a group of 15 patients was given ketanserin at the daily dose of 20 mg twice daily for 15 days and of 40 mg twice daily for the subsequent 75 days, while the other group of 15 patients was given propranolol for 90 days at the dose of 80 mg twice daily. Blood pressure and pulse rate in the supine and standing positions were evaluated every 15 days. After the beginning of treatment with ketanserin there was a gradual but highly significant decrease of the systolic and diastolic blood pressure values. No relevant side-effects or significant biochemical alterations were observed during treatment with ketanserin.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Ketanserin; Male; Piperidines

Pharmacokinetic and antihypertensive effects of the S2-serotonergic antagonist ketanserin were determined in 10 patients with essential hypertension (WHO stages I-II) after a single intravenous (0.15 mg/kg) and a single oral (40 mg) dose as well as during steady-state conditions on 40 mg once-daily dose regimen. The maximal plasma concentration (Cmax) of 99 +/- 14 and 97 +/- 14 ng/ml occurred approximately 1 h after single oral and chronic oral intake, respectively. The minimum steady-state concentration (Cssmin) was 13 +/- 2 ng/ml on a 40 mg once-daily regimen. Terminal half-lives (T1/2 beta) were 6.5 +/- 0.4 and 9.0 +/- 0.9 h after intravenous and single oral administration. During steady-state therapy the elimination half-life (24.7 +/- 2.6 h) was significantly increased compared to single dose administration. Bioavailability ranged between 15 and 60%, indicating a substantial first-pass effect. After intravenous ketanserin, mean supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) were maximally reduced after 30 min. A single oral 40 mg dose reduced mean supine SBP/DBP by 31 +/- 8/16 +/- 5 (P less than 0.01/P less than 0.05) at maximal plasma ketanserin concentrations. The SBP and DBP were reduced over 24 h during steady-state conditions on 40 mg once-daily treatment and the mean supine blood pressure reduction 24 h after dose intake was 23 +/- 7/16 +/- 4 mmHg compared to placebo control (P less than 0.05/P less than 0.01). The data from this study indicate that ketanserin monotherapy may lower blood pressure over 24 h in a once-daily regimen.

Topics: Aged; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines

A randomized crossover trial was conducted in 15 patients with essential hypertension to compare the actions of prazosin, a specific alpha 1-adrenoceptor blocker, and ketanserin, an antagonist at alpha 1-adrenergic and serotonin receptors. After placebo dosing for 2 weeks, active drug was given double-blind in two 4-week phases. Satisfactory control of supine blood pressure was obtained in nine of the 12 subjects who completed the prazosin phase and 11 of the 15 subjects who completed the ketanserin phase. Whether comparison was based on supine, erect, postexercise, or ambulatory values, the blood pressure responses to prazosin (2 or 4 mg/day) and ketanserin (40 or 80 mg/day) were closely similar. Neither of the drugs significantly altered supine or erect pulse rates, body weight, serum triglyceride concentrations, plasma renin activity, or urinary aldosterone excretion, and their side effect profiles were similar. The serum cholesterol concentration was lowered by prazosin but was not affected by ketanserin. However, no other features were observed that distinguished the clinical effects of ketanserin from those of prazosin.

Topics: Adult; Aldosterone; Blood Pressure; Cholesterol; Drug Evaluation; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Physical Exertion; Piperidines; Prazosin; Random Allocation; Renin

The effect of intravenous ketanserin on the pressor response to sternotomy was studied in 36 patients undergoing coronary artery surgery. Two doses of the drug (10 mg and 20 mg) were compared with a placebo injection of saline. After induction of anaesthesia, haemodynamic variables were measured until the institution of cardiopulmonary bypass. Plasma and platelet 5-hydroxyindoles and 5-hydroxytryptamine were measured in a subset of 13 patients. Ketanserin induced a dose-dependent amelioration of the pressor response to sternotomy. Plasma 5-hydroxyindoles and platelet 5-hydroxytryptamine levels did not correlate with clinical response. The increased effectiveness of the higher dose of ketanserin may be due to an effect other than serotonin antagonism.

Topics: Drug Evaluation; Hemodynamics; Humans; Hypertension; Indoles; Intraoperative Complications; Ketanserin; Middle Aged; Myocardial Revascularization; Piperidines; Premedication; Serotonin; Serotonin Antagonists; Sternum

Ketanserin is a new strong antiserotoninergic drug that, unlike the previous ones, is selective for 5-hydroxytryptamine receptors. This drug has been employed successfully in the treatment of arterial hypertension and of some peripheral vascular diseases. The authors are carrying out a trial on medium term treatment with ketanserin (K) or propranolol (P) in comparison with placebo, to evaluate their effects on blood pressure, haemocoagulative parameters and peripheral circulation. The trial is a double-blind cross-over random trial on subjects with mild or moderate hypertension. Until now 13 patients have ended the study; six of them are suffering from arteriosclerosis obliterans of the lower limbs at 1st or 2nd stage according to Fontaine. Both propranolol and ketanserin significantly reduced the blood pressure, although the decrease in systolic blood pressure was more evident after propranolol. Heart rate diminished significantly only after propranolol administration. The noninvasive, intermittent (every 30 min) monitoring of blood pressure showed a significant 24-hour reduction of blood pressure after administration of propranolol or ketanserin without significant changes of circadian behaviour of the blood pressure. After administration of ketanserin a slight improvement in peripheral circulation was demonstrated, evaluated by using strain-gauge plethysmography. As regards the results obtained for platelet function and other haemocoagulative parameters examined, adenosine diphosphate-induced platelet aggregation, adenosine diphosphate slope, collagen lag period, antithrombin III biological activity, and serum fibrinogen did not show noticeable modifications after treatment, while beta-thromboglobulin levels decreased slightly after ketanserin administration.

Topics: Adult; Antihypertensive Agents; Arteriosclerosis Obliterans; Blood Coagulation; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Leg; Male; Middle Aged; Piperidines; Propranolol; Random Allocation; Regional Blood Flow

Ketanserin (120 mg/day) or placebo was given orally to 14 patients with mild to moderate essential hypertension according to a double-blind crossover protocol, each treatment period lasting 6 weeks. Resting intraarterial pressure in the recumbent position was reduced from 150/84 to 141/77 mm Hg; the hypotensive effect persisted throughout an uninterrupted graded exercise test to the point of exhaustion. The hemodynamic effects were similar at rest and during exercise. Overall, systemic vascular resistance decreased by 14%, heart rate fell by 5%, but stroke volume and cardiac output increased. The pressor responses to methoxamine and to phenylephrine were reduced by ketanserin.

Topics: Adult; Cardiac Output; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Ketanserin; Male; Methoxamine; Phenylephrine; Physical Exertion; Piperidines; Random Allocation; Serotonin Antagonists; Stroke Volume; Vascular Resistance

This double-blind study, which is still in progress, aims to compare ketanserin (K) and propranolol (P) during long-term treatment of hypertensive patients in general practice. After a run-in period on placebo, active treatment was initiated with 20 mg K or 40 mg P, b.i.d., during a 2-week period, whereafter the daily dose of either drug was doubled. Presently, 331 patients have been randomized, two-thirds to the K group (n = 221) and one-third to the P group (n = 110). Both groups were similar at randomization, with blood pressure (BP) averaging 171/105 mm Hg. The presently available data concerning the initial 3 months of the trial show that up to the 2nd month after randomization, systolic BP was significantly (p less than 0.05) higher in the K than in the P group, whereas the differences in diastolic BP were mostly not significant. The change in BP after 3 months on K treatment was positively and independently related to both the initial BP and the concurrent changes in body weight. Heart rate was lower (p less than 0.001) during P, whereas body weight was not statistically different between both groups. Differences in complaints between the K and P group were small. However, in the K group dry mouth was transiently more frequently reported at 1 month (p = 0.02) and multiple complaints at 3 months (p = 0.03).

Topics: Adult; Aged; Antihypertensive Agents; Body Weight; Clinical Trials as Topic; Double-Blind Method; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Patient Compliance; Piperidines; Propranolol; Random Allocation

To assess efficacy and side effects during chronic oral therapy, we studied the effect of ketanserin (Kn) in 17 hypertensive patients for a period up to 1 year. Ketanserin controlled blood pressure satisfactorily in 25%, in part in 50% and had little or no effect in 25%. Reduction in diastolic pressure equalled that in systolic pressure at rest and after exercise and during handgrip. Pulse rate was slowed. Dosage in excess of 60 mg of Kn per day caused troublesome central nervous system symptoms or headache in some patients. A nonsteroidal antiinflammatory drug appeared to antagonize the antihypertensive effect of Kn in one patient. Red cell rigidity and platelet aggregation to ADP and collagen were significantly decreased. Serum potassium and uric acid were significantly decreased; serum creatinine increased during Kn treatment. The antihypertensive and pulse slowing effects of Kn were confirmed during the year's study, in a randomized placebo-controlled crossover study.

Topics: Aged; Blood Pressure; Clinical Trials as Topic; Diuretics; Erythrocyte Deformability; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Physical Exertion; Piperidines; Pulse; Random Allocation; Serotonin Antagonists; Time Factors

In 10 patients with primary arterial hypertension of mild or moderate degree, ketanserin, a competitive antagonist of serotonin receptors, was given for a period of 4 weeks, 40 mg twice daily. In a control group, patients were given 100 mg twice daily of metoprolol for 4 weeks for each treatment. A randomized double-blind crossover model was used. Blood pressure and heart rate were measured at rest and during exercise testing on a bicycle; peripheral blood flow was measured by strain-gauge plethysmography. A slight reduction in resting systolic and diastolic blood pressure without change in heart rate was observed during treatment with ketanserin. Cardiac workload during exercise test did not change over the observation period. A slight increase in resting blood flow to the lower limbs, with a decrease in peripheral resistance was demonstrated by strain-gauge plethysmography.

Topics: Adult; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Heart Rate; Humans; Hypertension; Ketanserin; Leg; Metoprolol; Physical Exertion; Piperidines; Random Allocation; Regional Blood Flow; Serotonin Antagonists

The antihypertensive effect of ketanserin in combination with beta-adrenergic blockade was assessed in a double-blind crossover (4 weeks) manner in 10 patients with essential hypertension. The addition of ketanserin (40 mg b.i.d.) to optimal doses of beta-adrenergic blockers had significant antihypertensive effects compared with treatment with beta-adrenergic blockers alone. When followed for 24 h at steady-state conditions, ketanserin effectively reduced the blood pressure during a major part of the day, with maximal effect occurring at the time of the peak plasma concentration of ketanserin (1-2 h after tablet intake). Six patients initially reported a slight sedation during ketanserin treatment.

Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Serotonin Antagonists; Time Factors

Seventeen subjects with essential hypertension (14 men, 3 women, 40-69 years of age), 13 of whom continued their previous antihypertensive therapy, completed a double-blind crossover trial of ketanserin 40 mg twice daily versus placebo tablets twice daily. Each treatment phase was 6 weeks in duration. For the group as a whole, blood pressure (BP) was reduced in the ketanserin phase compared with the placebo phase: supine mean BP decrease: 4 +/- 1 mm Hg (p less than 0.05); standing mean BP decrease: 7 +/- 1 mm Hg (p less than 0.001). Heart rate (HR) was also significantly decreased in the ketanserin phase (5 +/- 1 beats/min) (p less than 0.001). When individual subgroups were analysed, the reductions in BP and HR were greater in subjects already receiving antihypertensive therapy, diuretics, and/or beta-adrenergic blockers. Changes were observed in 24-h urine sodium and potassium excretion: Sodium (mmol/day): placebo 137 +/- 17, ketanserin 174 +/- 19 (p less than 0.05); potassium (mmol/day): placebo 74 +/- 8, ketanserin 57 +/- 5. For the group as a whole, there were no significant adverse effects during the ketanserin phase, although two subjects had a dose reduction of ketanserin because of drowsiness and dizziness. Two additional subjects withdrew from the study owing to adverse effects, one in the placebo phase. In conclusion, ketanserin in the dose administered has a modest hypotensive effect, which is best seen in subjects already receiving other antihypertensive agents.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Antihypertensive Agents; Blood Pressure; Body Weight; Clinical Trials as Topic; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Random Allocation

Serotonin is known to have aldosterone-stimulating properties in humans, which are counteracted by the serotonin-antagonist metergoline. Suppression of aldosterone levels by cyproheptadine in patients with idiopathic aldosteronism has also been shown. Since ketanserin, a more specific 5-HT2-serotoninergic (5-HT2) antagonist, has been shown to affect aldosterone secretion in essential hypertension, we have further investigated this mechanism by injecting ketanserin (10 mg i.v.) in 10 patients with primary aldosteronism (four adenoma, six idiopathic aldosteronism). A transient decrease (20% when compared with the basal levels) of plasma aldosterone was seen at 30 min. A concomitant decrease of plasma cortisol was also noticed, whereas plasma renin activity and potassium did not change. Blood pressure decreased in all cases. These observations suggest that ketanserin acts directly at the adrenal level by interfering with a possible modulatory activity of serotonin. However, an adrenocorticotropic hormone-mediated effect cannot be completely ruled out at the present time.

Topics: Aldosterone; Blood Pressure; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Ketanserin; Piperidines; Potassium; Renin; Serotonin Antagonists; Time Factors

The sodium content of erythrocytes from patients with essential hypertension is increased. In a double-blind, placebo-controlled study, a 5-day treatment with ketanserin, a serotonergic antagonist lowered significantly the sodium content of the red blood cells (RBC). Ouabain induces an increase of sodium content of the RBC, which is paralleled by a decrease in RBC deformability. The ouabain-dependent fraction of RBC deformability is significantly reduced after a single oral dose of ketanserin. In vitro, serotonin (5-HT) decreases RBC deformability; this effect could be antagonized by ketanserin. These data might suggest a regulating role of 5-HT in transmembrane ion fluxes.

Topics: Adult; Aged; Erythrocyte Deformability; Erythrocytes; Humans; Hypertension; Ketanserin; Middle Aged; Myocardial Infarction; Ouabain; Piperidines; Serotonin; Serotonin Antagonists; Sodium

The role of serotonin in the pathogenesis of hypertension is interesting, and its investigation is much in vogue at present. This study compared the hypotensive effect of ketanserin, a specific 5-hydroxytryptamine receptor antagonist, with metoprolol in essential hypertension. On a double-blind basis, one treatment group (19 patients on ketanserin) was compared with another (21 patients on metoprolol). There was a significant reduction in diastolic blood pressure with both ketanserin and metoprolol (P less than 0,001). Side-effects were insignificant. One patient on metoprolol and 2 on ketanserin complained of dizziness. The dose of ketanserin was 40 mg twice a day and that of metoprolol 100 mg twice a day. Ketanserin does not appear to cause abnormal haematological values or biochemical adverse effects. It can be given to hypertensive patients with cardiac failure or bronchial asthma without adverse effects and may improve the peripheral vascular status of a hypertensive patient.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Ketanserin; Male; Metoprolol; Middle Aged; Piperidines; Random Allocation; Time Factors

Topics: Alcoholism; Blood Pressure; Chronic Disease; Female; Humans; Hypertension; Ketanserin; Male; Piperidines

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Vascular Resistance

Ketanserin, an investigational, antiserotonergic agent, at a dose of 40 mg bid was given to 18 patients with mild to moderate primary hypertension in a randomized, double-blind, crossover study, with 100-mg metoprolol bid for four weeks each. The following parameters were evaluated: blood pressure, heart rate, cardiac workload (product of systolic blood pressure and heart rate during bicycle exercise), systolic time intervals, and peripheral blood flow (by strain-gauge plethysmography). Significant reductions in diastolic and concomitant slight decreases in systolic blood pressure without changes in heart rate were observed during ketanserin treatment; cardiac oxygen demands during exercise test did not change, however. Pre-ejection period and left ventricular ejection time were unchanged, while significant increase in rest flow to the lower limbs and decrease in peripheral resistance were demonstrated by strain-gauge plethysmography. The results indicate that ketanserin has vasodilating properties and hypotensive activity that may be useful in the management of patients with essential hypertension.

Topics: Adult; Blood Pressure; Body Weight; Exercise Test; Heart Rate; Hemodynamics; Humans; Hypertension; Ketanserin; Metoprolol; Middle Aged; Piperidines; Regional Blood Flow; Serotonin Antagonists; Vascular Resistance

The antihypertensive effect of the selective serotonin antagonist ketanserin was examined in a double-blind, placebo-controlled, parallel group study in 20 patients with essential hypertension. After 7 weeks treatment with ketanserin (mean dose 71 mg/d) there was a significant fall of both systolic and diastolic blood pressure, as compared to placebo, with a peak effect of 19.1/9.1 mmHg lying (P less than 0.01/P less than 0.01), and 16.5/11.3 mmHg standing (P less than 0.01/P less than 0.01); twice daily dosage appeared satisfactory. Subjective side effects were similar in the ketanserin and placebo groups. Ketanserin is an effective antihypertensive drug of moderate potency when given twice daily, with no orthostatic effect.

Topics: Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines

We have completed a double-blind parallel group comparison of the 5-HT2 receptor antagonist ketanserin with placebo in 22 hypertensive patients. Ketanserin (20-40 mg twice daily) lowered sitting blood pressure more than placebo by 6.9 mm Hg systolic (NS), 13.1 mm Hg diastolic (P less than 0.05) and by 11.4 mm Hg mean arterial pressure (P less than 0.02). The fall in standing blood pressure was similar and we observed no first dose hypotensive effect. Ketanserin lowered the sitting heart rate by 11.1 beats/min (P less than 0.01). The drug was well tolerated.

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Receptors, Serotonin

17 subjects with essential hypertension (14 male, 3 female - ages: 40-69 years), 13 of whom continued their previous anti-hypertensive therapy, completed a double-blind cross-over trial of ketanserin 40 mg twice daily versus placebo tablets twice daily - each treatment phase was six weeks in duration. For the group as a whole, blood pressure (BP) was reduced in the ketanserin phase compared with the placebo phase; supine mean BP decrease: 4 +/- 1 mm Hg (p less than 0.05); standing mean BP decrease: 7 +/- 1 mm Hg (p less than 0.001). Heart rate (HR) was also significantly decreased in the ketanserin phase by 5 +/- 1 beats/minute (p less than 0.001). When individual subgroups were analysed the reductions in BP and HR were greater in subjects already receiving anti-hypertensives, diuretic and/or beta blockers. Changes were observed in 24 hour urine sodium and potassium excretion - sodium (mmol/day): placebo 137 +/- 17, ketanserin 174 +/- 19 (p less than 0.05); potassium (mmol/day): placebo 74 +/- 8, ketanserin 57 +/- 5. For the group as a whole there were no significant adverse effects during the ketanserin phase, although two subjects had a dose reduction of ketanserin because of drowsiness and dizziness. Two additional subjects withdrew from the study due to adverse effects, one in the placebo phase. In conclusion ketanserin in the dose administered has a modest hypotensive effect which is best seen in subjects already receiving other anti-hypertensive agents.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Diuretics; Double-Blind Method; Drug Therapy, Combination; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Random Allocation; Serotonin Antagonists

The antihypertensive properties of ketanserin, a 5-HT2 receptor antagonist, was investigated in combination with beta-adrenoceptor blockade. Ketanserin was given 40 mg twice daily to 10 hypertensive patients during 4 weeks in a double-blind placebo-controlled trial. Ketanserin significantly reduced supine and erect blood pressure compared to double-blind placebo, while no changes in heart rate were seen. When the blood pressure was assessed during 24 h at steady state conditions, the blood pressure reduction was maximal 1-2 h after tablet intake, corresponding to peak plasma concentrations of ketanserin. The blood pressure remained significantly reduced until next tablet intake (12 h). At steady state, on a 40 mg twice daily regimen, Css was 41.6 +/- 4.22, 36.9 +/- 5.19 and 39.8 +/- 4.81 ng/ml, Cmax 102.4 +/- 15.64 ng/ml and tmax 1.6 +/- 0.32 h. A slight sedation was observed in six patients. This side effect occurred 1-2 h after tablet intake and tended to subside with continued treatment.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines

Ketanserin (120 mg/day) or placebo was given orally to 14 patients with mild to moderate essential hypertension according to a double blind crossover protocol, each treatment period lasting six weeks. Resting intra-arterial pressure in the recumbent position was reduced from 150/84 to 141/77 mm Hg; the hypotensive effect persisted throughout an uninterrupted graded exercise test to the point of exhaustion. The haemodynamic effects were similar at rest and during exercise. Overall, systemic vascular resistance decreased by 14%, heart rate fell by 5%, but stroke volume and cardiac output increased. Mean pulmonary arterial pressure and capillary wedge pressure were not significantly affected, but pulmonary vascular resistance decreased by 15%. The pressor response to methoxamine was significantly reduced by ketanserin. Both plasma noradrenaline and adrenaline concentrations increased, plasma renin activity and angiotensin II concentration decreased, and plasma aldosterone concentration was unchanged. The data indicate that ketanserin induces arteriolar dilatation, possibly related to an alpha-1-antagonistic action and to a reduced circulating angiotensin II concentration. The haemodynamic response is complex, and an increase in cardiac output limits the hypotensive effect. There is no firm evidence of an effect on venous tone as cardiac filling pressures do not change.

Topics: Adult; Antihypertensive Agents; Clinical Trials as Topic; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Ketanserin; Male; Methoxamine; Physical Exertion; Piperidines; Pressoreceptors; Renin-Angiotensin System

Topics: Administration, Oral; Clinical Trials as Topic; Female; Humans; Hypertension; Infusions, Parenteral; Ketanserin; Male; Piperidines; Serotonin Antagonists

Ketanserin ia a quinazoline derivative which acts selectively on serotonin (S2) receptors. The compound has been shown to possess antihypertensive properties. BP and HR were measured blindly on 14 patients with essential hypertension during one year. Ketanserin 40 mg, once or twice daily, reduced BP (and HR to a slight extent) largely unchanged from 14 days after initiation of therapy. Response rate varied from 57-77% at the regular control visits. During the one year follow up period the reduction in supine SBP was 9 +/- 3% (p less than 0.001) and DBP was 12 +/- 1% (p less than 0.001). The only side effect was a slight sedation that passed with time. It is concluded that ketanserin is effective in the chronic treatment of hypertension and may offer a new alternative to existing pharmacotherapy.

Topics: Adult; Aged; Chronic Disease; Clinical Trials as Topic; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Placebos; Serotonin Antagonists

We investigated the effect of peripheral serotonin receptor blockade on preeclamptic hypertension in 20 postpartum patients by the use of ketanserin, a serotonin receptor antagonist. In a study consisting of a double-blind crossover with placebo, parenteral ketanserin significantly reduced blood pressure from 167/105 to 126/71 mm Hg compared to a decline from 157/98 to 150/91 mm Hg for the placebo (p less than 0.001). All patients became hypertensive again following infusion, although no abrupt rebound in pressure occurred. Side effects were minimal. The results demonstrate that preeclamptic hypertension can be controlled by ketanserin and suggest that serotonin may have a role in the modulation of preeclampsia.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Infusions, Parenteral; Ketanserin; Piperidines; Pre-Eclampsia; Pregnancy; Random Allocation; Serotonin Antagonists

Ketanserin, a 5-HT type 2 receptor antagonist, was administered intravenously to nine patients with essential hypertension in a double-blind placebo controlled study to investigate the drug's effects on blood pressure, heart rate, the renin-angiotensin system and sympatho-adrenal function. Average blood-pressure for the group prior to injection of the drug was 150 +/- 7/94 +/- 4 (s.e. mean) mm Hg and decreased significantly (P less than 0.01) to 137 +/- 8/88 +/- 5 mm Hg during the 2 h after injection; heart rate increased immediately after injection of ketanserin, reaching a maximum of 81 +/- 4 beats/min. After drug administration systolic and diastolic blood pressure decreased on tilting, but the heart rate response was not different from that with placebo. Ketanserin did not affect the blood pressure response to graded infusion of the alpha 1-adrenoceptor agonist phenylephrine. Plasma active renin, angiotensin II and aldosterone concentrations increased slightly but not significantly after the drug; plasma noradrenaline increased transiently. 5-HT may be important in the maintenance of blood pressure but alternative mechanisms for the action of ketanserin in reducing blood pressure require investigation.

Topics: Adrenal Glands; Adult; Aged; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Norepinephrine; Phenylephrine; Piperidines; Posture; Renin-Angiotensin System; Serotonin Antagonists; Sympathetic Nervous System

Topics: Adrenergic alpha-Antagonists; Humans; Hypertension; Ketanserin; Piperidines; Serotonin Antagonists

Ketanserin, a new 5-hydroxy-tryptamine antagonist, was given at three different dosage levels (double-blind, randomized) in a dose finding study for 2 months to 31 patients with mild to moderately severe essential hypertension. Treatment with ketanserin was then continued until 9 months had been completed. A significant antihypertensive effect was demonstrated at daily dosages of 20 mg t.i.d. or 40 mg t.i.d. The antihypertensive effect was similar to that of previous multiple drug treatment with conventional drugs. However, 60 mg t.i.d. was not acceptable, at least not as initial dosage. At this dose level, 8 out of 10 patients had to be withdrawn from the study during the initial phase due to unwanted effects. It is conceivable that alpha 1-adrenoceptor blockade may have played a role at this dose level, since postural reactions were observed which was otherwise not the case during this study. Ketanserin is a new and interesting alternative in the treatment of hypertension. At the same time it offers a tool by which the role of 5-hydroxy-tryptamine in the regulation of arterial pressure can be investigated.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Random Allocation; Serotonin Antagonists

Ketanserin is a new, specific serotonin receptor blocking agent, which causes vasodilatation, presumably by an action on the vascular wall. The antihypertensive response to ketanserin 40 mg twice daily as monotherapy was assessed in 8 patients with essential hypertension. The investigation was an 8 week, double-blind, cross over study, which also included measurements during isometric (handgrip) and dynamic exercise (bicycle ergometry), as well as determination of plasma catecholamines and ketanserin. Ketanserin caused a reduction of supine and standing systolic and diastolic blood pressure (BP) during rest and a slight bradycardia. Although there was attenuation of the pressor response to handgrip, treatment with ketanserin did not really affect the changes in BP or heart rate during exercise, i.e. the base-line differences remained the same. There was no significant correlation between the effect on BP and the plasma level of ketanserin. The changes in BP produced by ketanserin showed little correlation with the initial levels of plasma catecholamines or with alterations in those levels. Although the results did not indicate direct interference by ketanserin with sympathetic tone, the lack of reflexogenic tachycardia, as well as the lack of increase in plasma noradrenaline during hand grip, indicates at least some modulation of autonomic function. It is concluded that ketanserin lowers BP in essential hypertension without interference with cardiovascular reflexes during standing or exercise, and that the compound may offer an alternative approach in the treatment of hypertension.

Topics: Antihypertensive Agents; Blood Pressure; Catecholamines; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Physical Exertion; Piperidines; Rest

In a first experiment, an acute intravenous administration of 10 mg R 41 468, a pure serotonin-receptor blocking agent with high selectivity for blood vessels and thrombocytes and devoid of central effects, dramatically reduced systolic and diastolic blood pressure in 23 elderly hypertensive patients. Heart rate and cardiac output remained virtually unchanged. In a second double-blind placebo-controlled cross-over study a highly significant decrease of systolic and diastolic blood pressure was obtained in 14 elderly hypertensive patients during an 8-day oral treatment with 40 mg t.i.d. of R 41 468. No serious side-effects were observed. An oral maintenance therapy with R 41 468 for 3 weeks showed a further reduction of blood pressure, resulting in a normalization of blood pressure, taking into account the advanced age of the patients. R 41 468 most probably acts by decreasing the venous capacitance bed constriction. Essential hypertension might be causally related to an impairment of venous function, in which serotonin might be an important pressor factor.

Topics: Age Factors; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Depression, Chemical; Female; Heart Rate; Humans; Hypertension; Injections, Intravenous; Ketanserin; Male; Middle Aged; Myocardial Contraction; Piperidines; Placebos; Receptors, Serotonin; Research Design; Serotonin Antagonists

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines

In a double-blind study under strict, standardized hospital conditions, the antihypertensive effect of etozolin was evalulated in 100 patients with hypertension. 50 patients received the drug, 50 placebo. The study was carried out over 22 days (5 days without medication, 12 days therapy, 5 days follow-up). A significantly better reduction of systolic and diastolic blood pressure in the supine and upright positions was observed with etozolin as compared to the pre-period and the placebo group. There were only minor side-effects; in 4 patients, therapy had to be interrupted because of orthostatic complaints.

Topics: Diuretics; Double-Blind Method; Drug Evaluation; Humans; Hypertension; Piperidines; Placebos; Thiazoles

Minoxidil, a new peripheral vasodilator, given orally to hypertensive men in single doses of 5-25 mg, produced no haemodynamic changes within one hour after administration. After repeated oral doses within 24 hours to a total of 15-45 mg and after 10 mg t.i.d. orally for one week, moderate decreases in BP were seen concomitant with tendencies to increased heart rate and cardiac output. Clinically, oral minoxidil 10-50 mg daily in combination with diuretics and adrenergic beta-receptor blocking agents achieved an improved BP control in five patients with sustained arterial hypertension and unsatisfactory response to previous treatment. However, in four of the five patients minoxidil had to be withdrawn because of side-effects. It is concluded that minoxidil, producing a hypotensive effect of slow onset, may find a place as a therapeutic addition to symptomatic patients with severe and therapy-resistant hypertensive cardiovascular disease, provided adequate measures are taken to counteract side-effects, especially water retention and development of oedemas.

Topics: Adrenergic beta-Antagonists; Adult; Clinical Trials as Topic; Drug Combinations; Humans; Hypertension; Male; Middle Aged; Piperidines; Pyrimidines; Vasodilator Agents

Topics: Adrenergic alpha-Antagonists; Adult; Alcohol Drinking; Analysis of Variance; Blood Pressure; Clinical Trials as Topic; Electrocardiography; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Physical Exertion; Piperidines; Placebos; Smoking; Tachycardia; Time Factors

Topics: Angiotensin II; Antihypertensive Agents; Benzamides; Blood Pressure; Body Weight; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Tolerance; Female; Heart Rate; Humans; Hypertension; Indoles; Isoproterenol; Male; Norepinephrine; Piperidines; Placebos; Regression Analysis; Time Factors

Topics: Aged; Amides; Clinical Trials as Topic; Clopamide; Diuretics; Drug Combinations; Ergotamine; Female; Humans; Hypertension; Male; Middle Aged; Piperidines

Topics: Adult; Aged; Amides; Bicarbonates; Blood Pressure; Chlorides; Clopamide; Creatinine; Depression, Chemical; Diuretics; Dose-Response Relationship, Drug; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Piperidines; Placebos; Potassium; Thiazines

Topics: Adrenergic alpha-Antagonists; Amides; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Indoles; Piperidines; Sympatholytics

Topics: Amides; Antihypertensive Agents; Clinical Trials as Topic; Humans; Hypertension; Indoles; Piperidines

Topics: Antihypertensive Agents; Blood Pressure; Humans; Hypertension; Indoles; Male; Piperidines; Placebos; Posture; Pulse

Topics: Amides; Antihypertensive Agents; Clopamide; Diuretics; Humans; Hypertension; Hypertension, Renal; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Aortic Valve Insufficiency; Biometry; Clinical Trials as Topic; Clopamide; Diuretics; Drug Synergism; Edema; Female; Furosemide; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Male; Middle Aged; Mitral Valve Insufficiency; Obesity; Piperidines; Pulmonary Heart Disease

Topics: Antihypertensive Agents; Clinical Trials as Topic; Clopamide; Diuretics; Ergot Alkaloids; Humans; Hypertension; Piperidines; Reserpine

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.

Topics: Amidohydrolases; Animals; Endocannabinoids; Hypertension; Monoacylglycerol Lipases; Monoglycerides; Piperidines; Rats; Rats, Inbred SHR

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

Topics: Adult; Aged; Atrial Fibrillation; Diarrhea; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Follicular; Musculoskeletal Pain; Piperidines; Pneumonia; Pyrazoles; Pyrimidines; Sepsis

Exposure to tobacco smoke (TS) has been considered a risk factor for osteonecrosis of the femoral head (ONFH). Soluble epoxide hydrolase inhibitors (sEHIs) have been found to reduce inflammation and oxidative stress in a variety of pathologies. This study was designed to assess the effect of sEHI on the development of ONFH phenotypes induced by TS exposure in spontaneously hypertensive (SH) rats. SH and normotensive Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or TS (80 mg/m3 particulate concentration) 6 h/day, 3 days/week for 8 weeks. During this period, sEHI was delivered through drinking water at a concentration of 6 mg/L. Histology, immunohistochemistry, and micro-CT morphometry were performed for phenotypic evaluation. As results, TS exposure induced significant increases in adipocyte area, bone specific surface (BS/BV), and trabecular separation (Tb.SP), as well as significant decreases in bone mineral density (BMD), percent trabecular area (Tb.Ar), HIF-1a expression, bone volume fraction (BV/TV), trabecular numbers (Tb.N), and trabecular thickness (Tb.Th) in both SH and WKY rats. However, the protective effects of sEHI were mainly observed in TS-exposed SH rats, specifically in the density of osteocytes, BMD, Tb.Ar, HIF-1a expression, BV/TV, BS/BV, Tb.N, and Tb.SP. Our study confirms that TS exposure can induce ONFH especially in SH rats, and suggests that sEHI therapy may protect against TS exposure-induced osteonecrotic changes in the femoral head.

Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Epoxide Hydrolases; Femur Head; Femur Head Necrosis; Hypertension; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Nicotiana; Osteocytes; Phenylurea Compounds; Piperidines; Rats, Inbred SHR; Rats, Inbred WKY; Smoke; Vascular Endothelial Growth Factor A

Glomerular endotheliosis is the pathognomonic glomerular lesion in pre-eclampsia that has also been described in those taking tyrosine kinase inhibitors for cancer treatment. Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). We report the first known case of glomerular endotheliosis on kidney biopsy in a patient on ibrutinib monotherapy.. The patient presented with acute on chronic kidney disease, proteinuria, low C3 and C4 and a high rheumatoid factor titer. A kidney biopsy was performed to confirm a preliminary diagnosis of membranoproliferative glomerulonephritis (MPGN), the most common glomerular disease in patients with CLL. Unexpectedly, the kidney biopsy showed pre-eclampsia-like lesions on light and electron microscopy: occlusion of glomerular peripheral capillary lumens by swollen reactive endothelial cells. Findings of glomerulonephritis were not seen, and there were no specific glomerular immune deposits by immunofluorescence or electron microscopy.. CLL is known to cause glomerular lesions, mainly MPGN. There is increasing evidence that ibrutinib, a major treatment for CLL, can cause kidney disease, but the precise pathology is not characterized. We present a patient with CLL on ibrutinib with signs of glomerular endotheliosis. Based on the absence of CLL-induced kidney pathologies typically seen on the kidney biopsy and the non-selectivity of ibrutinib, we attributed the glomerular endotheliosis to ibrutinib. In pre-eclampsia, increased soluble fms-like tyrosine kinase 1 (sFlt1) levels induce endothelial dysfunction by decreasing vascular endothelial growth factor (VEGF). Ibrutinib has been demonstrated to have non-selective tyrosine kinase inhibition, including inhibition of VEGF receptor (VEGFR) and epidermal growth factor receptor (EGFR). VEGFR and EGFR inhibitors have recently been described in the literature to cause hypertension, proteinuria, and glomerular endotheliosis. Kidney biopsy should be performed in CLL patients on ibrutinib that present with acute kidney injury (AKI) or proteinuria to determine whether the clinical picture is attributable to the disease itself or a complication of the therapy.

Topics: Adenine; Aged, 80 and over; Endothelial Cells; ErbB Receptors; Glomerulonephritis, Membranoproliferative; Humans; Hypertension; Kidney; Kidney Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Proteinuria; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Ibrutinib is a tyrosine kinase inhibitor most commonly associated with atrial fibrillation. However, additional cardiotoxicities have been identified, including accelerated hypertension. The incidence and risk factors of new or worsening hypertension following ibrutinib treatment are not as well known.. We conducted a retrospective study of 144 patients diagnosed with B cell malignancies treated with ibrutinib (n=93) versus conventional chemoimmunotherapy (n=51) and evaluated their effects on blood pressure at 1, 2, 3 and 6 months after treatment initiation. Descriptive statistics were used to compare baseline characteristics for each treatment group. Fisher's exact test was used to identify covariates significantly associated with the development of hypertension. Repeated measures analyses were conducted to analyse longitudinal blood pressure changes.. Both treatments had similar prevalence of baseline hypertension at 63.4% and 66.7%, respectively. There were no differences between treatments by age, sex and baseline cardiac comorbidities. Both systolic and diastolic blood pressure significantly increased over time with ibrutinib compared with baseline, whereas conventional chemoimmunotherapy was not associated with significant changes in blood pressure. Baseline hypertensive status did not affect the degree of blood pressure change over time. A significant increase in systolic blood pressure (defined as more than 10 mm Hg) was noted for ibrutinib (36.6%) compared with conventional chemoimmunotherapy (7.9%) at 1 month after treatment initiation. Despite being hypertensive at follow-up, 61.2% of patients who were treated with ibrutinib did not receive adequate blood pressure management (increase or addition of blood pressure medications). Within the ibrutinib group, of patients who developed more than 20 mm Hg increase in systolic blood pressure, only 52.9% had hypertension management changes.. Ibrutinib is associated with the development of hypertension and worsening of blood pressure. Cardiologists and oncologists must be aware of this cardiotoxicity to allow timely management of blood pressure elevations.

Topics: Adenine; Blood Pressure; Humans; Hypertension; Piperidines; Retrospective Studies

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.

Topics: Animals; Antihypertensive Agents; Atrasentan; Blood Pressure; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hemodynamics; Hypertension; Kidney; Nitric Oxide; Oligopeptides; Piperidines; Rats, Inbred SHR; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Elimination

Resistant hypertension (RH) is more prevalent in the advanced stages of chronic kidney disease (CKD) and contributes to a greater likelihood of poor cardiovascular and renal outcomes. However, RH often goes untreated in this population as the currently available recommended add-on therapy, steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone, may lead to unacceptable side effects, mainly hyperkalemia in a cohort with reduced kidney function. KBP-5074 is a novel non-steroidal MRA that addresses the unmet need of treating RH in the CKD population without hyperkalemia.. We provide an overview of the current state of RH treatment in stage 3B/4 CKD as it relates to available steroidal MRAs and the current limitations of this treatment. We then explore the emerging data on nonsteroidal MRAs, particularly the novel agent KBP-5074 and its applicability to treatment in this context.. In a randomized, double-blind, placebo-controlled phase 2b trial, the novel nonsteroidal MRA KBP-5074 demonstrated clinical efficacy and safety in treating RH in stage 3B/4 CKD and offers a potential new treatment option in this population at high risk for cardiovascular disease (CVD) and CKD progression.

Topics: Antihypertensive Agents; Disease Progression; Drug Resistance; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Piperidines; Pyrazoles; Quinolines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Hypertension-induced epithelial-mesenchymal transition (EMT) is a major mechanism of renal fibrosis. Adiponectin protects against hypertension-induced target organ damage. AdipoRon is an orally active synthetic adiponectin receptor agonist. However, it is unclear whether AdipoRon could attenuate EMT and renal fibrosis in hypertensive mice. C57BJ/6J mice were utilized to induce DOCA-salt-sensitive hypertensive model. Hypertension results in an altered adiponectin expression and promotes EMT in the kidney. In vitro, AdipoRon inhibits aldosterone (Aldo)-induced EMT and promotes autophagic flux in HK-2 epithelial cells. Mechanically, AdipoRon activates AMPK/ULK1 pathway in epithelial cells. Blockade of AMPK activation, as well as inhibition of autophagy, blocks the effects of AdipoRon on Aldo-induced EMT. Moreover, AdipoRon treatment promotes autophagy and improves renal fibrosis in DOCA-salt-hypertensive mice. Our data suggest that AdipoRon could be a potential therapeutic option to prevent renal fibrosis in hypertensive patients. Graphical abstract.

Topics: AMP-Activated Protein Kinases; Animals; Autophagy; Autophagy-Related Protein-1 Homolog; Cell Line; Disease Models, Animal; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney; Kidney Diseases; Mice, Inbred C57BL; Phosphorylation; Piperidines

During oxidative stress mitochondria become the main source of endogenous reactive oxygen species (ROS) production. In the present study, we aimed to clarify the effects of pharmacological PARP-1 inhibition on mitochondrial function and quality control processes.. L-2286, a quinazoline-derivative PARP inhibitor, protects against cardiovascular remodeling and heart failure by favorable modulation of signaling routes. We examined the effects of PARP-1 inhibition on mitochondrial quality control processes and function in vivo and in vitro. Spontaneously hypertensive rats (SHRs) were treated with L-2286 or placebo. In the in vitro model, 150 μM H. PARP-inhibition prevented the development of left ventricular hypertrophy in SHRs. The interfibrillar mitochondrial network were less fragmented, the average mitochondrial size was bigger and showed higher cristae density compared to untreated SHRs. Dynamin related protein 1 (Drp1) translocation and therefore the fission of mitochondria was inhibited by L-2286 treatment. Moreover, L-2286 treatment increased the amount of fusion proteins (Opa1, Mfn2), thus preserving structural stability. PARP-inhibition also preserved the mitochondrial genome integrity. In addition, the mitochondrial biogenesis was also enhanced due to L-2286 treatment, leading to an overall increase in the ATP production and improvement in survival of stressed cells.. Our results suggest that the modulation of mitochondrial dynamics and biogenesis can be a promising therapeutical target in hypertension-induced myocardial remodeling and heart failure.

Topics: Animals; Cells, Cultured; Citrate (si)-Synthase; DNA, Mitochondrial; Electrocardiography; Glutathione; Hypertension; Hypertrophy, Left Ventricular; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Proteins; Myocytes, Cardiac; Natriuretic Peptide, Brain; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quinazolines; Rats, Inbred SHR; Rats, Wistar

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and "in vitro." Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an "in vivo" heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure.

Topics: Animals; Animals, Newborn; Cell Culture Techniques; Citrate (si)-Synthase; DNA; DNA Damage; DNA, Mitochondrial; Dynamins; Electron Transport; Energy Metabolism; Genome, Mitochondrial; Heart Failure; Hypertension; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Mitochondrial Dynamics; Mitochondrial Proteins; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organelle Biogenesis; Oxidative Stress; Oximes; Oxygen Consumption; Piperidines; Rats, Inbred SHR; Rats, Inbred WKY

Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

Glucagon-like peptide-1 (GLP-1), a novel type of glucose-lowering agent, has been reported to exert cardioprotective effects. However, the cardioprotective mechanism of GLP-1 on spontaneous hypertension-induced cardiac hypertrophy has not been fully elucidated. In this study, we revealed that liraglutide or alogliptin treatment ameliorated spontaneous hypertension-induced cardiac hypertrophy, as evidenced by decreased levels of cardiac hypertrophic markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain), as well as systolic blood pressure, diastolic blood pressure, mean arterial pressure, and histological changes. Both drugs significantly reduced the levels of angiotensin II (AngII) and AngII type 1 receptor (AT1R) and upregulated the levels of AngII type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2), as indicated by a reduced AT1R/AT2R ratio. Simultaneously, treatment with liraglutide or alogliptin significantly increased GLP-1 receptor expression and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and downregulated the phosphorylation of mammalian target of rapamycin (mTOR), p70 ribosomal S6 protein kinase, and eukaryotic translation initiation factor 4E binding protein 1 in spontaneous hypertension rats. Furthermore, our data demonstrated that the AMPK inhibitor compound C or mTOR activator MHY1485 inhibited the anti-hypertrophic effect of GLP-1. In summary, our study suggests that liraglutide or alogliptin protects the heart against cardiac hypertrophy by regulating the expression of AngII/AT1R/ACE2 and activating the AMPK/mTOR pathway, and GLP-1 agonist can be used in the treatment of patients with cardiac hypertrophy.

Topics: Adenylate Kinase; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Cell Line; Disease Models, Animal; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; Morpholines; Myocytes, Cardiac; Piperidines; Rats; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Triazines; Uracil

Iloperidone, second generation antipsychotic drug, reported in clinical trial to produce orthostatic hypotension as side effect. It was claimed to be antagonistic at alpha adrenergic receptor in central nervous system. We evaluated effect of Iloperidone on peripheral alpha 1 adrenoreceptor by in silico and in vitro methods while in vivo hypotensive, antihypertensive and ocular hypotensive activity was evaluated in animals.. Pharmacological activity prediction of Iloperidone was done using PASSOnline and SwissTargetPrediction softwares and molecular docking with Alpha 1A adrenoreceptor using AutoDock Vina. Hypotensive activity in normotensive and antihypertensive activity against DOCA-salt induced hypertension in rats were evaluated at doses 0.03 mg/Kg and 0.1 mg/Kg, i.p of Iloperidone. Blood pressure was measured by invasive blood pressure measurement technique using PowerLab 4/30 and intraocular pressure was measured using digital tonometer.. Iloperidone (0.1 mg/Kg) showed significant decrease in blood pressure (38.96 ± 1.1%) in normotensive rats, while in DOCA salt induced hypertensive rats, systolic blood pressure was found to be decreased by 29.04 ± 1.45% and 31.43 ± 1.21% in 0.03 mg/Kg and 0.1 mg/Kg treated rats respectively. Iloperidone prevented rise in systolic BP with adrenaline. Intraocular pressure was found to be decreased by 36.66 ± 3.15% in rabbits after 1 h of instillation of 0.1% Iloperidone.. Iloperidone exerted hypotensive and/or anti-hypertensive activity in rats and ocular hypotensive activity in rabbits.

Topics: Animals; Antihypertensive Agents; Antipsychotic Agents; Blood Pressure; Desoxycorticosterone Acetate; Drug Repositioning; Female; Hypertension; Intraocular Pressure; Isoxazoles; Male; Molecular Docking Simulation; Piperidines; Rats, Wistar; Receptors, Adrenergic, alpha-1; Rotarod Performance Test

This study evaluated the efficacy of the soluble epoxide hydrolase (sEH) inhibitor, TPPU on chronic NG-Nitro L-arginine methyl ester (L-NAME)-induced hypertension in rats and its effects on plasma Angiotensin II (Ang II), cardiac Angiotensin-converting enzyme (ACE) and Angiotensin II receptor type 1 (AT1R) expressions.. Forty Sprague Dawley rats were divided into 5 groups. Two groups served as control and received orally either vehicle or TPPU (3 mg/kg) for five weeks. The other three groups were given L-NAME (50 mg/kg/day) in drinking water for five weeks. Two weeks after the L-NAME treatment, animals received orally either saline or TPPU (3 mg/kg/day) or lisinopril (10 mg/kg/day) daily for 3 weeks. Blood pressure (BP) was measured weekly. At the end of the experiment, plasma Ang II, cardiac ACE and AT1R protein and gene expressions were determined.. L-NAME caused a significant increase in BP of the animals. TPPU and lisinopril resulted in normalization of L-NAME-induced hypertension. They also caused a significant reduction in Ang II and ACE protein and gene expressions compared to L-NAME and vehicle-treated animals.. This study demonstrates that TPPU effectively lowers L-NAME-induced hypertension in rats. The mechanism of its antihypertensive effect is likely mediated by the suppression of ACE gene and protein expression, leading to a lower Ang II level.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Epoxide Hydrolases; Hypertension; Male; NG-Nitroarginine Methyl Ester; Phenylurea Compounds; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on

Topics: Acute Kidney Injury; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Enzyme Inhibitors; Epoxide Hydrolases; Fibrosis; Glomerular Mesangium; Glomerulonephritis; Hypertension; Male; Mice; Phenylurea Compounds; Piperidines; Reperfusion Injury

Uridine 5'-triphosphate (UTP) has an important role as an extracellular signaling molecule that regulates inflammation, angiogenesis, and vascular tone. While chronic hypertension has been shown to promote alterations in arterial vascular tone regulation, carotid artery responses to UTP under hypertensive conditions have remained unclear. The present study investigated carotid artery responses to UTP in spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats (WKY). Accordingly, our results found that although UTP promotes concentration-dependent relaxation in isolated carotid artery segments from both SHR and WKY after pretreatment with phenylephrine, SHR exhibited significantly lower arterial relaxation responses compared with WKY. Moreover, UTP-induced relaxation was substantially reduced by endothelial denudation and by the nitric oxide (NO) synthase inhibitor N

Topics: Animals; Carotid Arteries; Furans; Hypertension; Piperidines; Purinergic P2Y Receptor Antagonists; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Uridine Triphosphate; Vasodilation

In addition to serving as an incretin-based treatment of type 2 diabetes mellitus (T2DM), glucagon-like peptide 1 (GLP-1) can also reverse cardiovascular diseases caused by vascular remodelling. However, a detailed mechanism underlying how GLP-1 reverses vascular remodelling remains unclear. Here, Spontaneous hypertension rats (SHR) were used as an in vivo model of vascular remodelling. Treatment with a GLP-1 receptor (GLP-1R) agonist Liraglutide or dipeptidyl peptidase 4 (DPP4) inhibitor Alogliptin decreased systolic blood pressure (SBP), diastolic blood pressure (DBP), thickness of vascular wall, and overall collagen levels in SHR. In vitro vascular remodelling can be induced by exposing rat aortic smooth muscle cells (RASMC) to angiotensin II (Ang II); GLP-1 treatment attenuated AngII induction of RASMC proliferation, migration, and excessive extracellular matrix (ECM) degradation. Downregulation of matrix metalloproteinase 1 (MMP1) enhanced the inhibitory effects of GLP-1, and extracellular regulated protein kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) signalling participated in these processes. These results provide a new mechanistic understanding of key therapeutic strategies for the treatment of vascular remodelling-related diseases.

Topics: Animals; Blood Pressure; Cells, Cultured; Dipeptidyl-Peptidase IV Inhibitors; Down-Regulation; Gene Expression Regulation, Enzymologic; Glucagon-Like Peptide 1; Hypertension; Liraglutide; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 1; Myocytes, Smooth Muscle; NF-kappa B; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Uracil; Vascular Remodeling

Topics: Analgesics, Opioid; Animals; Calcium; Humans; Hypertension; Kidney; Kidney Diseases; Kidney Glomerulus; Male; Piperidines; Podocytes; Pyrrolidines; Rats; Rats, Inbred Dahl; Signal Transduction; Sodium Chloride, Dietary; TRPC Cation Channels; TRPC6 Cation Channel

Topics: Adenine; Humans; Hypertension; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Adult; Antihypertensive Agents; Female; Humans; Hypertension; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data.

Topics: Antihypertensive Agents; Benchmarking; Benzimidazoles; Blood Pressure; Homeostasis; Humans; Hypertension; Male; Morpholines; Piperidines; Renin; Renin-Angiotensin System

Hypertensive transgenic (mRen2)27 rats exhibit impaired baroreflex sensitivity (BRS) for control of heart rate (HR). Intracerebroventricular infusion of Ang-(1-7) improves indices of vagal BRS independent of lowering mean arterial pressure (MAP), whereas AT1 receptor blockade normalizes MAP and indices of sympathetic tone without correcting the vagal BRS. Scavenging cellular reactive oxygen species (ROS) with tempol in brain fails to correct either hypertension or sympathovagal balance in these animals, despite reports that mitochondrial ROS contributes to Ang II-infusion hypertension. To examine effects of a putative preferential mitochondrial ROS scavenger in the brain of (mRen2)27 rats, ICV infusions of Mito-TEMPO (3.2 μg/2.5 μL/h) were compared with artificial cerebrospinal fluid (aCSF; 2.5 μL/h) and combination AT1 receptor antagonist candesartan (CAN: 4 μg/2.5 μL/h) plus Ang-(1-7) (0.1 μg/2.5 μL/h) treatment. MAP was lower after CAN + Ang-(1-7) treatment, and both vagal and sympathetic components of BRS and sympathovagal balance were improved. By contrast, Mito-TEMPO improved sympathetic components of BRS and tended to improve overall sympathovagal balance but failed to alter MAP in this model of hypertension. Although further studies are required to determine whether Mito-TEMPO or CAN + Ang-(1-7) treatment at the doses used altered mitochondrial ROS, optimal therapeutic benefits are achieved by shifting the balance from Ang II toward Ang-(1-7) in this model of chronic RAS-dependent hypertension.

Topics: Angiotensin I; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Arterial Pressure; Baroreflex; Benzimidazoles; Biphenyl Compounds; Brain; Disease Models, Animal; Drug Combinations; Free Radical Scavengers; Heart; Heart Rate; Hypertension; Male; Mitochondria; Organophosphorus Compounds; Peptide Fragments; Piperidines; Rats, Transgenic; Reactive Oxygen Species; Renin; Sympathetic Nervous System; Tetrazoles; Vagus Nerve

The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM).. Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM.. After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%).. Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM.. Registration Number for Clinical Trial: UMIN000007722.

Topics: Aged; Arterial Pressure; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Prospective Studies; Time Factors; Treatment Outcome; Uracil; Vascular Stiffness

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Atropine; Blood Pressure; Heart Rate; Hypertension; Hypotension; Male; Muscarinic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperazines; Piperidines; Pirenzepine; Pyrazoles; Rats, Inbred SHR; Rats, Wistar; Receptor, Muscarinic M1; Receptor, Muscarinic M3

Vandetanib and pazopanib are clinically available, multi-targeted inhibitors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. Short-term VEGF receptor inhibition is associated with hypertension in 15%-60% of patients, which may limit the use of these anticancer therapies over the longer term. To evaluate the longer-term cardiovascular implications of treatment, we investigated the "on"-treatment (21 days) and "off"-treatment (10 days) effects following daily administration of vandetanib, pazopanib, or vehicle, in conscious rats. Cardiovascular variables were monitored in unrestrained Sprague-Dawley rats instrumented with radiotelemetric devices. In Study 1, rats were randomly assigned to receive either daily intraperitoneal injections of vehicle (volume 0.5 mL; n = 5) or vandetanib 25 mg/kg/day (volume 0.5 mL; n = 6). In Study 2, rats received either vehicle (volume 0.5 mL; n = 4) or pazopanib 30 mg/kg/day (volume 0.5 mL; n = 7), dosed once every 24 hours for 21 days. All solutions were in 2% Tween, 5% propylene glycol in 0.9% saline solution. Vandetanib caused sustained increases in mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to baseline and vehicle. Vandetanib also significantly altered the circadian cycling of MAP, SBP, and DBP. Elevations in SBP were detectable 162 hours after the last dose of vandetanib. Pazopanib also caused increases in MAP, SBP, and DBP. However, compared to vandetanib, these increases were of slower onset and a smaller magnitude. These data suggest that the cardiovascular consequences of vandetanib and pazopanib treatment are sustained, even after prolonged cessation of drug treatment.

Topics: Animals; Arterial Pressure; Disease Models, Animal; Drug Administration Schedule; Humans; Hypertension; Indazoles; Male; Piperidines; Pyrimidines; Quinazolines; Random Allocation; Rats; Rats, Sprague-Dawley; Sulfonamides

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Topics: Adenine; Age Factors; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Aspirin; Atrial Fibrillation; Atrial Flutter; Female; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

We have previously reported that the long-term exposure of organophosphorus induces vascular dementia (VD) in rats. As a coenzyme, vitamin B6 is mainly involved in the regulation of metabolisms. Whether vitamin B6 improves VD remains unknown.. The model of VD was induced by feeding rats with isocarbophos (0.5 mg/kg per two day, 12 weeks). The blood flow of the posterior cerebral artery (PCA) in rat was assessed by transcranial Doppler (TCD). The learning and memory were evaluated by the Morris Water Maze (MWM) test.. Administration of vitamin B6 increased the blood flow in the right and left posterior cerebral arteries and improved the functions of learning and memory in isocarbophos-treated rats. Vitamin B6 increased the protein levels of N-methyl-D-aspartate receptor (NMDAR) 2B, postsynaptic densities (PSDs) protein 95, and calmodulin-dependent protein kinase II (CaMK-II) in the hippocampus, which were decreased by isocarbophos in rats. Morphological analysis by light microscope and electronic microscope indicated disruptions of the hippocampus caused by isocarbophos were normalized by vitamin B6. Importantly, the antagonist of NMDAR signaling by eliprodil abolished these beneficial effects produced by vitamin B6 on PCA blood flow, learning, memory, and hippocampus structure in rats, as well as the protein expression of NMDAR 2B, PSDs protein 95, and CaMK-II in the hippocampus.. Vitamin B6 activates NMDAR signaling to prevent isocarbophos-induced VD in rats.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cerebrovascular Circulation; Dementia, Vascular; Disks Large Homolog 4 Protein; Excitatory Amino Acid Antagonists; Hippocampus; Hypertension; Malathion; Male; Maze Learning; Memory; Piperidines; Posterior Cerebral Artery; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Ultrasonography, Doppler; Vitamin B 6; Vitamin B Complex

It has been suggested that voltage-dependent anion channels (VDACs) control the release of superoxide from mitochondria. We have previously shown that reactive oxygen species (ROS) such as superoxide (O

Topics: Animals; Blood Pressure; Cyclic N-Oxides; Epithelial Sodium Channels; Hydrogen Peroxide; Hypertension; Ion Transport; Kidney; Mice; Mice, Knockout; Mitochondria; Mitochondrial Membrane Transport Proteins; Organophosphorus Compounds; Piperidines; Sodium; Spin Labels; Superoxides; Voltage-Dependent Anion Channels

Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that CB1 receptor in the RVLM may play a critical role in the development of obesity-induced hypertension.. To this end, we evaluated the levels of endocannabinoids and CB1 receptors in the RVLM in high-fat diet (HFD)-induced hypertensive rats. We then used pharmacological and molecular methods to examine the role of RVLM CB1 receptors in regulation of BP, heart rate (HR), and RSNA in obesity-induced hypertensive rats.. We found that HFD-fed rats exhibited higher basal BP, HR, and RSNA than standard diet-fed rats, which were associated with increased levels of endocannabinoids and CB1 receptor expression in the RVLM. Furthermore, unilateral intra-RVLM microinjections of AM251 (0, 100, or 500 nM/0.5 μl/site) dose-dependently decreased BP, HR, and RSNA to a greater extent in HFD-fed rats than in standard diet-fed rats. Finally, siRNA-mediated knockdown of CB1 receptor expression in the RVLM robustly decreased BP, HR, and RSNA in HFD-fed rats.. Taken together, our results suggested that enhanced CB1 receptor-mediated neurotransmissions in the RVLM may play a role in the development of obesity-induced hypertension.

Topics: Animals; Blood Pressure; Diet, High-Fat; Endocannabinoids; Gene Silencing; Heart Rate; Hypertension; Kidney; Male; Medulla Oblongata; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sympathetic Nervous System

Poly(ADP-ribose) polymerase (PARP) proteins are used by cells in several DNA repair processes. PARP inhibition can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Two PARP inhibitors, olaparib and rucaparib, have been approved by the US Food and Drug Administration (FDA) for the treatment of recurrent, BRCA-associated ovarian cancer. More recently, these two and a third PARP inhibitor, niraparib, were approved by the FDA as maintenance therapy following platinum-based chemotherapy for recurrent ovarian cancer. This has caused a paradigm shift in disease management and a challenge for clinicians, who must decide how best to use these agents in individualized treatment. The oral formulation is attractive to patients, but adverse effects such as nausea and fatigue can impact quality of life. As clinicians become comfortable selecting PARP inhibitors and managing associated toxicities, future steps will be to investigate how to safely administer them in combination with other therapies.

Topics: Anemia; Creatinine; Drug Administration Schedule; Drug Interactions; Exanthema; Fatigue; Female; Genes, BRCA1; Genes, BRCA2; Heart Rate; Humans; Hypertension; Indazoles; Leukopenia; Mutation; Myelodysplastic Syndromes; Nasopharyngitis; Nausea; Ovarian Neoplasms; Piperidines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia; Transaminases; Vomiting

Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure. 32 weeks of L-2286 treatment attenuated these processes by modulating mitogen activated protein kinase phosphatase-1 cellular levels in carotid arteries. In hypertensive animals, vascular inflammation and endothelial dysfunction was observed by NF-κB nuclear accumulation and impaired vasodilation to acetylcholine, respectively. Pharmacological poly(ADP-ribose)polymerase-1 inhibition interfered in these processes and mitigated Apoptosis Inducing Factor dependent cell death events, thus improved structural and functional alterations of carotid arteries, without affecting blood pressure. Chronic poly(ADP-ribose)polymerase-1 inhibition protected neuronal tissue against oxidative damage, assessed by nitrotyrosine, 4-hydroxinonenal and 8-oxoguanosine immunohistochemistry in the area of Cornu ammonis 1 of the dorsal hippocampus in hypertensive rats. In this area, extensive pyramidal cell loss was also attenuated by treatment with lowered poly(ADP-ribose)polymer formation. It also preserved the structure of fissural arteries and attenuated perivascular white matter lesions and reactive astrogliosis in hypertensive rats. These data support the premise in which chronic poly(ADP-ribose)polymerase-1 inhibition has beneficial effects on hypertension related tissue damage both in vascular tissue and in the hippocampus by altering signaling events, reducing oxidative/nitrosative stress and inflammatory status, without lowering blood pressure.

Topics: Animals; Blood Pressure; Carotid Arteries; Hippocampus; Hypertension; Male; Oxidative Stress; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Quinazolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vascular Remodeling

Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic nerve activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that abnormal expression of CB1 receptor in the RVLM may play a critical role in the pathogenesis of essential hypertension.. We evaluated the effects of intra-RVLM infusions of arachidonyl-2'-chloroethylamide (ACEA), selective CB1 receptor agonist, with or without AM251, selective CB1 receptor antagonist, on BP, heart rate (HR), and RSNA in spontaneously hypertensive rats and wild-type rats. We also assessed the protein level and surface expression of CB1 receptor in the RVLM in these rats.. We found that spontaneously hypertensive rats exhibited higher basal BP, HR, and RSNA than wild-type rats. Furthermore, unilateral intra-RVLM microinjections ACEA (0, 10, or 100 nM/0.5 μl/site) increased BP, HR, and RSNA to a greater extent in spontaneously hypertensive rats than in wild-type rats. These effects were abolished by co-administrations of AM251 (500 nM/0.5 μl/site) into the RVLM. In addition, the protein level of CB1 receptor in the RVLM was robustly increased in spontaneously hypertensive rats, which is correlated with ACEA-induced maximum changes of RSNA, and this was also associated with reduced expression of β-arrestin 2 in the RVLM in spontaneously hypertensive rats. Finally, overexpression of β-arrestin 2 in the RVLM in spontaneously hypertensive rats attenuated BP, HR and RSNA.. Taken together, our results suggested that alterations of CB1 receptor desensitization in the RVLM may play a role in the pathogenesis of essential hypertension.

Topics: Animals; Arachidonic Acids; beta-Arrestin 2; Blood Pressure; Essential Hypertension; Heart Rate; Hypertension; Kidney; Male; Medulla Oblongata; Microinjections; Piperidines; Pyrazoles; Rats; Rats, Inbred SHR; Receptor, Cannabinoid, CB1; Sympathetic Nervous System

Oxidant stress contributes to the initiation and progression of hypertension (HTN) by enhancing endothelial dysfunction and/or causing perturbations in nitric oxide homeostasis. Differences in mitochondrial function may augment this process and provide insight into why age of onset and clinical outcomes differ among individuals from distinct ethnic groups. We have previously demonstrated that variation in normal mitochondrial function and oxidant production exists in endothelial cells from individuals of Caucasian and African-American ethnicity and that this variation contributes to endothelial dysfunction. To model these distinct mitochondrial redox phenotypes, we used C57Bl/6N (6N) and C57Bl/6J (6J) mice that also display unique mitochondrial functional properties due to the differential expression nicotinamide nucleotide transhydrogenase (NNT). We demonstrate that the absence of NNT in 6J cells led to distinct mitochondrial bioenergetic profiles and a pro-oxidative mitochondrial phenotype characterized by increased superoxide production and reduced glutathione peroxidase activity. Interestingly, we found that 6J animals have significantly higher systolic blood pressure compared to 6N animals, and this difference is exacerbated by angiotensin II treatment. The changes in pressure were accompanied by both mitochondrial and vascular dysfunction revealed by impaired respiratory control ratios and endothelial-dependent vessel dilation. All end points could be significantly ameliorated by treatment with the mitochondria-targeted superoxide dismutase mimetic MitoTEMPO demonstrating a critical role for the production of mitochondrial reactive oxygen species in the development of HTN in these animals. Taken together, these data indicate that the absence of NNT leads to variation in mitochondrial function and contributes to a unique mitochondrial redox phenotype that influences susceptibility to HTN by contributing to endothelial and vascular dysfunction.

Topics: Angiotensin II; Animals; Antioxidants; Blood Pressure; Carotid Arteries; Cells, Cultured; Disease Models, Animal; Endothelium; Humans; Hypertension; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Proteins; Myography; NADP Transhydrogenase, AB-Specific; Nitric Oxide; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Piperidines; Primary Cell Culture; Superoxide Dismutase; Superoxides; Vasoconstrictor Agents

We report the chemical synthesis of Ofornine mimics from l-vasicine, structure-activity relationship studies and their in vivo screening for anti-hypertensive action in Wistar rats. It was observed that most of the analogs possessed anti-hypertensive effect; however, the duration of the effect was variable and mostly transient. The results demonstrated that the analogs 12, 13, 14, 15, and 16 showed a sharp and significant decrease in systolic and diastolic blood pressure for 30-60min after intravenous administration. Analog (S)-(3-hydroxypyrrolidin-1-yl)(2-(pyridin-4-ylamino)phenyl)methanone (8) showed a significant decrease in blood pressure in a dose dependent manner whose maximal response lowered to 79.29±4.26mmHg of SBP and 62.55±2.9 of DBP at 10mg/kg intravenous dose. Further, the significant anti-hypertensive effect of 8 lasted for about 2.5h at 10mg/kg dose. We also evaluated the acute toxicity of the analog 8 as per the OECD guidelines and the compound was found to be safe up to the dose of 2000mg/kg body weight. These preclinical findings suggest that the analog 8 could be considered as a promising lead and a durable anti-hypertensive drug candidate and deserves further investigation. The SAR studies clearly showed that the amide, hydroxyl and pyridine ring plays important role in showing the activity.

Topics: Alkaloids; Aminopyridines; Animals; Antihypertensive Agents; Biological Products; Blood Pressure; Dose-Response Relationship, Drug; Female; Hypertension; Injections, Intravenous; Mice; Molecular Structure; Piperidines; Quinazolines; Rats; Rats, Wistar; Structure-Activity Relationship

Topics: Bipolar Disorder; Electroconvulsive Therapy; Electroencephalography; Humans; Hypertension; Hypnotics and Sedatives; Male; Middle Aged; Piperidines; Remifentanil; Seizures

The herbal formula (Sahatsatara, STF), the Thai traditional poly-herbal recipe, has been used for treatment of muscle pain, anti-flatulence and numbness on hands and feet, with the caution when used in hypertensive patients. However, there is no scientific evidence to prove its effects on cardiovascular system. Piperine is the proposed major active compound in STF. It is shown to have antihypertensive effect in the L-NAME-induced endothelial dysfunction rats.. This study investigated the pharmacokinetics, mechanism of action, as well as the hemodynamic and vasoactive effect and toxicity of STF and piperine using spontaneously hypertensive rats (SHR) and normal Wistar rats (NWR).. The amount of piperine in STF was measured by ultra performance liquid chromatography (UPLC). SHR and NWR were gavaged with piperine (50mg/kg/day) or STF (100, 300, or 1000mg/kg/day) alone or together with L-NAME (in drinking water) for 28 days. Hemodynamic effects were monitored by noninvasive tail cuff every 7 days. Vasorelaxation effect on the thoracic aorta in organ chamber was observed through force transducer at the end of the experiment. Biochemical parameters for kidney and liver toxicity were measured. In addition, pharmacokinetic study was performed using non-compartment analysis.. The amount of piperine in STF was 1.29%w/w. Both STF and piperine did not affect blood pressure and heart rate in both SHR and NWR. Interestingly, STF and piperine increased acetylcholine-induced vasorelaxation of isolated thoracic aorta and have vascoluprotective effect in nitric oxide (NO) impaired rats. No liver or kidney toxicity was found in this study. Non-compartment pharmacokinetic analysis showed that the time to reach maximum concentration (T. STF had no effect on blood pressure in both SHR and NWR. However, it was able to relax isolated thoracic aorta and had the potential for vasculoprotective effect in hypertensive and NO impaired condition. The effects of STF were comparable to those of piperine.

Topics: Alkaloids; Animals; Antihypertensive Agents; Benzodioxoles; Blood Pressure; Hypertension; Male; Phytotherapy; Piperidines; Plant Extracts; Plants, Medicinal; Polyunsaturated Alkamides; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Thailand; Vasodilation

We designed a study to evaluate the cardioprotective effect of two soluble epoxide hydrolase (sEH) inhibitors, 1-(1-propanoylpiperidin-4-yl)-3-(4-trifluoromethoxy)phenyl)urea (TPPU) and trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB), in ischemia-reperfusion (IR) model.. Cardioprotective effects of the sEH inhibitors were evaluated against IR-induced myocardial damage in hearts from normal, hypertensive, and diabetic rats using Langendorff's apparatus. In addition, the effect of sEH inhibitors on endothelial function was evaluated in vitro and ex vivo using isolated rat thoracic aorta.. Ischemia-reperfusion (IR) increased the myocardial damage in hearts from normal rats. IR-induced myocardial damage was augmented in hearts isolated from hypertensive and diabetic rats. Myocardial damage as evident from increase in the activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in heart perfusate was associated with significant decrease in the heart rate and developed tension, and increase in the resting tension in isolated heart. Both sEH inhibitors protected the heart in normal, hypertensive, and diabetic rats subjected to IR injury. The sEH inhibitor t-TUCB relaxed phenylephrine precontracted aorta from normal rats. Relaxant effect of acetylcholine (ACh) was reduced in aortas from diabetic and hypertensive rats compared to normal rats. Pretreatment of sEH inhibitors to diabetic and hypertensive rats increased relaxant effect of ACh on aortas isolated from these rats.. Prophylactic treatment with sEH inhibitors decreased myocardial damage due to IR, hypertension and diabetes, and decreased endothelial dysfunction created by diabetes and hypertension. Therefore, inhibitors of sEH are useful probes to study cardiovascular pathology, and inhibition of the sEH is a potential approach in the management of IR-induced cardiac damage and endothelial dysfunction-related cardiovascular disorders.

Topics: Animals; Aorta, Thoracic; Benzoates; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epoxide Hydrolases; Heart Rate; Hypertension; Isolated Heart Preparation; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phenylurea Compounds; Piperidines; Rats, Wistar; Vasodilation

The aim was to evaluate the clinical profile and effectiveness of ECT in women. A retrospective chart review was carried out to identify female patients who had received ECT during the period September 2013-February 2015. Details regarding their sociodemographic, clinical, and treatment data were extracted from these records for the present study. The total number of patients, admitted to our psychiatry inpatient clinic during the survey period, was 802. During this period, 26 (3.24 %) female patients received ECT. Patients who received ECT were mostly in age group of 25-44 years (76.9 %). Twenty percent of patients were in the postpartum period. Psychotic disorders (46.1 %) was the most common diagnosis for which ECT was used, followed by bipolar affective disorder, current episode manic (19.2 %). At the end of ECT courses, 70 % of the patients showed good response with a CGI-I of 1 or 2, and 30 % showed minimal response with a CGI-I score of 3. The most common side effects were post-ECT confusion (15.4 %) and prolonged seizure (11.5 %). This rate of prolonged seizure was higher the rates reported in the literature. The bronchospasm related with remifentanil, post-ECT bradycardia, hypertensive crisis and oligohydramnios were also reported in one case each. ECT is a safe and effective treatment option in women with severe psychiatric disorders and disorders in the perinatal/postpartum period are a major area of ECT use. The female gender may be a contributing factor for the higher rates of prolonged seizure.

Topics: Adult; Aged; Anesthetics, Intravenous; Bipolar Disorder; Bradycardia; Bronchial Spasm; Depression, Postpartum; Depressive Disorder; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Hypertension; Middle Aged; Oligohydramnios; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Puerperal Disorders; Remifentanil; Retrospective Studies; Treatment Outcome; Turkey; Young Adult

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated.. Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee.. Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0-3: 2.8%; Months 3-6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1-3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE).. Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

Topics: Arthritis, Rheumatoid; Blood Pressure; Cardiovascular Diseases; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials, Phase III as Topic; Heart Failure; Humans; Hyperlipidemias; Hypertension; Incidence; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Triglycerides

Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin-1 (ET-1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET-1.. Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II-dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET-1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E-cadherin and α-smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK-2 proximal tubular cells expressing the ETB receptor subtype, the effects of ET-1 with or without ET-1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E-cadherin and increased αSMA expression. Irbesartan and the mixed ET-1 receptor antagonist bosentan prevented these changes in a blood pressure-independent fashion (P < 0.001 for both versus controls). In HK-2 cells ET-1 blunted E-cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ETB receptor antagonist BQ-788. Evidence for involvement of the Rho-kinase signaling pathway and dephosphorylation of Yes-associated protein in EMT was also found.. In angiotensin II-dependent hypertension, ET-1 acting via ETB receptors and the Rho-kinase and Yes-associated protein induces EMT and thereby renal fibrosis.

Topics: Actins; Angiotensin Receptor Antagonists; Animals; Animals, Genetically Modified; Biphenyl Compounds; Bosentan; Cadherins; Endothelin B Receptor Antagonists; Endothelin-1; Epithelial-Mesenchymal Transition; Fibrosis; Humans; Hypertension; Irbesartan; Kidney; Kidney Diseases; Kidney Tubules, Proximal; Oligopeptides; Piperidines; Rats; Receptor, Endothelin B; rho-Associated Kinases; Signal Transduction; Sulfonamides; Tetrazoles

Cyclosporine (CSA) elevates blood pressure (BP) and alters arterial baroreflex sensitivity (BRS) and vasoreactivity. In this study we determined whether the renin-angiotensin system (RAS) interplays with other vasopressor pathways in mediating the CSA actions.. Whole animal and isolated vascular preparations were employed to determine the effects of pharmacologic interruption of angiotensin II (Ang II), endothelin (ET), or thromboxane (TXA2) signaling on the adverse cardiovascular effects of CSA.. CSA (25mg/kg/day i.p. for 7days) caused significant increases in BP that were paralleled with (i) reduced BRS measured by phenylephrine (BRSPE) or sodium nitroprusside (BRSSNP), (ii) enhanced aortic contractile responses to Ang II and U-46619 (thromboxane analogue), and (iii) reduced aortic eNOS expression and acetylcholine, but not SNP, vasorelaxations. Except for the reduced BRSSNP, the CSA effects disappeared upon concurrent administration of losartan (angiotensin AT1 receptor antagonist), captopril (angiotensin converting enzyme inhibitor), or their combination. Moreover, CSA augmentation of Ang II contractions was abolished after cyclooxygenase inhibition (indomethacin) or endothelin ETA/ETB receptor blockade (atrasentan/BQ788). By contrast, the blockade of thromboxane receptors (terutroban) failed to alter the CSA-evoked facilitation of Ang II responsiveness.. The facilitation of baroreflex control and inhibition of vascular responsiveness to Ang II and thromboxane contribute to the BP lowering effect of RAS inhibitors in CSA-treated rats. Further, endothelin receptors and vasoconstrictor prostanoids contribute to the CSA-evoked exaggeration of Ang II vascular responsiveness and hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Angiotensin II; Animals; Aorta; Atrasentan; Baroreflex; Blood Pressure; Captopril; Cyclosporine; Hypertension; Indomethacin; Losartan; Male; Naphthalenes; Nitric Oxide Synthase Type III; Nitroprusside; Oligopeptides; Phenylephrine; Piperidines; Propionates; Pyrrolidines; Rats; Renin-Angiotensin System; Vasoconstriction; Vasodilation

A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to undergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense, she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmonary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breathing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings, Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was discharged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount of retained medication when the anesthesia resident established the intravenous line, which caused severe respiratory depression. It is important to note that adverse effects such as severe respiratory depression and bradycardia can be caused by even small doses of remifentanil.

Topics: Aged; Analgesics, Opioid; Anesthesia, General; Bradycardia; Cardiopulmonary Resuscitation; Cataract Extraction; Coronary Angiography; Electrocardiography; Epilepsy; Epinephrine; Female; Humans; Hypertension; Piperidines; Remifentanil; Respiratory Insufficiency; Takotsubo Cardiomyopathy; Vasoconstrictor Agents

Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways. Earlier reports have shown that diacylglycerol produced during calcium signal generation can be converted to an endocannabinoid, 2-arachidonoylglycerol (2-AG). Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension. Rat and mouse aortic rings were examined by myography. Vascular expression of CB1R was demonstrated with immunohistochemistry. Rat aortic vascular smooth muscle cells (VSMCs) were cultured for calcium measurements and 2-AG-determination. Inhibition or genetic loss of CB1Rs enhanced vasoconstriction induced by angiotensin II (AngII) or phenylephrine (Phe), but not by prostaglandin(PG)F2α. AngII-induced vasoconstriction was augmented by inhibition of diacylglycerol lipase (tetrahydrolipstatin) and was attenuated by inhibition of monoacylglycerol lipase (JZL184) suggesting a functionally relevant role for endogenously produced 2-AG. In Gαq/11-deficient mice vasoconstriction was absent to AngII or Phe, which activate Gq/11-coupled receptors, but was maintained in response to PGF2α. In VSMCs, AngII-stimulated 2-AG-formation was inhibited by tetrahydrolipstatin and potentiated by JZL184. CB1R inhibition increased the sustained phase of AngII-induced calcium signal. Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice. These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation. Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone. Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.

Topics: Angiotensin II; Animals; Aorta; Arachidonic Acids; Benzodioxoles; Calcium; Calcium Signaling; Dinoprost; Endocannabinoids; Gene Expression Regulation; Glycerides; GTP-Binding Protein alpha Subunits, Gq-G11; Hypertension; Lactones; Lipoprotein Lipase; Male; Mice; Mice, Knockout; Monoacylglycerol Lipases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Orlistat; Phenylephrine; Piperidines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Tissue Culture Techniques; Vasoconstriction

Superoxide ( [Formula: see text] ) has been implicated in the pathogenesis of many human diseases including hypertension. Mitochondria-targeted superoxide scavenger mitoTEMPO reduces blood pressure; however, the structure-functional relationships in antihypertensive effect of mitochondria-targeted nitroxides remain unclear. The nitroxides are known to undergo bioreduction into hydroxylamine derivatives which reacts with [Formula: see text] with much lower rate. The nitroxides of pyrrolidine series (proxyls) are much more resistant to bioreduction compared to TEMPOL derivatives suggesting that mitochondria-targeted proxyls can be effective antioxidants with antihypertensive activity. In this work we have designed and studied two new pyrrolidine mitochondria targeted nitroxides: 3-[2-(triphenyphosphonio)acetamido]- and 3-[2-(triphenyphosphonio) acetamidomethyl]-2,2,5,5-tetramethylpyrrolidine-1-oxyl (mCP2) and (mCP1). These new mitochondria targeted nitroxides have 3- to 7-fold lower rate constants of the reaction with O2(-•) compared with mitoTEMPO; however, the cellular bioreduction of mCP1 and mCP2 was 3- and 2-fold slower. As a consequence incubation with cells afforded much higher intracellular concentration of mCP1 and mCP2 nitroxides compared to mitoTEMPO nitroxide. This has compensated for the difference in the rate of O2(-•) scavenging and all nitroxides similarly protected mitochondrial respiration in H2O2 treated endothelial cells. Treatment of hypertensive mice with mCP1 and mCP2 (1.4mg/kg/day) after onset of angiotensin II-induced hypertension significantly reduced blood pressure to 133±5mmHg and 129±6mmHg compared to 163±5mmHg in mice infused with angiotensin II alone. mCP1 and mCP2 reduced vascular O2(-•) and prevented decrease of endothelial nitric oxide production. These data indicate that resistance to bioreduction play significant role in antioxidant activity of nitroxides. Studies of nitroxide analogs such as mCP1 and mCP2 may help in optimization of chemical structure of mitochondria-targeted nitroxides for improved efficacy and pharmacokinetics of these drugs in treatment of hypertension and many other conditions including atherosclerosis, diabetes and degenerative neurological disorders in which mitochondrial oxidative stress seems to play a role.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Antioxidants; Aorta; Blood Pressure; Cell Line; Cyclic N-Oxides; Endothelial Cells; Humans; Hydrogen Peroxide; Hypertension; Infusion Pumps, Implantable; Male; Mice; Mice, Inbred C57BL; Mitochondria; Molecular Targeted Therapy; Organophosphorus Compounds; Piperidines; Superoxides

Ibrutinib is an orally administered inhibitor of Bruton tyrosine kinase that antagonizes B-cell receptor, chemokine, and integrin-mediated signaling. In early-phase studies, ibrutinib demonstrated high response rates and prolonged progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). The durable responses observed with ibrutinib relate in part to a modest toxicity profile that allows the majority of patients to receive continuous therapy for an extended period. We report on median 3-year follow-up of 132 patients with symptomatic treatment-naïve and relapsed/refractory CLL or small lymphocytic lymphoma. Longer treatment with ibrutinib was associated with improvement in response quality over time and durable remissions. Toxicity with longer follow-up diminished with respect to occurrence of grade 3 or greater cytopenias, fatigue, and infections. Progression remains uncommon, occurring primarily in some patients with relapsed del(17)(p13.1) and/or del(11)(q22.3) disease. Treatment-related lymphocytosis remains largely asymptomatic even when persisting >1 year and does not appear to alter longer-term PFS and overall survival compared with patients with partial response or better. Collectively, these data provide evidence that ibrutinib controls CLL disease manifestations and is well tolerated for an extended period; this information can help direct potential treatment options for different subgroups to diminish the long-term risk of relapse.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Chromosome Deletion; Disease-Free Survival; Drug Resistance, Neoplasm; Fatigue; Female; Follow-Up Studies; Humans; Hypertension; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Piperidines; Pneumonia; Pyrazoles; Pyrimidines; Recurrence; Remission Induction; Time Factors; Treatment Outcome; Young Adult

It is hypothesized that chronic increase of availability of acetylcholine, resulting from the effect of antiacetylcholinesterases, may prevent autonomic imbalance and reduce inflammation yielding benefic effects for cardiovascular disorders in hypertension. The effect of long-term administration of antiacetylcholinesterase agents with central and/or peripheral action, i.e., donepezil and pyridostigmine, were investigated on arterial pressure (AP), sympathovagal balance, plasma cytokine levels, and cardiac remodeling in spontaneously hypertensive rats (SHR).. Chronic treatment with donepezil or pyridostigmine started before the onset of hypertension. AP was measured by plethysmography every 4 weeks. At the end of 16 weeks of treatment, methylatropine was used to evaluate the cardiac vagal tone; AP and pulse interval (PI) variability were also evaluated followed by plasma and heart collection for analysis.. Pyridostigmine, which does not cross the blood-brain barrier, increased cardiac vagal tone, and reduced cardiomyocyte diameter and collagen density, but did not affect the AP and plasma cytokine levels. Donepezil, which crosses the blood-brain barrier, attenuated the development of hypertension, increased cardiac vagal tone, and improved AP and PI variability. Likewise, donepezil reduced the plasma levels of tumor necrosis factor-α, interleukin 6, and interferon γ, besides reducing cardiomyocyte diameter and collagen density.. Donepezil attenuated the development of hypertension in SHR probably involving antiinflammatory effects, indicating that acetylcholinesterase inhibition yields benefic effects for antihypertensive therapy.

Topics: Animals; Blood Pressure; Cholinesterase Inhibitors; Cytokines; Donepezil; Drug Evaluation, Preclinical; Heart; Heart Rate; Hypertension; Indans; Inflammation; Male; Piperidines; Pyridostigmine Bromide; Rats, Inbred SHR; Rats, Inbred WKY; Ventricular Remodeling

Haemodynamic changes after sympathetic stimuli like tracheal intubation are more pronounced in hypertensive patients than in normotensive patients. Heart rate (HR)-corrected QT (QTc) interval changes related to intubation may also be more prominent in hypertensive patients. We hypothesised that there would be a difference in the effect-site concentration (Ce) of remifentanil to attenuate QTc interval prolongation in normotensive and hypertensive patients following intubation.. Twenty-two normotensive and 22 hypertensive female patients (≥ 50 year) were enrolled and anaesthesised with remifentanil and propofol using a target-controlled infusion. All hypertensive patients received oral antihypertensive medications for > 6 months and took the medications in the morning of the surgery. The effective concentration of remifentanil Ce in 50% (EC50 ) and 95% of the population (EC95 ) required to maintain QTc interval prolongation < 15 ms following intubation was calculated using the isotonic regression and a bootstrapping approach following the Dixon's up-and-down method.. Median duration of hypertension was 6 years. Isotonic regression revealed that the EC50 (83% confidence interval) of remifentanil Ce for reducing QTc interval prolongation following intubation was 3.8 (3.5-4.1) ng/ml in normotensive and 6.1 (5.8-6.2) ng/ml in hypertensive female patients. The EC95 (95% confidence interval) of remifentanil Ce was 4.4 (4.3-4.5) ng/ml in normotensive and 6.5 (6.4-6.5) ng/ml in hypertensive female patients.. The Ce of remifentanil required to attenuate QTc interval prolongation following intubation was significantly higher in hypertensive patients than it was in normotensive patients. Thus, more caution should be taken related to QTc interval prolongation when intubating hypertensive patients.

Topics: Adult; Aged; Electrocardiography; Female; Heart Rate; Humans; Hypertension; Intubation, Intratracheal; Middle Aged; Piperidines; Remifentanil

The effects of chronic blockade of vasopressin type 1a receptors (V1aR) and the additive effects of a type 2 receptor (V2R) antagonist on the treatment of hypertension-induced heart failure and renal injury remain to be unknown. In this study, Dahl salt-sensitive hypertensive rats were chronically treated with a vehicle (CONT), a V1aR antagonist (OPC21268; OPC), a V2R antagonist (tolvaptan; TOLV), or a combination of OPC21268 and tolvaptan (OPC/TOLV) from the pre-hypertrophic stage (6 weeks). No treatment altered blood pressure during the study. Significant improvements were seen in median survival for the OPC and TOLV, and the OPC/TOLV showed a further improvement in Kaplan-Meier analysis. Echocardiography showed suppressed left ventricular hypertrophy in the OPC and OPC/TOLV at 11 weeks with improved function in all treatment groups by 17 weeks. In all treatment groups, improvements were seen in the following: myocardial histological changes, creatinine clearance, urinary albumin excretion, and renal histopathologic damage. Also, key mRNA levels were suppressed (eg, endothelin-1 and collagen). In conclusion, chronic V1aR blockade ameliorated disease progression in this rat model, with additive benefits from the combination of V1aR and V2R antagonists. It was associated with protection of both myocardial and renal damage, independent of blood pressure.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Disease Models, Animal; Drug Therapy, Combination; Fibrosis; Gene Expression Regulation; Heart Failure; Heart Ventricles; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Kidney; Kidney Diseases; Male; Piperidines; Quinolones; Rats, Inbred Dahl; Receptors, Vasopressin; Time Factors; Tolvaptan; Ventricular Function, Left; Ventricular Remodeling

Oxidative stress and neurohumoral factors play important role in the development of hypertension-induced vascular remodeling, likely by disregulating kinase cascades and transcription factors. Oxidative stress activates poly(ADP-ribose)-polymerase (PARP-1), which promotes inflammation and cell death. We assumed that inhibition of PARP-1 reduces the hypertension-induced adverse vascular changes. This hypothesis was tested in spontaneously hypertensive rats (SHR).. Ten-week-old male SHRs and wild-type rats received or not 5mg/kg/day L-2286 (a water-soluble PARP-inhibitor) for 32 weeks, then morphological and functional parameters were determined in their aortas. L-2286 did not affect the blood pressure in any of the animal groups measured with tail-cuff method. Arterial stiffness index increased in untreated SHRs compared to untreated Wistar rats, which was attenuated by L-2286 treatment. Electron and light microscopy of aortas showed prominent collagen deposition, elevation of oxidative stress markers and increased PARP activity in SHR, which were attenuated by PARP-inhibition. L-2286 treatment decreased also the hypertension-activated mitochondrial cell death pathway, characterized by the nuclear translocation of AIF. Hypertension activated all three branches of MAP-kinases. L-2286 attenuated these changes by inducing the expression of MAPK phosphatase-1 and by activating the cytoprotective PI-3-kinase/Akt pathway. Hypertension activated nuclear factor-kappaB, which was prevented by PARP-inhibition via activating its nuclear export.. PARP-inhibition has significant vasoprotective effects against hypertension-induced vascular remodeling. Therefore, PARP-1 can be a novel therapeutic drug target for preventing hypertension-induced vascular remodeling in a group of patients, in whom lowering the blood pressure to optimal range is harmful or causes intolerable side effects.

Topics: Animals; Aorta; Blood Pressure; Cell Death; Collagen; Hypertension; Male; Mitochondria; Mitogen-Activated Protein Kinases; NF-kappa B; Oxidative Stress; Phosphatidylinositol 3-Kinase; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Quinazolines; Rats; Rats, Inbred SHR; Rats, Wistar; Signal Transduction

Mediators of antihypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxy docosapentaenoic acid), is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and antihypertensive arachidonic acid epoxides, epoxyeicosatrienoic acids (EETs). Based in part on plasma levels of EDPs after a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the antihypertensive actions of DHA in angiotensin-II (Ang-II)-dependent hypertension. Treatment individually with 19, 20-EDP and a potent sEH inhibitor TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared with Ang-II-infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected not only most metabolites of the P450 pathway but also renal levels of prostaglandin-E2. Our findings suggest that 19, 20-EDP is a mediator of the antihypertensive effects of DHA in Ang-II-dependent hypertension. It seems that 19, 20-EDP requires metabolic stabilization with a sEH inhibitor to be most effective in lowering BP, although both TPPU and 19, 20-EDP are so effective on their own that demonstrating additive or synergistic interactions is difficult.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Docosahexaenoic Acids; Epoxide Hydrolases; Fatty Acids, Omega-3; Hypertension; Male; Mice; Phenylurea Compounds; Piperidines

Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3β(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3β(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/βII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.

Topics: Animals; Blood Pressure; Extracellular Signal-Regulated MAP Kinases; Forkhead Transcription Factors; Gene Expression Regulation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart Failure; HSP90 Heat-Shock Proteins; Hypertension; Hypertrophy, Left Ventricular; Isoenzymes; Male; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Phosphorylation; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Kinase C; Proto-Oncogene Proteins c-akt; Quinazolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.

Topics: Administration, Oral; Amides; Animals; Blood Pressure; Disease Models, Animal; Furosemide; Half-Life; Hypertension; Macaca fascicularis; Piperazines; Piperidines; Protease Inhibitors; Rats; Rats, Transgenic; Renin; Structure-Activity Relationship

Subtle perturbations in intraglomerular VEGF/VEGFR-2 signaling or in the influencing microenvironment can profoundly affect renal function, resulting in the apparently paradoxical observation that VEGF blockade attenuates proteinuria development in experimental diabetes despite exerting the opposite effect under other circumstances. In the present study, we sought to explore the role of eNOS-NO activity in regulating the differential response to VEGF blockade in the diabetic and nondiabetic settings. In a rodent model of accelerated renal injury, the transgenic (mRen-2)27 (Ren-2) rat, VEGFR-2 inhibition with the small molecule vandetanib resulted in an increase in urine protein excretion preceding a subsequent rise in systolic blood pressure. When compared to their normoglycaemic counterparts, diabetic Ren-2 rats exhibited an increase in the renal expression of eNOS and in urinary excretion of nitric oxide (NO) metabolites. In contrast to the heavy proteinuria observed with vandetanib in nondiabetic TGR(mRen-2)27 rats, VEGFR-2 inhibition reduced urine protein excretion in diabetic animals, despite a comparable magnitude of histological injury. However, proteinuria was markedly increased by concomitant treatment of diabetic Ren-2 rats with vandetanib and the nitric oxide synthase inhibitor L-NAME. These observations highlight the pivotal role that the eNOS-NO system plays in regulating the biologic response to VEGF within the glomerulus.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Hypertension; Kidney; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Piperidines; Proteinuria; Quinazolines; Rats; Receptors, Vascular Endothelial Growth Factor; Systole

Endocannabinoids are among the most intensively studied lipid mediators of cardiovascular functions. In the present study the effects of decreased and increased activity of the endocannabinoid system (achieved by cannabinoid-1 (CB1) receptor blockade and inhibition of cannabinoid reuptake, respectively) on the systemic and cerebral circulation were analyzed under steady-state physiological conditions and during hypoxia and hypercapnia (H/H).. In anesthetized spontaneously ventilating rats the CB1-receptor antagonist/inverse agonist AM-251 (10 mg/kg, i.v.) failed to influence blood pressure (BP), cerebrocortical blood flow (CoBF, measured by laser-Doppler flowmetry) or arterial blood gas levels. In contrast, the putative cannabinoid reuptake inhibitor AM-404 (10 mg/kg, i.v.) induced triphasic responses, some of which could be blocked by AM-251. Hypertension during phase I was resistant to AM-251, whereas the concomitant CoBF-increase was attenuated. In contrast, hypotension during phase III was sensitive to AM-251, whereas the concomitant CoBF-decrease was not. Therefore, CoBF autoregulation appeared to shift towards higher BP levels after CB1-blockade. During phase II H/H developed due to respiratory depression, which could be inhibited by AM-251. Interestingly, however, the concomitant rise in CoBF remained unchanged after AM-251, indicating that CB1-blockade potentially enhanced the reactivity of the CoBF to H/H. In accordance with this hypothesis, AM-251 induced a significant enhancement of the CoBF responses during controlled stepwise H/H.. Under resting physiological conditions CB1-receptor mediated mechanisms appear to have limited influence on systemic or cerebral circulation. Enhancement of endocannabinoid levels, however, induces transient CB1-independent hypertension and sustained CB1-mediated hypotension. Furthermore, enhanced endocannabinoid activity results in respiratory depression in a CB1-dependent manner. Finally, our data indicate for the first time the involvement of the endocannabinoid system and CB1-receptors in the regulation of the cerebral circulation during H/H and also raise the possibility of their contribution to the autoregulation of CoBF.

Topics: Animals; Arachidonic Acids; Arterial Pressure; Cerebrovascular Circulation; Endocannabinoids; Heart Rate; Hemodynamics; Hypercapnia; Hypertension; Hypoxia; Laser-Doppler Flowmetry; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.

Topics: Animals; Antihypertensive Agents; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dogs; Ether-A-Go-Go Potassium Channels; Humans; Hypertension; Piperidines; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Structure-Activity Relationship

In the vascular system angiotensin II (Ang II) causes vasoconstriction via the activation of type 1 angiotensin receptors. Earlier reports have shown that in cellular expression systems diacylglycerol produced during type 1 angiotensin receptor signaling can be converted to 2-arachidonoylglycerol, an important endocannabinoid. Because activation of CB(1) cannabinoid receptors (CB(1)R) induces vasodilation and reduces blood pressure, we have tested the hypothesis that Ang II-induced 2-arachidonoylglycerol release can modulate its vasoconstrictor action in vascular tissue. Rat and mouse skeletal muscle arterioles and mouse saphenous arteries were isolated, pressurized, and subjected to microangiometry. Vascular expression of CB(1)R was demonstrated using Western blot and RT-PCR. In accordance with the functional relevance of these receptors WIN55212, a CB(1)R agonist, caused vasodilation, which was absent in CB(1)R knock-out mice. Inhibition of CB(1)Rs using O2050, a neutral antagonist, enhanced the vasoconstrictor effect of Ang II in wild type but not in CB(1)R knock-out mice. Inverse agonists of CB(1)R (SR141716 and AM251) and inhibition of diacylglycerol lipase using tetrahydrolipstatin also augmented the Ang II-induced vasoconstriction, suggesting that endocannabinoid release modulates this process via CB(1)R activation. This effect was independent of nitric-oxide synthase activity and endothelial function. These data demonstrate that Ang II stimulates vascular endocannabinoid formation, which attenuates its vasoconstrictor effect, suggesting that endocannabinoid release from the vascular wall and CB(1)R activation reduces the vasoconstrictor and hypertensive effects of Ang II.

Topics: Analgesics; Angiotensin II; Animals; Arteries; Benzoxazines; Endocannabinoids; Endothelium, Vascular; Hypertension; Male; Mice; Mice, Knockout; Morpholines; Muscle, Skeletal; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Vasoconstriction

Substance P (SP), a neurokinin-1 receptor (NK-1R) agonist, is mainly produced and stored in primary sensory nerves and, upon its release, participates in cardiovascular and renal functional regulation. This study tests the hypothesis that activation of the NK-1Rs by SP occurs during hypertension induced by deoxycorticosterone (DOCA)-salt treatment, which contributes to renal injury in this model. C57BL/6 mice were subjected to uninephrectomy and DOCA-salt treatment in the presence or absence of administration of selective NK-1 antagonists, L-733,060 (20 mg/kg·d, ip) or RP-67580 (8 mg/kg·d, ip). Five weeks after the treatment, mean arterial pressure determined by the telemetry system increased in DOCA-salt mice but without difference between NK-1R antagonist-treated or NK-1R antagonist-untreated DOCA-salt groups. Plasma SP levels were increased in DOCA-salt compared with control mice (P < 0.05). Renal hypertrophy and increased urinary 8-isoprostane and albumin excretion were observed in DOCA-salt compared with control mice (P < 0.05). Periodic acid-Schiff and Masson's trichrome staining showed more severe glomerulosclerosis and tubulointerstitial injury in the renal cortex in DOCA-salt compared with control mice, respectively (P < 0.05). Hydroxyproline assay and F4/80-staining showed that renal collagen levels and interstitial monocyte/macrophage infiltration were greater in DOCA-salt compared with control mice, respectively (P < 0.05). Blockade of the NK-1R with L-733,060 or RP-67580 in DOCA-salt mice suppressed increments in urinary 8-isoprostane and albumin excretion, interstitial monocyte/macrophage infiltration, and glomerulosclerosis and tubulointerstitial injury and fibrosis (P < 0.05). Thus, our data show that blockade of the NK-1Rs alleviates renal functional and tissue injury in the absence of alteration in blood pressure in DOCA-salt-hypertensive mice. The results suggest that elevated SP levels during DOCA-salt hypertension play a significant role contributing to renal damage possibly via enhancing oxidative stress and macrophage infiltration of the kidney.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Hydroxyproline; Hypertension; Isoindoles; Kidney; Male; Mice; Mice, Inbred C57BL; Piperidines; Receptors, Neurokinin-1; Substance P; Telemetry; Time Factors

Oxidative stress in the brain is implicated in increased sympathetic drive, inflammatory status, and vascular dysfunctions, associated with development and establishment of hypertension. However, little is known about the mechanism of this impaired brain-vascular communication. Here, we tested the hypothesis that increased oxidative stress in the brain cardioregulatory areas, such as the paraventricular nucleus of the hypothalamus, is driven by mitochondrial reactive oxygen species and leads to increased inflammatory cells (ICs) and decreased/dysfunctional endothelial progenitor cells (EPCs), thereby compromising vasculature repair and accelerating hypertension. Chronic angiotensin II infusion resulted in elevated blood pressure and sympathetic vasomotor drive, decreased spontaneous baroreflex gain, and increased microglia activation in the paraventricular nucleus. This was associated with 46% decrease in bone marrow (BM)-derived EPCs and 250% increase in BM ICs, resulting in 5-fold decrease of EPC/IC ratio in the BM. Treatment with mitochondrial-targeted antioxidant, a scavenger of mitochondrial O(2)(-·), intracerebroventricularly but not subcutaneously attenuated angiotensin II-induced hypertension, decreased activation of microglia in the paraventricular nucleus, and normalized EPCs/ICs. This functional communication between the brain and BM was confirmed by retrograde neuronal labeling from the BM with green fluorescent protein-tagged pseudorabies virus. Administration of green fluorescent protein-tagged pseudorabies virus into the BM resulted in predominant labeling of paraventricular nucleus neurons within 3 days, with some fluorescence in the nucleus tractus solitarius, the rostral ventrolateral medulla, and subfornical organ. Taken together, these data demonstrate that inhibition of mitochondrial reactive oxygen species attenuates angiotensin II-induced hypertension and corrects the imbalance in EPCs/ICs in the BM. They suggest that an imbalance in vascular reparative and ICs may perpetuate vascular pathophysiology in this model of hypertension.

Topics: Angiotensin II; Animals; Animals, Newborn; Autonomic Nervous System; Blood Pressure; Bone Marrow; Brain; Cells, Cultured; Endothelial Cells; Flow Cytometry; Green Fluorescent Proteins; Hematopoietic Stem Cells; Hypertension; Infusions, Intraventricular; Lymphocytes; Macrophages; Male; Neurons; Organophosphorus Compounds; Paraventricular Hypothalamic Nucleus; Piperidines; Rats; Rats, Sprague-Dawley

The aim was to investigate effects of selective endothelin (ET) receptor antagonists on renal hemodynamics and dynamic renal blood flow autoregulation (RBFA) in angiotensin II (Ang II)-infused rats on a high NaCl intake.. Sprague-Dawley rats received Ang II (250 ng/kg/min, s.c.) and an 8% NaCl diet for 14 days after which renal clearance experiments were performed. After baseline measurements animals were administered either: (a) saline vehicle; (b) ETA receptor antagonist BQ-123 (30 nmol/kg/min); (c) ETB receptor antagonist BQ-788 (30 nmol/kg/min); or (d) BQ-123 + BQ-788, for six consecutive 20-minute clearance periods.. BQ-123 reduced arterial pressure (AP) and selectively increased outer medullary perfusion versus vehicle (p<0.05). These effects were attenuated or abolished by combined BQ-123 and BQ-788. BQ-788 reduced renal blood flow and increased renovascular resistance (p<0.05). Ang II-infused rats on high NaCl intake showed abnormalities in dynamic RBFA characterized by an impaired myogenic response that were not significantly affected by ET receptor antagonists.. In hypertensive Ang II-infused rats on a high-NaCl intake selective ETA antagonism with BQ-123 reduced AP and specifically increased OM perfusion and these effects were dependent on intact ETB receptor stimulation. Furthermore, ET receptor antagonists did not attenuate abnormalities in dynamic RBFA.

Topics: Angiotensin II; Animals; Blood Pressure; Disease Models, Animal; Endothelin Receptor Antagonists; Hemodynamics; Hypertension; Kidney; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sodium Chloride, Dietary

Both severe hypokalemia and persistent hypertension are clinical symptoms of hyperaldosteronism. Hyperaldosteronism may occur as a primary or secondary syndrome. Excess ACTH produced ectopically by tumors may induce hyperaldosteronism through the mineralocorticoid activity of glucocorticoids that are upregulated by ACTH. Licorice, with the active ingredient glycyrrhiza, is also a well-known inducer of hyperaldosteronism under specific conditions. In this report, we describe a case of severe hypokalemia caused by ectopic ACTH syndrome (EAS) elicited by an intrathoracic carcinoid tumor, which had transformed to produce ACTH during the 6-year clinical course, and was modulated by licorice ingestion. Hypokalemia was not clearly recognized preoperatively but became obvious within 3 h of general anesthesia with epidural blockade. At the end of anesthesia, arterial blood gas analysis indicated severe hypokalemia ([K(+)] = 1.7 mEq/l) and metabolic alkalosis (pH 7.56, PaCO(2) = 54.9 mmHg, HCO(3)(-) = 44.5 mmol/l, BE = 21.8 mmol/l), without any typical symptoms such as muscle weakness or ECG abnormalities. The hypokalemia was resistant to potassium supplementation and persisted for 4 days. Perioperative imbalance between the administration and elimination of potassium and surgical stress might contribute to the rapid exacerbation and induce the clinical manifestation of EAS.

Topics: ACTH Syndrome, Ectopic; Adjuvants, Anesthesia; Anesthesia; Anesthetics, Intravenous; Blood Gas Analysis; Blood Pressure; Carcinoid Tumor; Fentanyl; Heart Rate; Hormones; Humans; Hypertension; Hypokalemia; Male; Middle Aged; Nicardipine; Perioperative Period; Piperidines; Pneumonia, Pneumocystis; Psychotic Disorders; Remifentanil; Thoracic Neoplasms; Tomography, X-Ray Computed

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

Topics: Catalysis; Cresols; Cyclopropanes; Enzyme Inhibitors; Hydrogenation; Hypertension; Molecular Structure; Piperidines; Pyridines; Renin; Stereoisomerism

Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP-competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Amines; Animals; Disease Models, Animal; Hypertension; Isoquinolines; Models, Chemical; Models, Molecular; Piperidines; Protein Kinase Inhibitors; Quinolones; Rats; rho-Associated Kinases; Structure-Activity Relationship

In eight studies included in the present Cochrane review the effects of orlistat or sibutramine versus placebo on mortality, cardiovascular mortality and adverse events were investigated in obese people with hypertension. No studies with rimonabant fulfilled the inclusion criteria. The weight loss was larger in the groups treated with orlistat or sibutramine compared with placebo therapy. Orlistat reduced systolic and diastolic blood pressure more than placebo, while blood pressure increased during treatment with sibutramine. The studies were too small and of too short duration to allow an evaluation of the effect on cardiovascular mortality and morbidity.

Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Blood Pressure; Cardiovascular Diseases; Cyclobutanes; Evidence-Based Medicine; Humans; Hypertension; Lactones; Obesity; Orlistat; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Time Factors; Treatment Outcome; Weight Loss

An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.

Topics: Animals; Dogs; Drug Design; Enzyme Inhibitors; Hypertension; Inhibitory Concentration 50; Models, Molecular; Molecular Structure; Piperidines; Pyridones; Rats; Renin; Structure-Activity Relationship

The design and optimization of a novel series of renin inhibitor is described herein. Strategically, by committing the necessary resources to the development of synthetic sequences and scaffolds that were most amenable for late stage structural diversification, even as the focus of the SAR campaign moved from one end of the molecule to another, highly potent renin inhibitors could be rapidly identified and profiled.

Topics: Alcohols; Animals; Antihypertensive Agents; Drug Design; Hypertension; Molecular Structure; Piperidines; Rats; Renin; Structure-Activity Relationship

We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Calcium Channels, T-Type; Cell Line; Guinea Pigs; Humans; Hypertension; Male; Piperidines; Rats; Rats, Inbred SHR; Structure-Activity Relationship

The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.

Topics: Animals; Antihypertensive Agents; Binding Sites; Catalytic Domain; Computer Simulation; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dogs; Drug Design; Humans; Hypertension; Macaca mulatta; Piperidines; Protease Inhibitors; Rats; Renin; Spiro Compounds; Structure-Activity Relationship

Expression of the vasoconstrictor and proinflammatory peptide endothelin (ET)-1 is increased in insulin-resistant (IR) subjects.. The aim of this study was to investigate whether ET-1 regulates skeletal muscle glucose uptake in IR subjects in vivo and in cultured human skeletal muscle cells.. Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ET(A) and ET(B) receptor antagonist, respectively), followed by coinfusion with insulin (0.05 mU/kg/min); B) insulin alone; and C) insulin followed by coinfusion with ET-1 (20 pmol/min).. Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells.. ET(A)/ET(B) receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ET(A)/ET(B) receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ET(A)/ET(B) receptor blockade increased FBF by 30% (P < 0.05), with a further 16% increase (P < 0.01) during insulin coinfusion. ET-1 decreased basal FBF by 35% without affecting FGU. ET-1 impaired basal and insulin-stimulated glucose uptake in cultured muscle cells (P < 0.01) via an effect that was prevented by ET(A)/ET(B) receptor blockade.. ET(A)/ET(B) receptor blockade enhances basal and insulin-stimulated glucose uptake in IR subjects. ET-1 directly impairs glucose uptake in skeletal muscle cells via a receptor-dependent mechanism. These data suggest that ET-1 regulates glucose metabolism via receptor-dependent mechanisms in IR subjects.

Topics: Biological Transport; Blood Glucose; Body Mass Index; Brachial Artery; C-Reactive Protein; Endothelin-1; Forearm; Glucose; Glycated Hemoglobin; Humans; Hypertension; Infusions, Intra-Arterial; Insulin; Insulin Resistance; Male; Middle Aged; Muscle, Skeletal; Oligopeptides; Peptides, Cyclic; Piperidines; Regional Blood Flow; Triglycerides

Brain-derived neurotrophic factor (BDNF) regulates food intake and body weight, but is not useful as a therapeutic because of its short half-life. Chronic activation of its receptor, tyrosine kinase receptor B (TrkB), represents an alternative strategy for lowering body weight. However, because BDNF can raise blood pressure (BP) acutely, it is possible that chronic TrkB activation will produce adverse cardiovascular effects.. We used radiotelemetry to test whether treatment with a TrkB agonist antibody (Ab) causes adverse cardiovascular effects in mice with diet-induced obesity.. High-dose (1 mg/kg) TrkB Ab reduced body weight and significantly increased BP, whereas low-dose (0.3 mg/kg) treatment lowered body weight without adverse cardiovascular effects. Rimonabant, through a different mechanism of action, lowered body weight in this model more than TrkB activation, but showed no adverse effects on heart rate (HR) or BP. These data suggest that elevated BP was a direct effect of high-dose TrkB Ab treatment rather than secondary to substantial weight loss.. Overall, high-dose TrkB Ab lowered body weight and increased BP, whereas low-dose TrkB Ab treatment caused therapeutic weight loss without adverse cardiovascular effects. We conclude that TrkB activation dose-dependently lowers body weight and transiently raises BP in mice with diet-induced obesity.

Topics: Animals; Anti-Obesity Agents; Antibodies, Monoclonal; Blood Pressure; Body Weight; Brain-Derived Neurotrophic Factor; Diet; Dietary Fats; Hypertension; Mice; Mice, Inbred C57BL; Obesity; Piperidines; Pyrazoles; Receptor, trkB; Rimonabant; Telemetry; Weight Loss

The presented study is aimed on exploring the effects of black pepper on blood pressure in the rat model of experimental hypertension induced by chronic NO synthesis inhibition.. Piperine, the compound of black pepper, can cause a significant decrease of blood pressure in normotensive rats possibly via calcium channel blockade, a pathway that is known to be effective in prevention of L-NAME (N(G)-nitro-L-arginine methyl ester) induced hypertension.. Wistar rats were administered clear water (C), L-NAME (40 mg/kg/day, L), piperine (20 mg/kg/day) in corn oil by oral gavage with L-NAME (LP) or without it (P) for 6 weeks. The systolic blood pressure was measured weekly. Specimens of thoracic aorta were processed in paraffin and histological slices were stained with hematoxylin and eosin, Mallory's phosphotungstic acid hematoxylin (PTAH), orcein, antibodies against inducible NO synthase (iNOS) and smooth muscle cells actin (SMCA). Microscopic pictures were digitally processed and morphometrically evaluated.. L-NAME increased the blood pressure, cross-sectional area of aorta, media thickness, elastin and SMCA synthesis and PTAH positive myofibrils relative and absolute content in the aortic media, wheras it decreased percentual content of iNOS, elastin and SMCA. Piperine decreased the blood pressure rise from the third week of treatment, synthesis of elastin and the percentual and absolute content of PTAH positive myofibrils, however, it did not affect other parameters.. Oral administration of piperine is able to partially prevent the increase of blood pressure caused by chronic L-NAME administration. This effect is probably caused by the blockage of voltage-dependent calcium channels and supported by filamentous actin disassembly (Tab. 1, Fig. 2, Ref. 35).

Topics: Alkaloids; Animals; Antibodies; Aorta, Thoracic; Benzodioxoles; Blood Pressure; Elastin; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

A 54-year-old man had emergency laparoscopic chelecystectomy for acute cholecystitis. General inflammatory change (CRP 26.6 mg x dl(-1), WBC 26,800) was noted preoperatively. Anesthesia was induced with propofol and remifentanil and maintained with sevoflurane in oxygen and remifentanil. Operation was performed uneventfully within 128 min. At the end of the surgery, 0.1 mg of fentanyl was administrated. After confirming adequate respiration and oxygenation, endotracheal tube was removed. At that period, hypertension (SBP 220 mmHg) and tachycardia (HR 122 beats x min(-1)) developed. Soon thereafter, he became agitated and complained of dyspnea with desaturation (Spo2 < 70%). After reintubation, massive pinkish babbly secretion flowed out from the endotracheal tube. Chest X-ray revealed diffuse bilateral infiltration of the lungs without cardiomegaly. He was transferred to the intensive care unit for mechanical ventilation. His condition improved progressively and was extubated on the POD 6. The cause of pulmonary edema is thought to be profound centralization of circulating volume associated with catecholamine-induced vasoconstriction due to rapid disappearance of remifentanil effect. Adequate analgesia is necessary during remifentanil-based anesthesia especially in patients suffering from general inflammatory changes.

Topics: Aged; Anesthesia; Anesthesia Recovery Period; Cholecystectomy, Laparoscopic; Cholecystitis, Acute; Humans; Hypertension; Intubation, Intratracheal; Male; Perioperative Care; Piperidines; Postoperative Complications; Pulmonary Edema; Remifentanil

To investigate the respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome after sedation interruption.. Prospective, interventional, single-center study in 30 ventilated ICU patients.. Metabolic [oxygen consumption (VO(2)), CO(2) production (VCO(2)), resting energy expenditure (REE)], respiratory [minute ventilation (V (E)), tidal volume (V (T)), respiratory rate (RR)] and hemodynamic (HR, SAP, MAP) parameters were measured in 30 ventilated ICU patients. Measurements were performed first under sedation with remifentanil-propofol, then after sedation interruption, and finally after clonidine administration (0.9-1.8 mg of clonidine in two doses of 10 min interval).. Sedation interruption produced significant increases in the hemodynamic parameters (SAP and MAP by 33%, HR by 37%), and metabolic rate (increase in VO(2) by 70%, VCO(2) by 88% and REE by 74%), leading to high respiratory demands (increase in V (E) from 9 to 15 l/min). The V (E) was increased due to a twofold increase in the RR; V (T) remained constant. In 25 out of 30 patients, clonidine administration decreased the hemodynamic (SAP, MAP and HR), metabolic (VO(2), VCO(2), REE) and respiratory parameters to values close to those observed with sedation. Clonidine induced mild sedation and patients became more cooperative with the ventilator. All patients responding to clonidine were weaned from the ventilator in 2 days (median, range 1-18 days).. Patients with withdrawal syndrome had significantly elevated hemodynamic, metabolic and respiratory demands. Clonidine significantly decreased these demands, induced mild sedation and facilitated patient cooperation with the ventilator, enabling ventilator weaning.

Topics: Adrenergic alpha-Agonists; Adult; Calorimetry, Indirect; Carbon Dioxide; Clonidine; Electrocardiography; Energy Metabolism; Female; Hemodynamics; Humans; Hypertension; Hypnotics and Sedatives; Male; Oxygen Consumption; Piperidines; Propofol; Prospective Studies; Remifentanil; Respiration, Artificial; Respiratory Insufficiency; Rest; Substance Withdrawal Syndrome; Tachycardia; Ventilator Weaning

The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.. We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.. Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].. These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.

Topics: Acute Disease; Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Benzoxazines; Blood Pressure; Cannabinoids; Carbamates; Consciousness; Endocannabinoids; Hindlimb; Hypertension; Infusions, Intravenous; Injections, Intravenous; Male; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Splanchnic Circulation; Vascular Resistance; Vasodilation

Oxidative stress followed by abnormal signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF.. SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L). At the beginning of the study, systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study, eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (P < 0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (P < 0.01) and favourably influenced all the measured gravimetric parameters (P < 0.05) and the extent of myocardial fibrosis (P < 0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (P < 0.05).. These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs.

Topics: Administration, Oral; Animals; Blood Pressure; Cardiovascular Agents; Disease Models, Animal; Disease Progression; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart Failure; Hypertension; Hypertrophy, Left Ventricular; Isoenzymes; JNK Mitogen-Activated Protein Kinases; Male; Myocardium; Natriuretic Peptide, Brain; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Piperidines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Kinase C; Proto-Oncogene Proteins c-akt; Quinazolines; Rats; Rats, Inbred SHR; Signal Transduction; Time Factors; Ventricular Function, Left; Ventricular Remodeling

We examined the hemodynamic responses to tracheal intubation during anesthetic induction by inhalational sevoflurane with continuous administration of remifentanil.. This study enrolled 30 ASA physical status 1-2 patients, aged 20-65 undergoing elective surgical procedure. Anesthesia was induced with 5% sevoflurane in all patients, and then adjusted to maintain BIS values ranging from 40 to 60. Remifentanil at the rate of 0.5 microg x kg(-1) x min(-1) was administrated continuously, and tracheal intubation was performed by each anesthesiologist, at various times after administration of remifentanil. We recorded blood pressure (BP), heart rate (HR) and the duration between the initiation of an administration of remifentanil and a tracheal intubation (DRI). Sympathetic response to tracheal intubation was defined as more than 20% increase in either BP or HR at the intubation compared with that at preintubation. We analyzed the P50, representing the duration of remifentanil infusion with 50% probability of blocking sympathetic response to tracheal intubation.. DRI for individual patients varied from 77 sec up to 660 sec. According to the present data, P50 was calculated as 210 +/- 16.4 sec (mean +/- SD).. During sevoflurane anesthesia, remifentanil infusion at 0.5 microg x kg(-1) x min(-1) for more than 210 sec could provide the effective blocking of the sympathetic response to tracheal intubation with more than 50% probability.

Topics: Adult; Aged; Anesthesia, Inhalation; Anesthetics, Intravenous; Elective Surgical Procedures; Female; Hemodynamics; Humans; Hypertension; Intraoperative Complications; Intubation, Intratracheal; Male; Methyl Ethers; Middle Aged; Piperidines; Remifentanil; Sevoflurane; Sympathetic Nervous System; Time Factors; Young Adult

3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blood Pressure; Epoxide Hydrolases; Humans; Hypertension; Models, Molecular; Piperidines; Protein Binding; Rats; Rats, Inbred SHR; Structure-Activity Relationship; Urea

We have reported that eucapnic intermittent hypoxia (E-IH) causes systemic hypertension, elevates plasma endothelin 1 (ET-1) levels, and augments vascular reactivity to ET-1 and that a nonspecific ET-1 receptor antagonist acutely lowers blood pressure in E-IH-exposed rats. However, the effect of chronic ET-1 receptor inhibition has not been evaluated, and the ET receptor subtype mediating the vascular effects has not been established. We hypothesized that E-IH causes systemic hypertension through the increased ET-1 activation of vascular ET type A (ET(A)) receptors. We found that mean arterial pressure (MAP) increased after 14 days of 7 h/day E-IH exposure (109 +/- 2 to 137 +/- 4 mmHg; P < 0.005) but did not change in sham-exposed rats. The ET(A) receptor antagonist BQ-123 (10 to 1,000 nmol/kg iv) acutely decreased MAP dose dependently in conscious E-IH but not sham rats, and continuous infusion of BQ-123 (100 nmol.kg(-1).day(-1) sc for 14 days) prevented E-IH-induced increases in MAP. ET-1-induced constriction was augmented in small mesenteric arteries from rats exposed 14 days to E-IH compared with those from sham rats. Constriction was blocked by the ET(A) receptor antagonist BQ-123 (10 microM) but not by the ET type B (ET(B)) receptor antagonist BQ-788 (100 microM). ET(A) receptor mRNA content was greater in renal medulla and coronary arteries from E-IH rats. ET(B) receptor mRNA was not different in any tissues examined, whereas ET-1 mRNA was increased in the heart and in the renal medulla. Thus augmented ET-1-dependent vasoconstriction via vascular ET(A) receptors appears to elevate blood pressure in E-IH-exposed rats.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Infusions, Parenteral; Male; Mesenteric Arteries; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renal Artery; Time Factors; Vasoconstriction

Recent evidence has suggested that pilocarpine (ACh receptor agonist) injected peripherally may act centrally producing salivation and hypertension. In this study, we investigated the effects of specific M(1) (pirenzepine), M(2)/M(4) (methoctramine), M(1)/M(3) (4-DAMP) and M(4) (tropicamide) muscarinic receptor subtype antagonists injected into the lateral cerebral ventricle (LV) on salivation, water intake and pressor responses to peripheral pilocarpine.. Male Holtzman rats with stainless steel cannulae implanted in the LV were used. Salivation was measured in rats anaesthetized with ketamine (100 mg per kg body weight) and arterial pressure was recorded in unanaesthetized rats.. Salivation induced by i.p. pilocarpine (4 micromol per kg body weight) was reduced only by 4-DAMP (25-250 nmol) injected into the LV, not by pirenzepine, methoctramine or tropicamide at the dose of 500 nmol. Pirenzepine (0.1 and 1 nmol) and 4-DAMP (5 and 10 nmol) injected into the LV reduced i.p. pilocarpine-induced water intake, whereas metoctramine (50 nmol) produced nonspecific effects on ingestive behaviours. Injection of pirenzepine (100 nmol) or 4-DAMP (25 and 50 nmol) into the LV reduced i.v. pilocarpine-induced pressor responses. Tropicamide (500 nmol) injected into the LV had no effect on pilocarpine-induced salivation, pressor responses or water intake.. The results suggest that central M(3) receptors are involved in peripheral pilocarpine-induced salivation and M(1) receptors in water intake and pressor responses. The involvement of M(3) receptors in water intake and pressor responses is not clear because 4-DAMP blocks both M(1) and M(3) receptors.

Topics: Animals; Blood Pressure; Diamines; Drinking Behavior; Heart Rate; Hypertension; Injections, Intraventricular; Male; Muscarinic Antagonists; Pilocarpine; Piperidines; Pirenzepine; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Saliva; Tropicamide

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40+/-0.5 degrees C and 75+/-5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 microg/cm(2)/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-à-vis marketed tablet (AUC(0 to t) : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.

Topics: Acrylates; Administration, Cutaneous; Animals; Antihypertensive Agents; Biological Availability; Blood Pressure; Disease Models, Animal; Drug Stability; Drug Storage; Enalapril; Excipients; Female; Hypertension; Male; Permeability; Piperidines; Polymers; Povidone; Rats; Skin Absorption

Since the vasorelaxant potency of the endocannabinoid anandamide is enhanced in perfused mesenteric vascular beds from rats made hypertensive by chronic inhibition of NO synthase (L-NAME in drinking water), we hypothesized that in vivo, anandamide-induced vasodilatation would be similarly enhanced in L-NAME-treated animals.. Male Sprague-Dawley rats were given L-NAME in drinking water (7.5 mg kg(-1) day(-1)) for 4 weeks. Relaxant effects of anandamide were measured in perfused mesenteric vascular beds and in isolated small mesenteric arteries. Renal, mesenteric and hindquarters haemodynamic responses to anandamide, methanandamide, the synthetic cannabinoid agonist WIN-55212-2 and the cannabinoid receptor antagonist AM251 were assessed in conscious, chronically-instrumented rats.. Vasorelaxant responses to anandamide were enhanced in the perfused mesentery but not in isolated mesenteric resistance vessels. In vivo, anandamide caused vasodilatation only in the hindquarters vascular bed and only in control rats. Methanandamide caused a late-onset (40 min after administration) tachycardia, mesenteric and hindquarters vasoconstriction, and renal vasodilatation, which did not differ between control and L-NAME-treated rats. AM251 had no effect on resting blood pressure in control or L-NAME-treated rats and WIN55212-2 caused pressor and renal and mesenteric vasoconstrictor responses, with hindquarters vasodilatation in both groups of animals.. The results provide no in vivo evidence for enhanced vasodilator responses to cannabinoids, or up-regulation of endocannabinoids or their receptor activity, following chronic NO synthase inhibition.

Topics: Animals; Arachidonic Acids; Benzoxazines; Blood Pressure; Cannabinoids; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Enzyme Inhibitors; Heart Rate; Hypertension; Male; Mesenteric Arteries; Morpholines; Muscle, Skeletal; Naphthalenes; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Renal Circulation; Splanchnic Circulation; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation; Vasodilator Agents

The hypertension induced by haemoglobin-based oxygen carriers could be a result of different pharmacological and physicochemical factors.. To investigate whether production of superoxide anion (O2*-) and release of endothelin could be the factors responsible.. We studied the variation in mean arterial pressure (MAP) in guinea pigs by carrying out a 50% isovolaemic exchange transfusion with conjugated oxyhaemoglobin (non-oxidized form) or conjugated methaemoglobin (fully oxidized form) in the presence or absence of BQ-788 (5 nmol/l), an endothelin receptor type B (ETR-B) antagonist. At key timepoints of variation in MAP, the plasma concentrations of O2*- were measured. The presence of conjugated oxyhaemoglobin and increases in ETR-B concentrations inside the vascular wall were investigated in different vessels, using western blotting.. We found that the administration of conjugated oxyhaemoglobin induced a significant increase in MAP, whereas conjugated methaemoglobin had no significant haemodynamic effect. Pretreatment with BQ-788 attenuated the increase in MAP induced by conjugated oxyhaemoglobin. This haemoglobin induced the production of high concentrations of O2*- that declined towards control values after 120 min and decreased in the presence of BQ-788. Western blot analysis showed that the presence of conjugated oxyhaemoglobin inside the vascular wall was time-dependent and correlated with increased ETR-B.. These results show that the release of O2*- during auto-oxidation of conjugated oxyhaemoglobin is associated with the observed increase in MAP, which may be a result of the vasoconstriction caused by an increase in activation of ETR-B. This activation may be caused by the massive release of endothelin induced by the production of O2*-.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood Substitutes; Endothelins; Guinea Pigs; Hypertension; Male; Methemoglobin; Oligopeptides; Oxyhemoglobins; Piperidines; Receptor, Endothelin B; Superoxides

Evidence suggests that Delta9-tetrahydrocannabinol (THC) may have antihypertensive effects and that the vasodilator effect of endocannabinoids is enhanced in rats made hypertensive by chronic NO synthase inhibition. Therefore, the aims of the present study were to investigate whether the in vitro and in vivo cardiovascular responses to THC are altered by Nomega-nitro-L-arginine methyl ester (L-NAME) treatment. The vasorelaxant effects of THC were enhanced in small mesenteric arteries from L-NAME-treated rats. This enhanced response was not inhibited by cannabinoid CB1 receptor antagonism [1 microM N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM251]. Pretreating vessels with the transient receptor potential vanilloid receptor receptor agonist capsaicin at 10 microM for 1 h reduced vasorelaxation to THC to a greater extent in L-NAME-treated than control rats. Inhibition of cyclooxygenase with 10 microM indomethacin inhibited THC responses in arteries from L-NAME-treated rats but not from control rats. In conscious, chronically instrumented rats, 1 mg kg-1 i.v. THC caused a pressor effect, with vasoconstriction of the renal and mesenteric vascular beds, and hindquarters vasodilatation. Pretreatment with 3 mg kg-1 i.v. AM251 reduced the pressor and vasoconstrictor effects of THC, abolished the hindquarters vasodilatation, and revealed a bradycardic response. L-NAME-treated rats showed similar pressor and vasoconstrictor responses to THC, but with bradycardia, and reduced hindquarter vasodilatation. These data show that, in vitro, isolated arteries of L-NAME-treated rats show enhanced vasorelaxant responses to THC through an increased sensory nerve component and stimulation of prostanoids. However, in vivo, THC causes a CB1 receptor-mediated pressor effect with hindquarters vasodilatation. There was no evidence of enhanced vasodilator effects of THC in L-NAME-treated animals in vivo.

Topics: Animals; Blood Pressure; Dronabinol; Enzyme Inhibitors; Heart Rate; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Vasodilation

Topics: Anesthesia, General; Bundle-Branch Block; Dermatomyositis; Dyslipidemias; Epoprostenol; Female; Fentanyl; Furosemide; Humans; Hypertension; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Mediastinal Diseases; Mediastinoscopy; Methyl Ethers; Middle Aged; Oxygen Inhalation Therapy; Piperidines; Preoperative Care; Raynaud Disease; Remifentanil; Sevoflurane; Spironolactone

We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension.. Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure.. Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%).. This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.

Topics: Animals; Aorta, Thoracic; Endothelin-1; Hypertension; Hypoxia; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Vasoconstriction

Topics: Antihypertensive Agents; Blood Pressure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Piperidines; Pyrazoles; Rimonabant; Thiazolidinediones

In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR.. Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state.. Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains.. The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.

Topics: Animals; Arachidonic Acids; Benzoxazines; Blood Pressure; Cannabinoids; Cardiovascular System; Consciousness; Endocannabinoids; Heart Rate; Hindlimb; Hypertension; Infusions, Intravenous; Injections, Intravenous; Male; Morpholines; Naphthalenes; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptor, Cannabinoid, CB1; Renal Circulation; Species Specificity; Splanchnic Circulation; Vascular Resistance; Vasodilation

Inhibiting the actions of VEGF is a new therapeutic paradigm in cancer management with antiangiogenic therapy also under intensive investigation in a range of nonmalignant diseases characterized by pathological angiogenesis. However, the effects of VEGF inhibition on organs that constitutively express it in adulthood, such as the kidney, are mostly unknown. Accordingly, we examined the effect of VEGF inhibition on renal structure and function under physiological conditions and in the setting of the common renal stressors: hypertension and activation of the renin-angiotensin system. When compared with normotensive Sprague-Dawley (SD) rats, glomerular VEGF mRNA was increased 2-fold in transgenic (mRen-2)27 rats that overexpress renin with spontaneously hypertensive rat (SHR) kidneys showing VEGF expression levels that were intermediate between them. Administration of either an orally active inhibitor of the type 2 VEGF receptor (VEGFR-2) tyrosine kinase or a VEGF neutralizing antibody to TGR(mRen-2)27 rats resulted in loss of glomerular endothelial cells and transformation to a malignant hypertensive phenotype with severe glomerulosclerosis. VEGFR-2 kinase inhibition treatment was well tolerated in SDs and SHRs; although even in these animals there was detectable endothelial cell loss and rise in albuminuria. Mild mesangial expansion was also noted in hypertensive SHR, but not in SD rats. These studies illustrate: (i) VEGF has a role in the maintenance of glomerular endothelial integrity under physiological circumstances, (ii) glomerular VEGF is increased in response to hypertension and activation of the renin-angiotensin system, and (iii) VEGF signaling plays a protective role in the setting of these renal stressors.

Topics: Animals; Antibodies; Cell Line; Endothelial Cells; Gene Expression Regulation; Health; Humans; Hypertension; Kidney; Kidney Function Tests; Male; Microscopy, Electron, Transmission; Phosphorylation; Piperidines; Quinazolines; Rats; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

In the present paper, the age-related changes in the vasoconstrictive endothelin-mediated response to insulin in aortas of normal and hypertensive, hypertriglyceridemic, hyperinsulinemic (HTG) rats were studied. To develop HTG rats, weanling male Wistar animals were given 30% sucrose in their drinking water for 4, 6, 12 and 18 months. Blood pressure was increased in HTG rats for up to 12 months showing a maximum at 6 months (138.9+/-0.8 mmHg). In vitro contractions were elicited with 40 mM KCl in the presence and absence 50 microU/ml insulin and of endothelin-receptor antagonists BQ123 and BQ788. Tension development to KCl was not modified during aging in control rats but was increased at 4 and 6 months in HTG rats. Increased endothelin release induced by insulin remained constant in normal rats, while in HTG rats it was higher than in controls at all ages. ET(A) blocker participation alone increased during aging in control rats while both receptor blockers participated in HTG rats. Our results suggest that the vasoconstrictive capacity to KCl plus insulin decreases during aging and that this decrease is greater in HTG rats. The participation of endothelin receptors in the aging process differs in control and HTG rats.

Topics: Aging; Animals; Antihypertensive Agents; Aorta; Blood Glucose; Blood Pressure; Endothelin Receptor Antagonists; Endothelins; Hypertension; Hypertriglyceridemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Chloride; Rats; Rats, Wistar; Triglycerides; Vasoconstriction; Weight Loss

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>>>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.

Topics: Acetates; Animals; Autonomic Nervous System; Autoradiography; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Indoles; Injections, Spinal; Male; Peptide Fragments; Piperidines; Quinolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-3; Spinal Cord; Substance P; Thoracic Vertebrae; Up-Regulation

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD), and one of the major causes of mental and physical disability in developed countries. As such, the identification and implementation of strategies which prevent the development of the condition or enable improvements in patients with VaD are healthcare objectives of the first order. VaD is now regarded as a combined group of clinical-pathological entities rather than one disease, that is, multiple pathogenic mechanisms and lesion types underlie a cognitive impairment of vascular origin. The clinical diagnosis of VaD is complex and difficult because of the heterogeneous nature of its clinical presentation and progression and the low sensitivity of existing clinical criteria. Moreover, there is growing evidence of the epidemiological significance of mixed forms of dementia, and that ischemic processes may precipitate and exacerbate cognitive impairment in AD. Numerous compounds have been proposed as potentially useful in the treatment of patients with VaD, comprising vasodilatative, antithrombotic, hemorrheological, nootropic, antiserotoninergic and, most recently, antiglutamatergic and cholinergic approaches. In spite of some initially favorable reports based on the use of memantine, donepezil and galantamine, there is as yet no conclusive evidence of a definitive treatment for VaD. Unsatisfactory results from VaD drug trials may be attributed in part to the diversity of the patients included (underlying pathogenic mechanisms, number, type, and location of vascular lesions), and to methodological limitations in the design of the trials (outcome measures, end-points, size, follow-up period). The treatment of modifiable vascular risk factors - hypertension, diabetes mellitus, hypercholesterolemia and heart disease - is an important strategy for the reduction of the risk of dementia, and is likely to slow the progress of cognitive decline.

Topics: Animals; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Excitatory Amino Acid Antagonists; Galantamine; Heart Diseases; Humans; Hypercholesterolemia; Hypertension; Indans; Memantine; Neuroprotective Agents; Patient Selection; Piperidines; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Stroke

Activation of renal mechanosensory nerves is enhanced by high and suppressed by low sodium dietary intake. Afferent renal denervation results in salt-sensitive hypertension, suggesting that activation of the afferent renal nerves contributes to water and sodium balance. Another model of salt-sensitive hypertension is the endothelin B receptor (ETBR)-deficient rat. ET and its receptors are present in sensory nerves. Therefore, we examined whether ET receptor blockade altered the responsiveness of the renal sensory nerves. In anesthetized rats fed high-sodium diet, renal pelvic administration of the ETBR antagonist BQ-788 reduced the afferent renal nerve activity (ARNA) response to increasing renal pelvic pressure 7.5 mmHg from 26+/-3 to 9+/-3% and the PGE2-mediated renal pelvic release of substance P from 9+/-1 to 3+/-1 pg/min. Conversely, in rats fed low-sodium diet, renal pelvic administration of the ETAR antagonist BQ-123 enhanced the ARNA response to increased renal pelvic pressure from 9+/-2 to 23+/-6% and the PGE2-mediated renal pelvic release of substance P from 0+/-0 to 6+/-1 pg/min. Adding the ETAR antagonist to ETBR-blocked renal pelvises restored the responsiveness of renal sensory nerves in rats fed a high-sodium diet. Adding the ETBR antagonist to ETAR-blocked pelvises suppressed the responsiveness of the renal sensory nerves in rats fed a low-sodium diet. In conclusion, activation of ETBR and ETAR contributes to the enhanced and suppressed responsiveness of renal sensory nerves in conditions of high- and low-sodium dietary intake, respectively. Impaired renorenal reflexes may contribute to the salt-sensitive hypertension in the ETBR-deficient rat.

Topics: Animals; Antihypertensive Agents; Diet, Sodium-Restricted; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelins; Ganglia, Spinal; Gene Expression Regulation; Hypertension; Kidney; Male; Mechanotransduction, Cellular; Neurons, Afferent; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium, Dietary; Substance P

We wanted to ascertain whether the lateral parabrachial nucleus was involved in mediating the heart-rate response evoked during stimulation of somatic nociceptors. Reversible inactivation of the lateral parabrachial nucleus, using a GABA(A) agonist, reduced the reflex tachycardia evoked during noxious (mechanical) stimulation of the forelimb by approximately 50%. The same effect was observed after blockade of neurokinin 1 receptors within the lateral parabrachial nucleus, indicating a possible involvement for substance P as a neurotransmitter. Immunocytochemistry revealed a strong expression of substance P-immunoreactive fibers and boutons in all lateral subnuclei, but they were particularly dense in the lateral crescent subnucleus. Histological verification showed that the most effective injection sites for attenuating the noxious-evoked tachycardia were all placed in or near to the lateral crescent nucleus of the lateral parabrachial complex. Many single units recorded from this region were activated by high-intensity brachial nerve stimulation. The brachial nerve evoked firing responses of some of these neurons was reversibly reduced after local delivery of a neurokinin 1 receptor antagonist. However, only a minority of these neurons followed a paired-pulse stimulation protocol applied to the spinal cord, suggesting a predominance of indirect projections from the spinal cord to the parabrachial nucleus. We conclude that the cardiac component of the response to somatic nociception involves indirect spinal pathways that most likely excite neurons located in the lateral crescent nucleus of the parabrachial complex via activation of neurokinin 1 receptors.

Topics: Afferent Pathways; Animals; Brachial Plexus; Decerebrate State; Efferent Pathways; Female; GABA Agonists; GABA-A Receptor Agonists; Heart Rate; Hypertension; Isonicotinic Acids; Male; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain; Piperidines; Pons; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Reflex; Spinal Cord; Substance P; Sympathetic Nervous System; Tachycardia

HELLP syndrome is a severe complication of pre-eclampsia characterised by hemolysis, elevated liver enzymes and a low platelet count. It is associated with an increased risk of adverse outcome for both the mother and the fetus. Patients with HELLP syndrome are also at greater risk of pulmonary edema, adult respiratory distress syndrome, abruptio placentae, intracerebral hemorrhage, eclamptic convulsions, disseminated intravascular coagulation, ruptured liver hematomas and acute renal failure. Perinatal mortality is equally high. Before delivery, aggressive obstetric management is directed toward stabilization of the affected organ systems, if possible, and interruption of the pregnancy in the early phase of the accelerated disease progression. Definitive therapy is delivery. Parturients HELLP syndrome often require general anesthesia for Cesarean section delivery. The anesthetic technique is critical for these patients with a high risk of uncontrollable hypertension, bleeding and multiple organ failure. Remifentanil is increasingly used as a very short analgesic agent providing cardiovascular stability in high-risk patients. We report the management of a patient presenting in labor with HELLP syndrome, and describe the successful use of remifentanil as part of the anesthetic technique for her subsequent Cesarean section.

Topics: Adult; Anesthesia, General; Anesthesia, Obstetrical; Anesthetics, Combined; Anesthetics, Intravenous; Antihypertensive Agents; Cesarean Section; Female; HELLP Syndrome; Hemodynamics; Humans; Hypertension; Methyldopa; Monitoring, Intraoperative; Neuromuscular Depolarizing Agents; Piperidines; Pregnancy; Remifentanil; Succinylcholine; Thiopental

We characterized vascular reactivity to endothelin-1 (ET-1) in mesenteric vessels from DOCA-salt hypertensive and SHAM control mice and assessed the effect that endothelial-derived vasodilators have on ET-1-induced vasoconstriction. Changes in the diameter of unpressurized small mesenteric arteries and veins (100- to 300-microm outside diameter) were measured in vitro using computer-assisted video microscopy. Veins were more sensitive than arteries to the contractile effects of ET-1. There was a decrease in arterial maximal responses (E(max)) compared to veins, this effect was larger in DOCA-salt arteries. The selective ET(B) receptor agonist, sarafotoxin 6c (S6c), contracted DOCA-salt and SHAM veins but did not contract arteries. The ET(B) receptor antagonist, BQ-788 (100 nM), but not the ET(A) receptor antagonist, BQ-610 (100 nM), blocked S6c responses. BQ-610 partially inhibited responses to ET-1 in mesenteric veins from DOCA-salt and SHAM mice while BQ-788 did not affect responses to ET-1. Co-administration of both antagonists inhibited responses to ET-1 to a greater extent than BQ-610 alone suggesting a possible functional interaction between ET(A) and ET(B) receptors. Responses to ET-1 in mesenteric arteries were completely inhibited by BQ-610 while BQ-788 did not affect arterial responses. Nitric oxide synthase inhibition potentiated ET-1 responses in veins from SHAM but not DOCA-salt mice. There was a prominent role for ET-mediated nitric oxide release in DOCA-salt but not SHAM arteries. In summary, these studies showed a differential regulation of ET-1 contractile mechanisms between murine mesenteric arteries and veins.

Topics: Algorithms; Animals; Cyclooxygenase Inhibitors; Desoxycorticosterone; Endothelin Receptor Antagonists; Endothelin-1; Heart; Hypertension; Indomethacin; Kidney; Male; Mesenteric Arteries; Mesenteric Veins; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocardium; Oligopeptides; Organ Size; Piperidines; Receptors, Endothelin; Vasodilator Agents; Viper Venoms

1. The roles of nitric oxide (NO), superoxide anion (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the modulation of spontaneous tone were investigated in isolated aorta from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Increases in preload from 1 to 5 g were accompanied by increases in spontaneous tone in aortic rings from DOCA-salt hypertensive rats but not from SHAM-normotensive rats. 3. Tone was higher in endothelium-denuded aortic rings than in endothelium-intact vessels. Inhibition of nitric oxide synthase (NOS) with 300 microM N(G)-nitro-L-arginine methyl ester (l-NAME) increased spontaneous tone. 4. Basal O(2)(-) generation was higher in aortic rings from DOCA-salt hypertensive rats than in those from SHAM-normotensive rats. Stretch increased O(2)(-) levels even further in the DOCA-salt group. In rings isolated from DOCA-salt hypertensive rats, administration of the O(2)(-) scavenger, superoxide dismutase (SOD, 150 U ml(-1)), or the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase inhibitor, apocynin (100 microM), completely abolished the development of spontaneous tone in endothelium-intact aortic rings but not in endothelium-denuded or in L-NAME-treated rings. SOD and apocynin decreased the generation of O(2)(-) in endothelium-intact, endothelium-denuded, and L-NAME-treated aortic rings. 5. Oral treatment of DOCA-salt hypertensive rats with the O(2)(-) scavengers, tempol or tiron, or with apocynin for 3 weeks prevented the development of hypertension and abolished the increases in O(2)(-) generation and spontaneous tone. 6. Administration of catalase (1000 U ml(-1)) to aortic rings increased spontaneous tone in vessels from DOCA-salt hypertensive rats. 7. Administration of the cyclooxygenase (COX) inhibitor, valeroyl salicylate, or the thromboxane/prostaglandin antagonist, SQ 29548, to aortic rings abolished tone. 8. The results suggest that NO plays a major role in preventing the generation of spontaneous tone in isolated aortic rings from DOCA-salt hypertensive rats. NADPH-oxidase-derived O(2)(-) enhanced spontaneous tone by inactivating NO. Endogenous H(2)O(2) appears to mitigate the increase in tone. In addition, a COX component may also contribute to spontaneous tone.

Topics: Acridines; Animals; Aorta, Thoracic; Blood Pressure; Blotting, Western; Calcium; Catalase; Cyclooxygenase Inhibitors; Desoxycorticosterone; Endothelium, Vascular; Hydrogen Peroxide; Hypertension; Immunohistochemistry; In Vitro Techniques; Luminescent Measurements; Male; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oligopeptides; Oxidative Stress; Oxygen; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Superoxides; Tyrosine; Xanthine Oxidase

Type-2 diabetes is characterized by endotheliopathy, which increases target organ damage and mortality. There is excessive endothelin-1 and TXA(2) production, and abnormal vascular reactivity to endothelin-1, manifested as a paradoxical hypotensive action in Zucker diabetic, but not lean rats. We examined the hypothesis that there is an alteration in the ET-A/ET-B receptor subtype sensitivity, and/or the interaction or cross-talk between ET-1 and TXA(2) in type-2 diabetes, using Zucker diabetic rats and their lean littermates.. Hemodynamic studies were performed in lean and Zucker fatty diabetic rats of both sexes. Laser doppler flowmetry was used to measure renal cortical (RCF) and medullary blood flow (MBF) responses. Dose response curves for mean arterial blood pressure (MAP), MBF and RCF in response to ET-1, U46619, acetylcholine, and L-NAME (25mg/kg) were constructed after pre-treatment of the rats with either BQ610 1mg/kg i.v. or BQ788 0.5mg/kg i.v. The effects of BQ610 and BQ788 on whole blood impedance aggregation were also assessed.. BQ788, but not BQ610 abolished both the paradoxical hypotensive action of ET-1 in Zucker diabetic rats (n=7 each, P<0.001 ANOVA) as well as the dose-dependent rise in MBF (P<0.001 ANOVA). BQ788, but not BQ610 abolished the difference in response to ET-1 between lean and diabetic Zucker rats. U46619 caused a hypotensive action in male Zucker rats which was abolished by L-NAME 25mg/kg or indomethacin 10mg/kg i.v. The U46619 interaction with BQ788 on both MAP and MBF was significantly (P<0.03 ANOVA) different between lean and diabetic Zucker rats. BQ788, but not BQ610 attenuated both the MAP and MBF responses to acetylcholine or L-NAME P<0.02 ANOVA). However, BQ610 dose-dependently attenuated the slope of platelet aggregation in both lean and Zucker diabetic rats (P<0.02 ANOVA).. ET-B receptor antagonism abolished the abnormal vascular reactivity and MBF responses to ET-1, and also normalized the vasoactive responses to the level seen in healthy lean Zucker rats. ET-1 receptor blockade influences the responses to TXA(2) receptor activation. In the systemic and renal circulation, this interaction appears to be mostly ET-B receptor mediated, whilst in platelets, ET-A receptor role may be predominant. The interaction or cross-talk between ET-1 and TXA(2) is altered in the type-2 diabetic state. Collectively, these pathophysiological changes may contribute to the vicious circle of diabetic endotheliopathy.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Antihypertensive Agents; Blood Flow Velocity; Blood Pressure; Diabetes Mellitus, Type 2; Drug Interactions; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Hypertension; Kidney Cortex; Kidney Medulla; Male; NG-Nitroarginine Methyl Ester; Oligopeptides; Piperidines; Platelet Aggregation; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor Cross-Talk; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Thromboxane A2

Superoxide anion (O2*-) production is elevated in the vasculature of hypertensive animals but it is not known if O2*- production is also elevated in the sympathetic nervous system. We measured O2*- levels in prevertebral sympathetic ganglia of deoxycorticosterone acetate (DOCA)-salt hypertensive rats using the dihydroethidine (DHE) fluorescence method. O2*- was elevated in ganglia from DOCA-salt rats compared with normotensive sham rats. Treatment of ganglia with endothelin (ET)-1 (3x10(-8) mol/L) resulted in a 200% increase in fluorescence intensity in neurons, which was attenuated by the ET(B) receptor antagonist BQ788 (10(-7) mol/L). ET-1 also increased the O2*- induced fluorescence in dissociated sympathetic neurons and PC-12 cells via activation of ET(B) receptors, but not ET(A) receptors. To evaluate whether elevated ET-1 levels in the ganglia might contribute to the elevated O2*- found in ganglia we measured the amount of ET-1 using an ELISA assay. ET-1 levels in sham rat celiac ganglia were 695.6+/-40.9 picogram per gram; they were not different than ET-1 levels in ganglia from DOCA-salt rats. We then compared ET(B) receptor levels in ganglia from sham and DOCA-salt animals. ET(B) receptor mRNA levels were 32% higher and ET(B) receptor protein levels were 20% higher in celiac ganglia from DOCA-salt rats than from sham rats separately. In conclusion, O2*- is elevated in prevertebral sympathetic ganglia in DOCA-salt hypertension, and ET-1 is a potent stimulus for the elevation of O2*- levels in sympathetic ganglia, an effect that may be mediated by the upregulation of ET(B) receptors.

Topics: Animals; Desoxycorticosterone; Endothelin A Receptor Antagonists; Endothelin-1; Ganglia, Sympathetic; Hypertension; Male; Nerve Growth Factor; Oligopeptides; Oxidative Stress; PC12 Cells; Piperidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Endothelin B; Sodium Chloride, Dietary; Superoxides; Sympathetic Fibers, Postganglionic; Up-Regulation; Viper Venoms

The pathogenesis of essential hypertension in blacks may differ from that in whites. In particular, black patients usually present with a salt-sensitive, low-renin form, which in animal models is associated with enhanced activity of endothelin-1 (ET-1). This study aimed to assess whether ethnic differences exist in the vascular activity of ET-1 in normotensive and hypertensive blacks and whites.. Forearm blood flow (FBF) responses to intraarterial infusion of an ET(A) receptor blocker (BQ-123) were analyzed by plethysmography in 37 normotensive patients and 27 hypertensive patients according to race. BQ-123 did not affect FBF in normotensive subjects (P=0.30), whereas it produced significant vasodilation in hypertensive subjects (P<0.001). In normotensives, FBF response to BQ-123 was similar in white (n =22) and black (n =15) patients (P=0.85). In contrast, in hypertensive patients, the vasodilator effect of ET(A) receptor blockade was significantly higher in blacks (n =13) than in whites (n =14) (P=0.01). To rule out differences in smooth muscle reactivity, the effects of race on FBF responses to exogenous ET-1 were analyzed in the hypertensive subgroups. Endothelin-1 induced a significant vasoconstriction in both white (n =7) and black patients (n =5) (both P<0.001), without differences between them (P=0.46). In 8 black hypertensives, the response to selective ET(A) blockade was not modified by nonselective blockade of ET-1 receptors by co-infusion of BQ-123 and BQ-788 (P=0.66).. Hypertensive blacks have enhanced ET(A)-dependent vasoconstrictor tone, probably related to increased production of ET-1. Given the negative vascular effects of ET-1, this abnormality may contribute to the pathogenesis of hypertension and its complications in black patients.

Topics: Black People; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Forearm; Humans; Hypertension; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Plethysmography; Vasoconstriction; White People

Effects of V(1) (OPC-21268) and V(2) (OPC-31260) vasopressin antagonists on blood pressure (BP) short-term variability were investigated in adult spontaneously hypertensive rats (SHR) under basal conditions and after the stimulation of vasopressin release by hemorrhage. BP was recorded intra-arterially and sampled at 20 Hz to be analyzed on a personal computer. BP time spectra were calculated on 30 stationary overlapping 2048 point-time series. Spectral power was estimated in total (0.00976 - 3 Hz), very low frequency (VLF: 0.00976 - 0.195 Hz), low frequency (LF: 0.195 - 0.605 Hz), and high frequency (HF: 0.8 - 3 Hz) regions. Under basal conditions a V(1) antagonist (5 mg/kg, i.v.) decreased BP without affecting BP variability, while combined (V(1) + V(2)) blockade or V(2) blockade (1 mg/kg, i.v.) alone did not affect cardiovascular parameters. Mild hemorrhage (5 ml/kg per min) increased HF-BP variability, while moderate (10 ml/kg per min) and massive (15 ml/kg per min) hemorrhage did not affect it. In V(1), but not V(2), antagonist pre-treated SHR HF-BP increased significantly after moderate and massive hemorrhage. V(1) or V(2) antagonist pre-treatment also enhanced VLF-BP variability during massive hemorrhage. Moreover V(1) blockade prevented hemorrhage-induced bradycardia, while V(2) blockade potentiated it. It follows that in adult SHR, vasopressin buffers BP oscillations in HF and VLF frequency domains only in hypovolaemic conditions and that the modulation of the autonomic adjustment of the HR to hemorrhage by vasopressin is preserved.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Vasopressin

Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.. In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats.. We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.

Topics: Amidohydrolases; Angiotensin II; Animals; Arachidonic Acids; Benzamides; Benzyl Compounds; Blood Pressure; Camphanes; Carbamates; Dronabinol; Endocannabinoids; Endothelium, Vascular; Hypertension; Male; Models, Cardiovascular; Myocardial Contraction; Myocardium; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Up-Regulation; Vascular Resistance; Vasodilation; Ventricular Function, Left

Endothelin (ET)-1 contributes to raising blood pressure (BP) and inducing cardiovascular disease by vasoconstriction and potent stimulation of aldosterone secretion. In the rat this latter effect occurs via ET(B) receptors; in humans in vitro studies implicated both ET(A) and ET(B) receptors, but there is no conclusive evidence in vivo.. We recruited 13 consenting hypertensive patients: six with primary aldosteronism (PA) and seven with high-to-normal renin hypertension (HNRH). They were infused with a low dose (200 nmol/min for 5 min followed by 100 nmol/min for 10 min) of the ET(A)-selective antagonist BQ-123 either alone or, on a different day, together with an identical dose of the ET(B)-selective antagonist BQ-788. Plasma aldosterone, cortisol and ACTH concentration and plasma renin activity (PRA) were measured with radioimmunoassay at -15, 0, 30, 60, 120, 240, 360 min, while BP was recorded non-invasively.. BQ-123 alone and combined with BQ-788 significantly lowered mean BP in both PA and HNRH patients (by 6-10 mmHg at nadir; P<0.01). In PA patients, a short-lived decrease of aldosterone was elicited by combined BQ-123 and BQ-788 (-14%; P<0.05), but not by BQ-123 alone; cortisol, ACTH, and PRA were unaffected by either treatment. In HNRH patients, BQ-123 both alone and combined with BQ-788 lowered aldosterone (-39 and -28%, respectively) and PRA (-43 and -16%, respectively), while cortisol and ACTH were unaffected.. Endogenous ET-1 contributes to maintaining the high BP values and the aldosterone secretion in both PA and HNRH patients. In the former patients, the aldosterone secretagogue effect of ET-1 is mediated via ET(B) receptors, while in the latter it occurs mainly via ET(A)-mediated stimulation of renin production.

Topics: Adrenocorticotropic Hormone; Aldosterone; Endothelin Receptor Antagonists; Female; Humans; Hydrocortisone; Hyperaldosteronism; Hypertension; Infusions, Intravenous; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Renin

Topics: Adrenal Gland Neoplasms; Adult; Anesthetics, Intravenous; Female; Humans; Hypertension; Intraoperative Complications; Male; Pheochromocytoma; Piperidines; Remifentanil

To test the hypothesis that activation of the vanilloid receptor (VR1) contributes to the anandamide-induced depressor effect in spontaneously hypertensive rats (SHR), we used a selective VR1 antagonist capsazepine (CAPZ) and a selective cannabinoid type 1 receptor antagonist SR141716A in conjunction with a VR1 agonist capsaicin in both SHR and Wistar-Kyoto rats (WKY). Mean arterial pressure was increased in SHR compared with WKY (P<0.05). Intravenous administration of capsaicin caused a greater depressor response in SHR compared with WKY (P<0.05), which was blocked by approximately 60% by CAPZ (P<0.05) in SHR only. Methanandamide caused a similar greater depressor response (P<0.05), which was blocked by approximately 50% and 60% by CAPZ and SR141716A, respectively, in SHR (P<0.05) but not in WKY. Radioimmunoassay showed that methanandamide increased plasma calcitonin gene-related peptide (CGRP) levels from baseline in both SHR and WKY (P<0.05), with no difference between 2 strains. Western blot showed that protein expression for the calcitonin receptor-like receptor-but not receptor activity modifying protein 1, VR1, and cannabinoid type 1 receptors-was increased in mesenteric resistance arteries in SHR compared with WKY (P<0.05). These data indicate that in addition to activation of cannabinoid type 1, anandamide may serve as an endogenous compound to stimulate VR1, leading to a decrease in blood pressure via CGRP release from sensory nerve terminals. Increased mesenteric CGRP receptor expression in SHR may account for increased sensitivity of blood pressure to anandamide and may serve as a compensatory response to buffer the increase in blood pressure in SHR.

Topics: Animals; Arachidonic Acids; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Endocannabinoids; Hypertension; Male; Mesenteric Arteries; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

We previously demonstrated that restraint stress-induced pressor responses were inhibited by bilateral microinjection of muscimol into the rostral part of the ventral zone of the lateral septal area (LSV). The caudal part of the lateral septal area is also reported to be involved in blood pressure regulation. In this study, we examined whether the LSV receives projections from the caudal part of the dorsal zone of the lateral septal area (LSD) in rats. Injections of a fluorescent tracer into the LSV produced maximal retrograde labeling within the LSD. Microinjection of carbachol (10-100 pmol) into the LSD produced a dose-dependent pressor response. The pressor response to carbachol was inhibited by microinjection of muscimol (80 pmol) or 4-DAMP (1 nmol) into the ipsilateral side of the LSV. Microinjection of muscimol (80 pmol) into the LSD also inhibited the pressor response induced by restraint stress. Repeated injections of carbachol (30 pmol) into the LSD produced Fos immunoreactivity in the ipsilateral side of the LSV. These findings suggest that the LSD projects to the LSV and that these projections may be involved in blood pressure increase.

Topics: Animals; Blood Pressure; Carbachol; Cholinergic Agonists; Dose-Response Relationship, Drug; Fluorescent Dyes; GABA Agonists; Hypertension; Male; Microinjections; Muscarinic Antagonists; Muscimol; Neural Pathways; Neurons; Piperidines; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Reaction Time; Septum of Brain; Stress, Physiological

The present study investigated the role possibly played by ET-receptor antagonism at periaqueductal grey (PAG) area level in decreasing the arterial blood pressure and heart rate values reached in DOCA-salt hypertensive rats. A 3-week DOCA-salt treatment induced an increase in blood pressure of up to 174+/-3 mmHg in Sprague-Dawley (SD) rats. This was paralleled by a significant increase in heart rate (HR), and endothelin-1 (ET-1) levels throughout the brain, as assessed by specific EIA ( P<0.05). In contrast, a 40% reduction of ETA mRNA levels into the brain was detected through RT-PCR. The basal MABP of DOCA rats was significantly modified by PAG injections of FR139317, an ETA receptor antagonist, or SB209670, an ETA/ETB receptor antagonist. BQ-788, an ETB receptor antagonist, was found to have no effect on blood pressure levels, while FR139317 and SB209670 also led to a significantly modified HR. PAG-endothelin ETA antagonism can therefore be said to counteract the cardiovascular changes induced by DOCA-salt treatment in rats.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Azepines; Blood Pressure; Desoxycorticosterone; Electrophoresis, Agar Gel; Endothelin Receptor Antagonists; Endothelin-1; Glyceraldehyde-3-Phosphate Dehydrogenases; Heart Rate; Hypertension; Indans; Indoles; Male; Oligopeptides; Periaqueductal Gray; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Mice with disruption of the kinin B(2) receptor (B(2)KO mice) are sensitive to salt-rich diets, which causes hypertension. The aim of the study was to assess the role of endothelin-1 (ET-1) and angiotensin-II in hypertensive B(2)KO mice on a salt-rich diet. We also wanted to verify if there is an upregulation of the mRNA expression of the precursors or receptors for these hormones. Two groups of B(2)KO mice (20-25 g) were investigated. The first group received an 8% NaCl diet with 1% NaCl in drinking water (HS) and the second was fed with normal food with tap water (NS). The antagonists tested were the ET(A) receptor antagonist BQ-123 (1 and 5 mg/kg), the ET(B) receptor antagonist BQ-788 (0.25 and 1 mg/kg), the angiotensin receptor type 1 antagonist losartan (10 mg/kg) and the angiotensin-converting enzyme inhibitor captopril (3 mg/kg). These were injected intraperitoneally 30 min prior to blood pressure measurement by the tail-cuff method. We also studied the level of expression of preproET-1, ET-1 receptors, angiotensinogen and angiotensin receptors by RNA extraction from the heart and kidneys of these mice followed by reverse transcriptase (RT)-PCR. B(2)KO mice (HS) were hypertensive after 8 weeks compared with B(2)KO mice on normal diet (HS, 93.4+/-1.5 mmHg, n=7; NS, 61.4+/-2.7 mmHg, n=7). In the HS group, the mean arterial blood pressure was significantly reduced by BQ-123 (5 mg/kg) to 61.9+/-1.8 mmHg (n=7), by BQ-788 (1 mg/kg) to 58.8+/-2.6 mmHg (n=6), by losartan (10 mg/kg) to 73.2+/-1.7 mmHg (n=8) and by captopril (3 mg/kg) to 86.0+/-2.3 mmHg (n=8). The expression studied by RT-PCR did not show any difference (either in precursors or receptors expression) between hypertensive and normal mice. The four antagonists used seemed to reverse the hypertension. These results suggest that ET-1 and angiotensin-II are probably involved in the mechanism that leads to hypertension since the effect of these hormones is probably not compensated by kinins in B(2)KO mice. Further studies are necessary to understand the implication of the cross-talk between these hormones in the hypertensive state.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Hypertension; Kidney; Losartan; Male; Mice; Mice, Knockout; Myocardium; Oligopeptides; Peptides, Cyclic; Piperidines; Protein Precursors; Receptor, Bradykinin B2; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Angiotensin; Receptors, Bradykinin; Receptors, Endothelin; RNA, Messenger; Sodium Chloride, Dietary

To estimate the prevalence, awareness, treatment and control of hypertension in a Canarian population; and their relationship with the glucose tolerance categories.. From a population of 6355 subjects over 29 years old, 690 were chosen in a random sampling. Blood pressure measurements, a standard oral glucose tolerance test (excluding known diabetic patients), and a questionnaire on diabetes and hypertension history and medication use was performed.. The total prevalence of hypertension was 50.3%; 62.0% of the hypertensive subjects were aware of their condition; 60.6% had their diastolic and 11.0% their systolic blood pressure controlled and 8.6% had both. For diabetic, glucose intolerant and normoglycemic subjects, the respective prevalences of hypertension were 79.4, 60.2 and 43.1% (higher in diabetic subjects, P < 0.001); the awareness of hypertension was 66.7, 61.8 and 59.5% (differences not significant); systolic blood pressure control was 4.8, 14.7 and 13.7% (lower in diabetic subjects, P = 0.017 versus glucose intolerant and P = 0.011 versus normoglycemic subjects); diastolic blood pressure control was 50.4, 72.1 and 63.2% (lower in diabetic subjects, P = 0.004 versus glucose intolerant and P = 0.025 versus normoglycemic subjects). There were no differences in the number and type of antihypertensive drugs among the different glucose tolerance categories.. Blood pressure was comparable in our population and in other European populations. The prevalence of hypertension was higher, the awareness was similar, and control was worse in diabetic than in non-diabetic subjects; the drug treatment pattern was not different.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Awareness; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus; Diastole; Diuretics; Drug Therapy, Combination; Female; Glucose Intolerance; Humans; Hypertension; Male; Middle Aged; Piperidines; Prevalence; Spain; Systole; Treatment Outcome

In hypertensive subjects, a single bout of dynamic exercise results in an immediate lowering of blood pressure back toward normal. This postexercise hypotension (PEH) also occurs in the spontaneously hypertensive rat (SHR). In both humans and SHRs, PEH features a decrease in sympathetic nerve discharge, suggesting the involvement of central nervous system pathways. Given that substance P is released in the nucleus tractus solitarius (NTS) by activation of baroreceptor and skeletal muscle afferent fibers during muscle contraction, we hypothesized that substance P acting at neurokinin-1 (NK-1) receptors in the NTS might contribute to PEH. We tested the hypothesis by determining, in conscious SHRs, whether NTS microinjections of the NK-1 receptor antagonist SR-140333 before exercise attenuated PEH. The antagonist, in a dose (60 pmol) that blocked substance P- and spared D,L-homocysteic acid-induced depressor responses, significantly attenuated the PEH by 37%, whereas it had no effect on blood pressure during exercise. Vehicle microinjection had no effect. The antagonist also had no effect on heart rate responses during both exercise and the PEH period. The data suggest that a substance P (NK-1) receptor mechanism in the NTS contributes to PEH.

Topics: Animals; Blood Pressure; Consciousness; Hypertension; Hypotension; Male; Microinjections; Neurokinin-1 Receptor Antagonists; Physical Exertion; Piperidines; Quinuclidines; Rats; Rats, Inbred SHR; Solitary Nucleus

The attenuation of baroreflex gain associated with hereditary hypertension could involve abnormal signalling by nitric oxide or substance P. Baroreflex gain was measured in age-matched male genetically hypertensive (GH) and nonnotensive (N) anaesthetised rats from heart rate changes in response to i.v. phenylephrine or sodium nitroprusside. In subgroups of these animals, nitric oxide synthesis was inhibited using NG-nitro-L-arginine methyl ester (L-NAME, 30 mg x kg(-1) i.v.), substance P transmission was blocked using the antagonist SR 140333 (360 nmoles x kg(-1) i.v.) or substance P release was inhibited with resiniferatoxin (4 doses of 0.3 microg x kg(-1) i.v. at 4 min intervals). Baroreflex gain was markedly reduced in GH compared to N animals (N -0.37 +/- 0.04 beat x min(-1) x mm Hg(-1), GH -0.17 +/- 0.02 beat x min(-1) x mm Hg(-1), p < 0.0001). Inhibition of nitric oxide synthase increased baroreflex gain in each strain, but the inter-strain difference in gain persisted (post-treatment N -0.57 +/- 0.07 beat x min(-1) x mm Hg(-1), GH -0.24 +/- 0.05 beat x min(-1) x mm Hg(-1) (p < 0.001). Blockade of receptors or inhibition of substance P release did not affect gain in either strain. Nitric oxide, but not substance P, appears to play an inhibitory role in the rat arterial baroreflex. Impairment of baroreflex gain in GH rats is not secondary to altered nitric oxide signaling.

Topics: Animals; Baroreflex; Blood Pressure; Diterpenes; Enzyme Inhibitors; Heart Rate; Hypertension; Male; Neurokinin-1 Receptor Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Phenylephrine; Piperidines; Quinuclidines; Rats; Rats, Inbred SHR; Rest; Substance P; Vasoconstrictor Agents; Vasodilator Agents

To identify the receptors by which endothelin-1 (ET-1) increases venomotor tone in hypertension.. Vascular reactivity to ET-1 and the selective endothelin receptor subtype B (ET(B)) agonist, sarafotoxin 6c (S6c), was studied in mesenteric blood vessels from deoxycorticosterone acetate (DOCA-salt) hypertensive and normotensive control rats. The diameter of small (< or = 280 microm) mesenteric arteries and veins was monitored in vitro using computer-assisted video microscopy. Contractions of mesenteric arteries (< or= 250 microm diameter) were also studied, using a myograph. ET-1 mRNA levels were measured in mesenteric arteries and veins using real-time RT-PCR techniques.. ET-1-induced contractions were reduced in arteries of DOCA-salt hypertensive rats compared with those of normotensive control rats; S6c produced negligible contractions in arteries from both groups. ET-1 concentration-responses curves in arteries measured using video microscopy or a myograph were similar. ET-1 and S6c caused veins to contract, and there were no differences between responses to these agonists in tissues from DOCA-salt hypertensive rats or normotensive control rats. Studies using ET(A) and ET(B) receptor antagonists indicated that ET-1-induced venoconstriction was mediated by ET(A) receptors. Potassium chloride concentration-response curves were similar in arteries and veins from normotensive control rats and DOCA-salt hypertensive rats. ET-1 mRNA levels in DOCA-salt hypertensive rat arteries or veins were not different from those in normotensive control rat arteries and veins.. These data indicate that ET-1 reactivity is maintained in mesenteric veins, but not arteries, in DOCA-salt hypertension. Therefore, the sustained increase in venomotor tone mediated by ET(A) receptors that is known to occur in vivo in DOCA-salt hypertensive rats is not caused by direct venoconstriction.

Topics: Animals; Desoxycorticosterone; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; In Vitro Techniques; Male; Mesenteric Arteries; Mesenteric Veins; Oligopeptides; Piperidines; Potassium Chloride; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Sodium, Dietary; Vasoconstriction; Vasoconstrictor Agents; Viper Venoms

In this study we investigated the role of endogenous endothelin in the cardiovascular response to acute stress, ie mild footshocks in conscious rats. Footshock-stress significantly increased mean arterial pressure and heart rate (P < 0.05). Peripheral or intracerebroventricular (IVT) administration of BQ 788, a selective antagonist of ET(B) receptor, did not alter pressor response to footshocks. Intraperitoneal injections of BQ 123 (1 mg/kg), a selective antagonist of the ET(A)-receptor, had a tendency to decrease, while BQ 123 (203 ng/5 microl) IVT administration significantly reduced the pressor response to footshocks (-12 mm Hg, P < 0.001). Neither ET(A) nor ET(B) antagonists, when injected centrally or peripherally, altered basal blood pressure or heart rate. Our results may indicate a role of brain endothelin in the sympathetic mediated cardiovascular response to stress, via stimulation of ET(A) receptor.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Electroshock; Endothelin Receptor Antagonists; Endothelins; Hypertension; Male; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley

Responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were compared in large (LPA) and small pulmonary artery (SPA) rings from normoxic and chronically hypoxic (CH) rats. In addition, the effects of a selective phosphodiesterase (PDE) 5 inhibitor, E-4021, on ACh-induced relaxation were evaluated. Chronic hypoxia markedly decreased both ACh- and SNP-induced relaxations in LPA but not in SPA rings. Pretreatment with E-4021 caused a much greater leftward shift of the concentration-response curve for ACh in hypoxic than in normoxic LPA rings, eliminating the difference in response to ACh between these two vessels. These results suggest that cGMP-dependent relaxation is impaired in the proximal but not in the distal pulmonary artery of CH rats and that increased PDE5 activity could be a mechanism responsible for this impaired responsiveness.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Acetylcholine; Animals; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Hypertension; Hypoxia; In Vitro Techniques; Male; Nitroprusside; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Pulmonary Artery; Quinazolines; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

Norepinephrine-induced vasoconstriction was significantly greater in perfused mesenteric arteries of stroke-prone spontaneously hypertensive rats (SHRSPs) compared with cases of age-matched Wistar Kyoto rats (WKYs). Neither endothelin ET(A) receptor antagonist FR139317 ((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methyl-pentanoyl] amino-3-[3-(1-methyl-1H-indoyl)]propionyl]amino-3-(2-pyridyl) propionic acid) nor endothelin ET(B) receptor antagonist BQ788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-g-methylleucyl-D-1-methoxycarbonyl-tryptophanyl-D-norleucine] affected the increased responses observed in SHRSPs, suggesting that endogenous endothelin-1 is not involved in this phenomenon. Norepinephrine-induced vasoconstriction was significantly enhanced by subpressor dose of endothelin-1 (0.3 nM), both in SHRSPs and WKYs. In SHRSPs, endothelin-1-induced enhancement was abolished by FR139317, in contrast to the case with WKYs, in which BQ788 markedly suppressed endothelin-1-induced augmentation of norepinephrine responses. Our results indicate that exogenous endothelin-1 enhances contractile responses to norepinephrine in mesenteric arteries of WKYs and SHRSPs, through activation of different receptor subtypes.

Topics: Animals; Azepines; Dose-Response Relationship, Drug; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Indoles; Mesenteric Arteries; Norepinephrine; Oligopeptides; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Species Specificity; Vasoconstriction; Vasoconstrictor Agents

Oral thrombin inhibitors are under development as potential drugs for prophylaxis and treatment of thrombotic events. The effect of pretreatment with two direct thrombin inhibitors, melagatran and inogatran, was evaluated in a rat model of cerebral infarction. Ischaemic stroke was induced by photochemical reaction after an injection of Rose Bengal and focused posterior and to the right of the intersection of the coronal and sagittal sutures on the intact calvarium. A single oral dose of melagatran (30 micromol/kg) significantly reduced the volume of the cortical infarct by 53% (P<.05) compared with control. In addition, following intravenous inogatran (6 micromol/kg) or oral inogatran (100 micromol/kg), the volume of the cortical infarct decreased by 83% and 19%, respectively, compared with control. This study showed that experimental focal ischaemic infarction, elicited by photochemically induced endothelial cell damage, can be significantly reduced with melagatran and inogatran, direct thrombin inhibitors.

Topics: Administration, Oral; Animals; Antithrombins; Azetidines; Benzylamines; Brain Infarction; Cerebral Cortex; Drug Evaluation, Preclinical; Glycine; Hypertension; Injections, Intravenous; Light; Male; Photochemistry; Piperidines; Rats; Rats, Inbred SHR

Polymorphism of the dopamine receptor type-2 (D(2)) gene is associated with essential hypertension. To assess whether D(2) receptors participate in regulation of blood pressure (BP), we studied mice in which the D(2) receptor was disrupted. In anesthetized mice, systolic and diastolic BPs (in millimeters of mercury) were higher in D(2) homozygous and heterozygous mutant mice than in D(2)+/+ littermates. BP after alpha-adrenergic blockade decreased to a greater extent in D(2)-/- mice than in D(2)+/+ mice. Epinephrine excretion was greater in D(2)-/- mice than in D(2)+/+ mice, and acute adrenalectomy decreased BP to a similar level in D(2)-/- and D(2)+/+ mice. An endothelin B (ET[B]) receptor blocker for both ET(B1) and ET(B2) receptors decreased, whereas a selective ET(B1) blocker increased, BP in D(2)-/- mice but not D(2)+/+ mice. ET(B) receptor expression was greater in D(2)-/- mice than in D(2)+/+ mice. In contrast, blockade of ET(A) and V(1) vasopressin receptors had no effect on BP in either D(2)-/- or D(2)+/+ mice. The hypotensive effect of an AT(1) antagonist was also similar in D(2)-/- and D(2)+/+ mice. Basal Na(+),K(+)-ATPase activities in renal cortex and medulla were higher in D(2)+/+ mice than in D(2)-/- mice. Urine flow and sodium excretion were higher in D(2)-/- mice than in D(2)+/+ mice before and after acute saline loading. Thus, complete loss of the D(2) receptor results in hypertension that is not due to impairment of sodium excretion. Instead, enhanced vascular reactivity in the D(2) mutant mice may be caused by increased sympathetic and ET(B) receptor activities.

Topics: Adrenergic alpha-Antagonists; Angiotensin Receptor Antagonists; Animals; Antidiuretic Hormone Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Body Weight; Catechols; Endothelin Receptor Antagonists; Endothelin-1; Female; Genotype; Hypertension; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Oligopeptides; Phentolamine; Piperidines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Adrenergic; Receptors, Dopamine D2; Receptors, Endothelin; Sodium; Sodium-Potassium-Exchanging ATPase; Urodynamics; Viper Venoms

Endothelin (ET) and the sympathoadrenal system contribute to the development and maintenance of deoxycorticosterone acetate (DOCA)-salt hypertension. ET can act directly on the adrenal medulla to enhance the release of catecholamines. In addition, the level of ET peptide is increased in the adrenal glands of DOCA-salt hypertensive rats. Therefore, we tested the hypothesis that ET enhances adrenal medullary catecholamine release during DOCA-salt hypertension. The infusion of exogenous ET-1 into an isolated, perfused adrenal gland preparation resulted in an increase in the basal release of norepinephrine (NE) and epinephrine (EPI) in control and DOCA-salt hypertensive rats. Nerve-stimulated (0.3 Hz) release of NE was significantly inhibited during ET-1 infusion in the DOCA-salt hypertensive rats but not in the control rats. The role of endogenous ET on basal and nerve-stimulated NE and EPI release was also examined. An infusion of either BQ-123 (10(-7) mol/L), an ET(A) receptor antagonist, or BQ-788 (10(-7) mol/L), an ET(B) receptor antagonist, did not alter basal NE or EPI release in either control or DOCA-salt hypertensive rats. BQ-788 did not alter nerve-stimulated release of NE and EPI. In contrast, the nerve-stimulated release of EPI, but not NE, was enhanced during BQ-123 infusion in DOCA-salt hypertensive rats. Nerve-stimulated NE and EPI release was unaffected by BQ-123 in the control rats. These data suggest that ET can stimulate adrenal medullary catecholamine release in normotensive and DOCA-salt hypertensive rats. However, ET also inhibits adrenal medullary catecholamine release in DOCA-salt hypertensive rats.

Topics: Adrenal Medulla; Animals; Antihypertensive Agents; Blood Pressure; Desoxycorticosterone; Electric Stimulation; Endothelin Receptor Antagonists; Endothelin-1; Epinephrine; Heart Rate; Hypertension; Infusions, Intravenous; Male; Nephrectomy; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Chloride; Sodium Chloride, Dietary; Splanchnic Nerves

To analyse the effects of endothelin-1 and vasopressin on the sympathetic vasoconstriction during hypertension.. Electrical field stimulation (4 Hz) was applied to isolated, 2 mm segments of the tail artery from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats prepared for isometric tension recording.. The contraction to electrical stimulation was potentiated by endothelin-1 (10(-10)-10(-8) M) in arteries from WKY but not from SHR, and by vasopressin (10(-12)-10(-10) M) more markedly in arteries from WKY than from SHR. The potentiation by endothelin-1 was reduced more markedly by the antagonist of endothelin ETA receptors BQ-123 (10(-5) M) than by the endothelin ETB receptor antagonist BQ-788 (10(-5) M). The potentiation by vasopressin was reduced by the antagonist of vasopressin V1 receptors d(CH2)5Tyr(Me)AVP (10(-7) M), but not by the vasopressin V2 receptor antagonist d(CH2)5D-Ile2, Ile4AVP (10(-7) M). The blocker of L-type calcium channels verapamil (10(-5) M) reduced the potentiation by both endothelin-1 and vasopressin in arteries from WKY rats, and increased the potentiation by vasopressin in arteries from SHR. Noradrenaline (10(-8)-10(-4) M) contraction was not modified by endothelin-1 (3 x 10(-9) M) or vasopressin (3 x 10(-11) M), and contraction to endothelin-1 (10(-9)-10(-7) M) and vasopressin (10(-10)-10(-7) M) was lower in arteries from SHR than from WKY rats.. (1) The potentiation by endothelin-1 and vasopressin of the sympathetic vasoconstriction, probably due to increased release of noradrenaline, is impaired during hypertension, and (2) this potentiation is mediated mainly by endothelin ETA receptors, and by vasopressin V1 receptors, in both WKY and SHR, and for both peptides it is mediated by L-type calcium channels in arteries from normotensive but not in those from hypertensive animals.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Calcium Channel Blockers; Electric Stimulation; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; In Vitro Techniques; Male; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction; Vasopressins; Verapamil

The airways of the genetically hypertensive rat (GH) are hyperinnervated by substance P-containing sensory nerves and exhibit reduced inflammatory responsiveness to substance P and to capsaicin. The present study measured tracheal inflammation to resiniferatoxin (1.0 microgram/kg i.v.), a capsaicin analogue, which lacks the hypotensive action of capsaicin itself, alone or after the neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) (50 mg/kg i.p.). The inflammatory response to resiniferatoxin alone was 50% lower in untreated GH than in control rats, a similar strain difference to that seen previously with capsaicin. Pre-treatment with TRIM had no effect on inflammation in either strain. Binding kinetics of the tachykinin NK(1) receptor antagonist [3H](S)-1-(2-[3-(3, 4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4- phenyl-l-azoniabicyclo[2,2,2,]octane chloride ([3H]SR140333)(0.125-16.0 nM) showed 50% reduction of B(max) in GH versus control tracheae (74+/-13 cf.165+/-26 fmol/mg protein). Our results indicate that the reduced neurogenic inflammatory responsiveness in GH rats can be attributed entirely to reduced tachykinin NK(1) receptor numbers.

Topics: Animals; Binding, Competitive; Capillary Permeability; Diterpenes; Hypertension; Inflammation; Male; Membranes; Piperidines; Quinuclidines; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Neurokinin-1; Spinal Cord; Substance P; Trachea; Tritium

The objective of the present study was to determine if endothelin-1 played a role in the elevated peripheral resistance in deoxycorticosterone-acetate (DOCA)-salt hypertension. Radioimmunoassay showed that the concentration of endothelin-1 was higher in thoracic aorta of the DOCA-salt group than that of the control normotensive (CN) group. Responses of arterioles in the rat cremaster to endothelin-1 were also observed using in vivo closed circuit television microscopy. Microvascular sensitivity to endothelin-1 was decreased in the DOCA-salt group. In the presence of an endothelin type A (ET-A) receptor antagonist, low concentrations of endothelin-1 induced a significant vasoconstriction in the DOCA-salt group. In the presence of endothelin type B (ET-B) receptor antagonist, microvascular responses to endothelin-1 were attenuated in the DOCA-salt group. These results indicated that the increased tissue level of endothelin-1 may decrease the ET-A receptor-mediated vascular response to endothelin-1. However, the ET-B receptor-mediated vasoconstriction is potentiated during DOCA-salt hypertension.

Topics: Animals; Aorta, Thoracic; Desoxycorticosterone; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Male; Microcirculation; Muscle, Skeletal; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Sodium Chloride

1. The role of arginine vasopressin (AVP) was examined in adrenocorticotrophin (ACTH)-induced hypertension in Sprague-Dawley rats using the non-peptide AVP V1a receptor antagonist OPC 21268. 2. In an acute study, six rats were pretreated with ACTH for 11 days and direct arterial blood pressure (4 h), plasma osmolality and electrolyte concentrations were measured after OPC 21268 gavage. In a chronic study, 40 rats were randomly divided into four groups: (i) sham injection + sham gavage; (ii) ACTH + sham gavage; (iii) sham injection + OPC 21268; or (iv) ACTH + OPC-21268 for 16 days. Systolic blood pressure (SBP), water intake, urine volume (UV), urine osmolality and electrolytes, food intake, bodyweight and plasma osmolality and electrolyte concentrations were measured. 3. In the acute study, direct mean arterial blood pressure did not change with OPC 21268 (122+/-2 and 120+/-3 mmHg at 0 and 240 min, respectively). 4. In the chronic study, OPC 21268 did not affect ACTH-induced rises in blood pressure (from 125+/-2 (control) to 145+/-5 mmHg (group 4) compared with 122+/-3 (control) to 149+/-5 mmHg (group2)). Water intake and UV increased (from 29+/-2 to 83+/-6 mL/day; and from 5+/-1 to 36+/-5 mL/day, respectively) and the change in bodyweight decreased from 0+/-2 to -107+/-7 g. 5. These results suggest that AVP (at the V1a receptor) does not play a significant role in the maintenance of ACTH-induced hypertension.

Topics: Adrenocorticotropic Hormone; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Body Weight; Hematocrit; Hypertension; Male; Organ Size; Osmolar Concentration; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Urodynamics

Homozygous knock-out of ET(A) or ET(B) receptor genes results in lethal developmental phenotypes in the mouse. Such deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially defective in ET(A) or ET(B) receptors display significant alterations in their responses to exogenous or endogenous endothelin-1 (ET-1). Furthermore, the anesthetized ET(B) (+/-) knock-out mice showed a significantly higher mean arterial blood pressure than the ET(A) (+/-) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ET(B) agonist, IRL-1620, was significantly reduced in the ET(A) (+/-) knock-out mice. In ET(B) (+/-) knock-out mice, the pressor effect of IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ET(A) and ET(B) receptors were found to be involved in the pressor effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123 (ET(A) antagonist) or BQ-788 (ET(B) antagonist). Also, ET(A)-selective or mixed ET(A)/ET(B)- but not ET(B)-selective antagonists reversed the hypertensive state of the ET(B) (+/-) knock-out mice to the level of wild-type littermates. Finally, radiolabeled ET-1 plasmatic clearance was altered in ET(B) (+/-) but not ET(A) (+/-) knock-out mice when compared with wild-type animals. Thus, heterozygous knock-out of ET(B) receptors results in a hypertensive state, suggesting an important physiological role for that particular receptorial entity in opposing the endogenous ET-1-dependent pressor effects in the mouse.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Heterozygote; Hypertension; Indans; Iodine Radioisotopes; Male; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

The mechanisms for the vascular actions of vasodilatory beta-blockers remain undetermined. For some kinds of beta-blockers, the involvement of nitric oxide (NO) has been suggested. We studied the effects of vasodilatory beta-blockers on renal perfusion pressure (RPP) and NO release in the rat kidney. Infusion of bopindolol, celiprolol, and nebivolol caused a dose-dependent reduction in RPP and an increase in NO release (RPP: bopindolol 10(-6) mol/L, -23+/-2%; celiprolol 10(-4) mol/L, -27+/-2%; nebivolol 10(-5) mol/L, -35+/-3%; NO: bopindolol 10(-6) mol/L, +33+/-2; celiprolol 10(-4) mol/L, +41+/-2; nebivolol 10(-5) mol/L, +45+/-5 fmol. min-1. g kidney-1, mean+/-SEM). Metergoline (10(-6) mol/L), a 5-hydroxytryptamine (5-HT)1/2 antagonist, or NAN-190 (10(-6) mol/L), a 5-HT1A antagonist, almost completely abolished the vasorelaxation and NO release caused by bopindolol, celiprolol, and nebivolol. However, neither propranolol nor bisoprolol decreased RPP. Celiprolol and nebivolol caused vasodilation in the rat thoracic aorta, and it was markedly reduced by endothelial denudation, Nomega-nitro-L-arginine methyl ester (10(-4) mol/L), or NAN-190 (10(-6) mol/L). In deoxycorticosterone acetate-salt hypertensive rats, 4-week administration of celiprolol (50 mg. kg-1. d-1 IV) restored the responses regarding RPP and NO release to acetylcholine. These results suggest that several beta-blockers exert their vasodilatory action through the 5-HT1A receptor/NO pathway and that treatment with these beta-blockers may protect against endothelial injury in hypertension.

Topics: Adrenergic beta-Antagonists; Animals; Aorta, Thoracic; Benzopyrans; Celiprolol; Desoxycorticosterone; Dose-Response Relationship, Drug; Endothelium, Vascular; Ethanolamines; Hypertension; In Vitro Techniques; Kidney; Male; Metergoline; Muscle, Smooth, Vascular; Nebivolol; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phenylephrine; Pindolol; Piperazines; Piperidines; Platelet Aggregation Inhibitors; Quinazolines; Rats; Rats, Wistar; Renal Circulation; Serotonin Antagonists; Vasoconstriction; Vasodilator Agents

We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade.

Topics: Endothelin-1; Endothelin-2; Female; Forearm; Humans; Hypertension; Male; Middle Aged; Oligopeptides; Peptides, Cyclic; Piperidines; Regional Blood Flow; Vasodilation

The physiological and pathophysiological functions of endothelin-1 in modulating the regional blood flow of normal and spontaneously hypertensive rats (SHR) were studied in the perfused mesenteric vascular bed, a useful model for investigating resistance vessels.. We used 12-week-old SHR and Wistar-Kyoto (WKY) rats. Endothelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2-2 mumol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafotoxin S6c concentration-response curves, obtained in the noradrenaline-precontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation.. In both groups, endothelin-1 induced concentration-dependent contraction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 concentration-response curves in both groups, with a higher pA2 (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) value in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response (EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which was not observed in SHR.. The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the presence of an ETA receptor subtype. This mechanism may be linked to the production of prostanoids that add to the direct endothelin-1-evoked vasoconstriction. These results, together with the lack of relaxation in response to sarafotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this strain.

Topics: Animals; Antihypertensive Agents; Azepines; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Hypertension; Indomethacin; Mesenteric Arteries; Oligopeptides; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vascular Resistance; Vasoconstriction

1. The inbred genetically hypertensive strain (GH) of the Otago Wistar rat possesses more sensory neurons containing the neuropeptide substance P (SP) than does its genetically related control normotensive strain. 2. As SP contributes to airway inflammation by increasing microvascular permeability, we assessed the extravasation of Evans Blue dye in trachea and main bronchus of anaesthetized GH and control rats, in the presence of endogenous (capsaicin-liberated) or exogenous SP. 3. Following intravenous administration of either capsaicin (75 microg kg(-1)) or SP (3.3 nmol kg(-1)), extravasation of Evans Blue in airways from GH rats was only about 60% of that in airways of control rats. This difference was not gender-specific and responses to capsaicin were abolished by pretreatment with a selective NK1 receptor antagonist SR 140333 (360 nmol kg(-1)). 4. By contrast, the extravasation of dye caused by intravenous 5-hydroxytryptamine (0.5 micromol kg(-1)) was similar in magnitude in both GH and control strains. 5. Falls in systemic arterial blood pressure in response to exogenous SP (0.1-3 nmol kg(-1)) or acetylcholine (0.2-2 nmol kg(-1)) were also very similar between strains, but those in response to capsaicin (75 microg kg(-1)) in the GH rats were about double those in control rats. The hypotensive response to SP was abolished by SR 140333, but that to capsaicin was unaffected. 6. Our results indicate that the increased peripheral innervation density by SP-nerves in GH rats is accompanied by reduced inflammatory responses to SP. This does not involve decreased vasodilator potency of SP and is therefore probably related to altered endothelial responsiveness.

Topics: Animals; Blood Pressure; Capillary Permeability; Capsaicin; Hypertension; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Substance P

In pregnant rats during hypertension induced by NO synthase inhibition, endothelin (ET) plasma levels are increased as in some preeclamptic women. Previously, the enhanced vasodepressor effect of endothelin-1 (ET-1) has been observed in this model, thus we decided to study the relaxation induced by ET-1 on the aorta. Non-pregnant or pregnant Wistar rats (n = 7 by group) were fed for 7 days (day 13-day 20) on a nitroarginine-enriched diet (L-NNA, 0.063% i.e. 30 mg/kg/day) or a control diet. Systolic blood pressure, measured by the tail cuff method on conscious rats at day 20 of gestation, was raised by the chronic L-NNA treatment (mean +/- s.e.m., mmHg, p < 0.001: pregnant L-NNA treated, 145 +/- 1.84 vs. pregnant control, 101 +/- 2.00 and non-pregnant L-NNA treated, 148 +/- 3.11 vs. non-pregnant control, 119 +/- 1.80). On day 20 ex vivo aortic ring relaxation was produced by ET-1 in vessels previously precontracted with norepinephrine only when endothelium was present. In control rats, ET-1 (10(-8) to 5 x 10(-8) M) produced a short but significant relaxation (mean value between 4 to 19%) followed by a long-lasting contracting phase, and a higher ET-1 concentration (10(-7) M) only produced contraction. Chronic L-NNA treatment decreased the level of relaxation (at least p < 0.05, in non-pregnant and pregnant rats) and with a 30 min L-NAME (10(-4) M) preincubation, relaxation was completely inhibited in non-pregnant and pregnant rats. BQ-123, an ETA receptor antagonist, did not produce any effect on ET-1 induced relaxation. BQ-788, an ETB receptor antagonist, significantly decreased it. In conclusion, in female rats, as in male rats, ET-1 induces a transient relaxation in the preconstricted aorta which involves endothelial ETB receptors. Despite a decrease in the systemic vascular reactivity during late gestation, the vasodilating and vasoconstricting properties of ET-1 on the aorta are not changed.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; Female; Growth; Hypertension; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Pregnancy; Rats; Rats, Wistar; Vasoconstrictor Agents

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K(+) (K(v)) channels and release of intracellular Ca(2+), were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K(+) current [I(K(v))], with maximum inhibition of 12-18% seen at a concentration of 0.1-1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I(K(v)) inhibition, a switch in coupling between ET-1 and I(K(v)) from ET(B) to ET(A) receptors occurred. This switch in receptor coupling, combined with reduced I(K(v)) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ET(A)-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.

Topics: Animals; Antihypertensive Agents; Calcium; Chronic Disease; Electrophysiology; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypoxia; Male; Muscle, Smooth, Vascular; Oligopeptides; Peptides, Cyclic; Piperidines; Potassium Channel Blockers; Potassium Channels; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptors, Endothelin

Insulin-elicited endothelin release in hypertriglyceridemic, hypertensive, hyperinsulinemic (HTG) rats was shown. Weanling male Wistar rats were given 30% sucrose in their drinking water for 20-24 wk. In vitro contractions of aorta and femoral arteries were elicited with 40 mM KCl. Endothelin release induced with KCl plus 50 microU/ml insulin resulted in increases in contractile responses: 41 +/- 5.9 and 57 +/- 6% for control and 65.5 +/- 6 and 95 +/- 9% for HTG aortas and femoral arteries, respectively. The endothelin ET(B)-receptor blocker BQ-788 decreased responses to KCl + insulin by 39 +/- 8 and 53 +/- 5% in control and 48 +/- 13 and 79 +/- 3.5% in HTG aortas and femoral arteries, respectively. The ET(A)-receptor antagonist PD-151242 inhibited these responses by 12 +/- 10 and 1 +/- 9% in control and by 51.5 +/- 9 and 58.5 +/- 1% in HTG aortas and femoral arteries, respectively. These results suggest that endothelin may contribute to the hypertension in this model.

Topics: Animals; Animals, Newborn; Antihypertensive Agents; Azepines; Endothelin-1; Glucose Tolerance Test; Hypertension; Hypertriglyceridemia; Insulin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oligopeptides; Piperidines; Potassium Chloride; Rats; Rats, Wistar

We describe the use of remifentanil in a woman with severe pre-eclampsia who presented for emergency caesarean section. Remifentanil was effective in obtunding the hypertensive response to laryngoscopy and intubation. Previous studies have found no significant adverse effects of remifentanil on the neonate. With its short duration of action, the use of this new opioid has several potential advantages in the above setting. Further studies are required to explore the use of remifentanil as an adjunct to obstetric general anaesthesia.

Topics: Adult; Analgesics, Opioid; Anesthesia, General; Anesthesia, Obstetrical; Cesarean Section; Emergencies; Female; Humans; Hypertension; Intubation, Intratracheal; Liver; Piperidines; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Remifentanil; Thrombocytopenia

We have shown previously that chronic intrahippocampal, intraperitoneal and subcutaneous administrations of non-peptide opioid receptor agonists induced depressor responses in the spontaneously hypertensive rat (SHR). However, it is not clear whether the hypotensive effect of systemic administration involves kappa receptors behind the blood-brain barrier. In this study, the relative roles of central vs peripheral kappa-opioid receptors in the hypotensive effect of kappa-agonists was examined in conscious SHRs following chronic subcutaneous administration of two selective kappa-agonists, BRL 52656 which freely penetrates the blood-brain barrier, and BRL 52974 which has only limited ability to do so. Initial studies determined the dose-response relationship for each of the two drugs given intraperitoneally twice a day, while monitoring systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) measured by the tail-cuff method. Both drugs caused biphasic arterial pressure responses, with lower doses of BRL 52656 causing depressor effects and higher doses resulting in pressor effects. By contrast, lower doses of BRL 52974 caused pressor effects and higher doses depressor effects. The biphasic effects occurred with BRL 52656 from 0.01 to 3.0 mg kg(-1) and that for BRL 52974 from 0.1 to 30 mg kg(-1). In subsequent studies the drugs were infused chronically, subcutaneously via osmotic minipumps over a 14-day period, BRL 52656 at 0.2 or 0.5 mg kg(-1)/day and BRL 52974 at 0.2 mg kg(-1)/day. At lower doses, BRL 52656 decreased SAP, MAP and HR but at higher doses only bradycardia was observed. BRL 52974 given chronically subcutaneously over 14 days had no significant effects on arterial pressure and decreased heart rate only after seven days of treatment. Collectively, the results established that only the kappa-agonist, which gained access to the central nervous system, lowered arterial pressure and heart rate, whereas the compound with limited ability to cross the blood-brain barrier was ineffective at equivalent doses. The complex dose-response pattern found with both drugs suggests that kappa-agonists have central hypotensive and bradycardic actions at low doses but at higher doses a mixture of both central and peripheral actions leads to hypertension and tachycardia.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood-Brain Barrier; Dose-Response Relationship, Drug; Drinking; Heart Rate; Hypertension; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Piperidines; Pyridines; Pyrrolidines; Rats; Rats, Inbred SHR; Receptors, Opioid, kappa; Weight Gain

To determine whether the vasoconstrictor response to endothelin-1 (ET-1) is altered in coronary vessels of hypertensive hearts and the role of ETA and ETB receptors in these responses to ET-1, the vasoconstrictor response to ET-1 in coronary vessels was measured with or without ETA and ETB receptor antagonists. In isolated hearts of spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat, the coronary perfusion pressure was measured on a Langendorff apparatus with constant pressure (75 mm Hg). Coronary perfusion resistance (CPR) (mm Hg/ml/min/g) was calculated. ET-1 elicited dose-dependent increases of CPR in both normotensive and SHR rat hearts. However, the responses were significantly greater in SHR than those of WKY. Pretreatment with the ETA antagonist FR139317 and the ETB antagonist BQ788 inhibited CPR increases with ET-1 infusion. However, vasoconstrictor responses to ET-1 were still greater in SHR than in WKY after FR139317 or BQ788 infusion. These findings suggest that the augmented vasoconstrictor response of coronary artery to ET-1 is mediated by both ETA and ETB receptors. These changes may contribute to the impaired coronary circulation in hypertension.

Topics: Animals; Azepines; Blood Pressure; Coronary Circulation; Coronary Vessels; Endothelin Receptor Antagonists; Hypertension; In Vitro Techniques; Indoles; Male; Oligopeptides; Perfusion; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction

The pathophysiological role of endothelin ET(B) receptor-mediated action on systemic and renal hemodynamics and urine formation in deoxYcorticosterone acetate (DOCA)-salt hypertensive rats was investigated. An intravenous bolus injection of a selective ET(B) receptor antagonist, BQ788 (1 mg/kg), produced a significant increase in mean arterial pressure (MAP) of DOCA-salt treated rats, whereas the agent-induced increase in MAP was less marked in normotensive sham rats. Administration of BQ788 caused a significant and sustained reduction in renal blood flow both in DOCA-salt and sham rats. No marked effects were observed on urine formation in both groups. Alternatively, a selective ET(A) receptor antagonist, FR139317 (10 mg/kg), produced a potent hypotensive effect, accompanied by significant renal vasodilation in DOCA-salt hypertensive rats, but these effects were partially reversed by the subsequent administration of BQ788. When renal perfusion pressure was protected from FR139317-induced hypotension by an aortic clamp, significant diuresis and natriuresis were observed, events partially reversed by the subsequent administration of BQ788. Our results indicate that the ET(B) receptor-mediated action tonically functions as a hypotensive and a renal vasodilatory factor and that these effects seem to be up-regulated in DOCA-salt hypertension. We also suggest that the ET(A) receptor blockade in DOCA-salt hypertensive rats unmasks the ET(B) receptor-mediated action which partially contributes to the antihypertensive effect induced by FR139317.

Topics: Animals; Azepines; Desoxycorticosterone; Endothelin-1; Hemodynamics; Hypertension; Indoles; Kidney; Male; Oligopeptides; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Receptors, Endothelin; Urination

The structural and mechanical properties of small arteries are altered in rat models of hypertension. The precise role of humoral factors in these changes has not been determined. In deoxycorticosterone acetate (DOCA) salt hypertension, endothelin-1 (ET-1) peptide content and gene expression are enhanced in mesenteric resistance arteries. These vessels also present augmented vasoconstrictor responsiveness to vasopressin versus control uninephrectomized rats. To determine whether an interaction exists between vasopressin and ET-1 in the pathogenesis of small-artery structural alterations in DOCA-salt rats, we examined the effect of chronic V1 vasopressin receptor antagonism (OPC-21268, 30 mg/kg BID) on the structure and mechanical properties of mesenteric resistance arteries using a pressure myograph and the effect on preproendothelin-1 (preproET-1) gene expression, determined by Northern blot analysis of preproET-1 mRNA. Tail-cuff systolic pressures were elevated in DOCA-salt (200+/-11 mm Hg) versus uninephrectomized rats (109+/-4 mm Hg) and decreased slightly but significantly by OPC-21268 to 187+/-7 mm Hg (P<0.01). Treatment with DOCA-salt increased vascular media-lumen ratios and media cross-sectional areas and reduced both stress and incremental elastic modulus for a given pressure. However, there was no change in distensibility or incremental elastic modulus versus media stress. OPC-21268 partially attenuated the vascular growth in DOCA-salt rats. PreproET-1 mRNA was increased 2-fold in mesenteric arteries of DOCA-salt rats versus uninephrectomized rats, an effect abrogated by OPC-21268. Thus, DOCA-salt hypertension is associated with altered morphology of the small-arterial wall, without altering stiffness of the arterial wall components. OPC-21268 regressed in part these changes, suggesting the involvement of vasopressin. The concomitant attenuation of enhanced ET-1 expression by OPC-21268 suggests that ET-1 may be involved in mediating in part the vascular effects of vasopressin in DOCA-salt hypertensive rats.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Biomechanical Phenomena; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Elasticity; Endothelin-1; Gene Expression; Hypertension; Male; Mesenteric Artery, Superior; Nephrectomy; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Vasodilation

Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H3 receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which new H3 receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H3 receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension. All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 mumol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H3 receptor agonists, R-(-)-alpha-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H3 binding sites (labelled by 3H-N alpha-methylhistamine; pKi 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 mumol/kg to about the same degree in rats of either strain. The present study confirms the occurrence of presynaptic H3 receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H3 receptors are

Topics: Adrenergic Fibers; Animals; Blood Pressure; Decerebrate State; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Hypertension; Imidazoles; Male; Methylhistamines; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagotomy; Vascular Resistance

To characterize the role of arginine vasopressin (AVP) V(1A) or V2 receptors and the possible interaction with the renin-angiotensin system in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR), young male SHR were treated from 6 to 10 wk of age with AVP V(1A) receptor blockade, angiotensin-converting enzyme (ACE) inhibition, combination of V(1A) receptor blockade and ACE inhibition, V2 receptor blockade, and vehicle. Treatments were then withdrawn, and systolic blood pressure (SBP) was measured until 19 wk of age. At both 10 and 19 wk of age, SBP was significantly reduced with V(1A) receptor blockade, ACE inhibition, and combined treatment compared with vehicle treatment, although no treatment normalized SBP to levels of Donryu normotensive rats. Throughout the experimental period, no significant additive effects were observed with combined treatment. At 10 wk of age, plasma AVP concentration and 24-h urinary AVP excretion were increased with AVP V2 receptor blockade. At 19 wk of age, SBP was significantly higher in rats previously treated with V2 receptor blockade (233 +/- 3 mmHg) than with vehicle (221 +/- 2 mmHg) (P < 0.01). Left ventricular mass was significantly reduced in rats previously treated with ACE inhibition or combined treatment. These results suggest that AVP (via V(1A) receptors) and angiotensin II contribute to the pathogenesis of SHR hypertension, whereas the AVP V2 receptor may be involved in preventing the full expression of the hypertension, in male SHR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Blood Pressure; Hypertension; Male; Myocardium; Organ Size; Piperidines; Quinolones; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Systole; Time Factors

To investigate the role of the endothelium in the functional interaction between endothelin-1 and norepinephrine in the contractile response of aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).. Thoracic aorta rings with and without endothelium from SHR and from WKY rats were suspended in an organ bath to record the isometric tension. After an equilibration period of 120 min, the preparations with and without endothelin-1 were subjected to single and cumulative additions of norepinephrine in different experiments. To characterize the mechanisms involved in the interaction between endothelin-1 and norepinephrine, the aortic rings were pretreated with a cyclooxygenase pathway inhibitor (piroxicam, SO29548), an inhibitor of NO synthase [NG-nitro-L-arginine (NLA)], or selective endothelin receptor blockers (BQ-123 or BQ-788). In some experiments we examined the contractile responses to norepinephrine in aortas pretreated either with angiotensin II (AII) or with U46619, an agonist of prostaglandin H2-thromboxane A2 receptors. Finally, we examined the effect of the combination of calcium-entry blockade by administration of nifedipine and treatment with either endothelin-1 or U46619 on the norepinephrine reactivity.. Administration of 3 x 10(-10) mol/l endothelin-1 potentiated the contractile response to norepinephrine in SHR aortas with endothelium, irrespective of whether they had been treated with NLA. No endothelin-1-mediated enhancement of the response to norepinephrine was observed in SHR denuded rings and in untreated and NLA-treated WKY rat aortas. All did not affect the response to norepinephrine in SHR rings with endothelium. The amplification by endothelin-1 of the response to (1-100) x 10(-9) mol/l norepinephrine was abolished by blockade of the cyclooxygenase pathway with piroxicam or SO29548. In WKY rat and SHR denuded aortas, 10(-8) mol/l U46619 potentiated the contractile responses to norepinephrine. Administration of 3 x 10(-6) mol/l BQ-123 abolished the increase in reactivity to norepinephrine evoked by endothelin-1 in intact SHR aorta, whereas 3 x 10(-6) mol/l BQ-788 failed to modify this potentiating effect. Administration of 10(-8) mol/l nifedipine inhibited the potentiation of the norepinephrine-induced contractions evoked both by endothelin-1 in SHR aortic rings with endothelium and by U46619 in SHR denuded rings.. Our results show that a low concentration of endothelin-1 induced potentiation of the contractile response to norepinephrine in SHR aortas but not in WKY rat aortas. This response was endothelium-dependent. Furthermore, our study affords functional arguments that both endothelial and smooth muscle pathways are involved in the potentiating interaction. We propose that endothelin-1 stimulates the production of endothelium- and cyclooxygenase-generated vasoconstrictor factors, which in turn may serve directly as priming stimuli at the vascular smooth muscle level, to activate the Ca(2+)-signal pathway and consequently to increase locally the vascular sensitivity to norepinephrine.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Male; Nifedipine; Norepinephrine; Oligopeptides; Peptides, Cyclic; Piperidines; Piroxicam; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Endothelin; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Both human essential hypertension and genetically induced hypertension in rats have been associated with a range of impairments of cognitive ability. The spontaneous hypertensive rat (SHR) previously has been shown to exhibit a decrease in the expression of brain nicotinic acetylcholine receptors, a factor that could play a role in the impaired ability of this strain in the performance of learning and memory-related tasks. The purpose of this study was to help determine whether task impairment by SHR was related to the reduced expression of central nicotinic acetylcholine receptors. Twelve-week-old SHR were tested in two phases of a water maze (spatial memory) task, and their performance was compared with that of two age-matched normotensive strains, Wistar Kyoto (WKY) and Wistar rats. During Phase 1, SHR exhibited significantly increased latencies to locate a hidden platform as compared with either WKY or Wistar rats. During Phase 2 (subsequent series of trials after a 4-day inter-phase period), where rats were required to find a new platform location, SHR again exhibited significantly impaired performance compared to the normotensive strains. In a single trial passive avoidance paradigm, SHR again displayed significantly reduced avoidance behavior as compared with both WKY and Wistar rats. In consecutive coronal sections, the density of [3H]cytisine binding sites was decreased in SHR by up to 25% in about half of the brain regions examined, with the deficits particularly apparent in cephalic regions. The binding of [125I]alpha-bungarotoxin to brain sections also was decreased in SHR; however, only certain brain areas exhibited significant interstrain differences. These alterations in the expression of putative nicotinic receptor subtypes in SHR were not due to changes in the density of cholinergic neurons since there were no interstrain differences in the binding densities for [3H]vesamicol, which labels the vesicular acetylcholine transporter. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from SHR as compared with those from normotensive rats. These results are consistent with the possibility that a reduction in the expression of cortical nicotinic receptors in SHR plays a role in this strain's impaired performance of both spatial and non-spatial learning and memory-related tasks.

Topics: Alkaloids; Animals; Autoradiography; Avoidance Learning; Azocines; Blood Pressure; Brain; Bungarotoxins; Carrier Proteins; Cognition Disorders; Corpus Striatum; Frontal Lobe; Humans; Hypertension; Iodine Radioisotopes; Male; Maze Learning; Membrane Transport Proteins; Organ Specificity; Piperidines; Quinolizines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Receptors, Nicotinic; Rubidium; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

To assess the chronic in vivo effects of OPC-21268, a vasopressin-V1 receptor antagonist, on renal injury, we investigated the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta1 and proliferating cell nuclear antigen (PCNA) in the glomeruli of spontaneously hypertensive rats (SHR) treated with OPC-21268 for 3 weeks. SHR aged 10 weeks were given 2% NaCl in drinking water for 3 weeks. The OPC group was fed a 0.5% OPC-21268-containing diet for 3 weeks and the control group was given a normal diet. There were no significant changes in the time course of systolic blood pressure, heart rate, urine volume, or urinary sodium, protein and N-acetyl-beta-glucosaminidase (NAG) excretion between the two groups. Serum electrolytes, protein and creatinine levels also did not differ between the groups. The mRNA expressions of PDGF B-chain, TGF-beta1 and PCNA in the glomerulus were examined using reverse transcriptase-polymerase chain reaction (RT-PCR) methods. The mRNA expressions of PDGF B-chain and PCNA among these were significantly suppressed in the OPC group. No significant differences in renal histology including the organ weights were found between the two groups; however, the glomerular size tended to be enlarged in the OPC group. These findings suggest that chronic V1-receptor blockade directly inhibits the glomerular proliferative injury of salt-loaded SHR at the established hypertension stage.

Topics: Acetylglucosaminidase; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Body Weight; Growth Substances; Heart Rate; Hypertension; Kidney Glomerulus; Organ Size; Piperidines; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Proliferating Cell Nuclear Antigen; Proteinuria; Quinolones; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium; Transforming Growth Factor beta; Urine

To elucidate the role of cerebral adenosine triphosphate (ATP)-sensitive K+ channels (KATP) on arterial pressure regulation during acute cerebral ischemia in spontaneously hypertensive rats (SHR), intracerebroventricular (i.c.v.) injections of either glibenclamide, a specific blocker of KATP, or pinacidil, a KATP opener, were performed in SHR and Wistar-Kyoto rats (WKY). Intracerebroventricular injections of glibenclamide elicited a vasopressor response in WKY with bilateral ligation of the carotid arteries, whereas the response was smaller in SHR. It increased plasma AVP, but decreased pituitary AVP in WKY with ligation, but not in SHR. Systemic administration of an AVP V1 receptor antagonist, OPC-21268, abolished the vasopressor responses to i.c.v. injections of glibenclamide in WKY. Bilateral ligation of the carotid arteries augmented the vasodepressor responses to i.c.v. injections of pinacidil in WKY, but not in SHR. Cerebral KATP may play a role in buffering a rise in arterial pressure by inhibiting the release of AVP from the pituitary glands during acute cerebral ischemia in WKY, but this mechanism might be deranged in SHR, probably due to impaired responsiveness of cerebral KATP to ischemia.

Topics: Adenosine Triphosphate; Adrenergic alpha-Antagonists; Animals; Antidiuretic Hormone Receptor Antagonists; Antihypertensive Agents; Arginine Vasopressin; Arterial Occlusive Diseases; Blood Pressure; Brain Ischemia; Carotid Arteries; Cerebral Cortex; Glyburide; Guanidines; Hypertension; Hypoglycemic Agents; Injections, Intravenous; Injections, Intraventricular; Ligation; Male; Pinacidil; Piperidines; Potassium Channels; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Endothelin-1 (ET-1) has been implicated in the regulation of vascular tone in various pathological conditions. To examine the effect of in vivo overexpression of the peptide in rats, we prepared recombinant adenovirus stocks encoding the human preproET-1 cDNA (Ad.ET-1) or Escherichia coli lacZ (Ad.betaGal), each driven by cytomegalovirus early promoter. Ad.ET-1 or Ad.betaGal was injected into the caudal vein of rats and the animals were studied under anesthesia 96 h later. Hepatic overexpression of the virus-derived human ET-1 mRNA was accompanied by a 13-fold elevation of liver ET-1 content in the Ad.ET-1 group. Circulating plasma ET-1 levels in the Ad.ET-1 group were sixfold higher than those in the Ad.betaGal group. Mean arterial blood pressure was increased by 28 mmHg in the Ad.ET-1 group as compared with the Ad.betaGal group. In the Ad.ET-1 group, intravenous infusion of the ET(A) receptor antagonist FR 139317 reduced the blood pressure to levels seen in the Ad.betaGal group, whereas the same antagonist did not significantly alter the blood pressure in the Ad.betaGal group. Intravenous infusion of the ET(B) receptor antagonist BQ-788 caused a small but significant increase in blood pressure in both groups. These findings demonstrate that endogenous overexpression of preproET-1, accompanied by an elevation of plasma ET-1 concentrations to the levels seen in pathophysiological states, can cause systemic hypertension through the activation of the ETA receptor.

Topics: Adenoviruses, Human; Animals; Azepines; Blood Pressure; Blotting, Northern; Cytomegalovirus; DNA, Complementary; Endothelin-1; Escherichia coli; Gene Expression Regulation; Genetic Vectors; Humans; Hypertension; Indoles; Kidney; Lac Operon; Liver; Male; Oligopeptides; Piperidines; Promoter Regions, Genetic; Rats; Recombination, Genetic; RNA, Messenger

SCH 51866 is a potent and selective PDE1 and PDE5 inhibitor. The antiplatelet, antiproliferative, and hemodynamic effects of SCH 51866 were compared with those of E4021, a highly selective PDE5 inhibitor. SCH 51866 inhibited PDE1 and PDE5 isozymes with a 50% inhibitory concentration (IC50) of 70 and 60 nM, respectively. SCH 51866 and E4021 inhibited washed human platelet aggregation induced by collagen with an IC50 of 10 and 4 microM, respectively, and attenuated (p < 0.05) the adhesion of 111indium-labeled platelets to the nylon filament-injured rat aorta. The doses of SCH 51866 and E4021 that inhibited platelet adhesion caused significant increases in platelet cyclic guanosine monophosphate (cGMP; p < 0.05). SCH 51866 (1-10 mg/kg, p.o. twice daily) but not E4021 (3-30 mg/kg, p.o twice daily) inhibited neointima formation in the carotid arteries of spontaneously hypertensive rats (SHRs) subjected to balloon angioplasty. Moreover, SCH 51866 (0.3-10 mg/kg, p.o.) elicited dose-dependent reduction in blood pressure in SHRs, whereas E4021 (3-30 mg/kg, p.o.) did not affect blood pressure in SHRs. In conclusion, the data suggest that inhibition of PDE1 and PDE5 isozymes by SCH 51866 exerts antiplatelet and vascular protective effects. In comparison, inhibition of PDE5 alone by E4021 exhibited antiplatelet effects without affecting neointima formation.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Arteries; Blood Platelets; Cattle; Cell Division; Cyclic Nucleotide Phosphodiesterases, Type 5; Dogs; Enzyme Inhibitors; Humans; Hypertension; Imidazoles; Nucleotides, Cyclic; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperidines; Platelet Aggregation Inhibitors; Quinazolines; Rats; Rats, Inbred SHR

To investigate the clinical significance of interactions between cisapride and sustained-release nifedipine, we compared the plasma nifedipine concentration and blood pressure after administration of nifedipine alone (20 mg) with those obtained after administration of nifedipine cisapride (2.5 mg) in 20 patients with hypertension. The plasma nifedipine level was not altered by cisapride at one hour after administration, but was significantly increased at two (p < 0.01), three (p < 0.01), and four (p < 0.05) hours when compared with the level measured after nifedipine alone. Cisapride significantly decreased the mean blood pressure at three hours (p < 0.05) after administration of nifedipine. The acetaminophen method was used to determine gastric emptying time. The plasma concentration of acetaminophen at 45 minutes after administration was significantly increased by cisapride, suggesting that enhanced gastrointestinal motility might be the basis for the increase in the plasma nifedipine concentration. These results suggest that enhancement of the antihypertensive effect of nifedipine can occur when the drug is prescribed with cisapride, and that caution is needed when using such a combination therapy.

Topics: Aged; Calcium Channel Blockers; Cisapride; Delayed-Action Preparations; Drug Interactions; Female; Gastric Emptying; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Hypertension; Male; Middle Aged; Nifedipine; Piperidines

1. The aim of this study was to clarify the extent to which vascular nitric oxide contributes to basal blood pressure in conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. 2. The contribution of vascular nitric oxide to maintenance of blood pressure was estimated by measuring the pressor response to an intravenous injection of nitric oxide synthase inhibitor, N omega-L-arginine methyl ester, given after serial injections of captopril, vasopressin V1-receptor antagonist (V1-antagonist) and ganglion blocker (pentolinium) in conscious spontaneously hypertensive and Wistar Kyoto rats aged 20-28 weeks. To estimate the 'amplifier property' of hypertrophied vasculature in spontaneously hypertensive rats, which is known to modulate pressor responses, the lower blood pressure plateau after serial injections of captopril, V1-antagonist and pentolinium and the maximum blood pressure elicited by subsequent injection of increasing doses of phenylephrine were also measured. 3. The serial injections of captopril, V1-antagonist and pentolinium decreased mean arterial pressure from 164 +/- 9 mmHg to 67 +/- 2 mmHg and from 117 +/- 2 mmHg to 49 +/- 1 mmHg in spontaneously hypertensive and Wistar Kyoto rats respectively. The subsequent injection of N omega-L-arginine methyl ester restored mean arterial pressure almost to its control levels in both spontaneously hypertensive and Wistar Kyoto rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Arginine; Blood Pressure; Captopril; Endothelium, Vascular; Heart Rate; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pentolinium Tartrate; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Abnormalities of the vasopressin system are found in genetic hypertension. This study compares the delayed effects of a brief period of vasopressin V1A receptor blockade and angiotensin-converting enzyme inhibition in young female and male spontaneously hypertensive rats (SHR) on the development of hypertension in adult life. In a separate study, the role of vasopressin in the maintenance of blood pressure in adult SHR was assessed. Young SHR received either the nonpeptide vasopressin V1A receptor antagonist OPC-21268, the angiotensin-converting enzyme inhibitor ramipril, or vehicle from 6 to 10 weeks of age. During the treatment period, OPC-21268 and ramipril reduced systolic blood pressure compared with control SHR (P < .001). Blood pressure in male SHR 7 weeks after treatment withdrawal was 178 +/- 1 mm Hg in ramipril-treated, 184 +/- 1 mm Hg in OPC-21268-treated, and 200 +/- 2 mm Hg in control SHR (P < .001). Similar results were seen in female SHR, although both OPC-21268 and ramipril were less effective antihypertensive agents in female compared with male SHR. The sustained attenuation in blood pressure was not associated with significant cardiovascular structural changes (left ventricular-to-body weight ratio, renal weight-to-body weight ratio, mesenteric resistance artery media-to-lumen ratio). Results of vasopressin V1A receptor binding kinetics and plasma renin or aldosterone concentrations did not suggest a lasting effect of OPC-21268 on the vasopressin system or of ramipril on the renin-angiotensin system following treatment withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Body Weight; Female; Hypertension; Male; Piperidines; Quinolones; Ramipril; Rats; Rats, Inbred SHR

Efficacy of orally available, selective vasopressin V1 and V2 receptor antagonists on the developing and established stage of DOCA-salt hypertension was investigated. Twenty-nine Wistar rats were heminephrectomized, and administered DOCA (50 mg/kg; intraperitoneally twice a week) and salt (5% NaCl diet) from week 0 to the end of study. Group 1 rats were served as control. Group 2 and 5 rats were given a V1 antagonist, and groups 3 and 6 rats were given a V2 antagonist, while groups 4 and 7 rats received both V1 and V2 antagonists. Each drug was started to groups 2, 3 and 4 at week 0, and to groups 5, 6 and 7 at week 4. Significant amelioration of the increase in blood pressure was observed in groups 3 and 4 at week 10, and a reduction in blood pressure occurred in groups 6 and 7 at week 10. Otherwise, a V1 antagonist alone slightly attenuated blood pressure rise in the group 2 without significance, and failed to lower blood pressure of the group 5 during the study. These results suggest that both V1 and V2 agonisms are involved in an increase in blood pressure at the developing stage of DOCA-salt hypertension, and that V2 agonism, but not V1 plays a major role in the maintenance of high blood pressure at the established stage.

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Body Weight; Desoxycorticosterone; Hypertension; Male; Piperidines; Quinolones; Random Allocation; Rats; Rats, Wistar; Sodium Chloride

Effects of novel, nonpeptide vasopressin V1 and V2 receptor antagonists on partially nephrectomized and salt-loaded spontaneously hypertensive rats (SHR), which develop severe hypertension and progressive nephrosclerosis, were investigated. SHR were 5/6-nephrectomized and fed a high salt diet. The rats were divided into four groups: group 1 was an untreated control, group 2 received the V1 antagonist OPC-21268, group 3 received the V2 antagonist OPC-31260, and group 4 received both the V1 and V2 antagonists. The V1 antagonist alone or combined with the V2 antagonist significantly decreased the increase in blood pressure (BP) of groups 2 and 4 rats, but the V2 antagonist alone did not reduce the increase in BP of the group 3 rats. The V2 antagonist alone or combined with the V1 antagonist induced a significant diuresis of rats in groups 3 and 4. The increase in urinary protein excretion and the progression of renal hyaline arteriolosclerosis were attenuated by the V1 antagonist with or without the V2 antagonist in rats in groups 2 and 4, but not by the V2 antagonist alone in rats in group 3. This implies that the progressive nephrosclerosis in SHR with partial renoablation and salt-loading was associated with V1 agonism.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Biomarkers; Blood Pressure; Body Weight; Disease Models, Animal; Diuresis; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney; Male; Nephrectomy; Nephrosclerosis; Piperidines; Proteinuria; Quinolones; Rats; Rats, Inbred SHR

To elucidate the effect of the arginine vasopressin (AVP) system in vivo, especially V1 and V2 activity, on blood pressure, we measured the acute changes in blood pressure and heart rate after AVP, OPC-21,268 (a V1 receptor antagonist), and OPC-31,260 (a V2 receptor antagonist) were injected intravenously in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at the age of 15 weeks. Compared with the control period, single injection of AVP 5 ng/kg significantly increased systolic blood pressure in WKY rats without a concomitant increase in heart rate, but there was no significant increase in blood pressure in SHR. In contrast, single injection of either OPC-21,268 3 mg/kg or OPC-31,260 3 mg/kg did not affect blood pressure or heart rate in either SHR or WKY rats. Injection of AVP after the administration of OPC-31,260 induced a greater increase in blood pressure in SHR than in WKY rats, whereas injection of AVP after the administration of OPC-21,268 did not induce any clear increase in blood pressure in SHR or WKY rats. These results suggest that SHR have enhanced pressor activity mediated by V1 receptors and that this increase may be due to an increase in their number. In conclusion, enhancement of V1 activity may contribute to the development of high blood pressure in SHR.

Topics: Animals; Arginine Vasopressin; Benzazepines; Blood Pressure; Heart Rate; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Vasopressin; Stimulation, Chemical

To determine whether the vasopressor and antidiuretic actions of arginine vasopressin (AVP) may participate in the development of salt-induced hypertension, we examined the long-term effects of AVP V1 and V2 receptor antagonists on blood pressure (BP) in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats. From age 7 weeks, DS and DR rats were fed a diet containing 8% NaCl, alone (control group); 8% NaCl and 1% OPC-21268 (V1 antagonist-treated group); or 8% NaCl and 0.05% OPC-31260 (V2 antagonist-treated group). The pressor response to AVP was significantly inhibited in DS rats treated with OPC-21268. Urinary volume and water intake were significantly increased by administration of OPC-31260; this increase was greater in DR rats than in DS rats. Indirect BP measurements obtained using tailcuff plethysmography showed that DS but not DR rats developed hypertension when fed high-salt diets. However, chronic treatment with either OPC-21268 or OPC-31260 did not alter the course of hypertension in DS rats, despite the effective blocking actions of these antagonists. This finding also was confirmed by direct BP measurements. Our results indicate that even if AVP plays a role in salt-induced hypertension peripheral blockade of either subtype of AVP receptors does not prevent the development of hypertension in DS rats.

Topics: Analysis of Variance; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Benzazepines; Blood Pressure; Blood Pressure Determination; Diuresis; Hypertension; Male; Piperidines; Quinolones; Rats; Sodium Chloride

Chronic effects of orally available, nonpeptide vasopressin V1 and V2 receptor antagonists on conscious spontaneously hypertensive rats (SHR) were investigated. SHR and Wistar rats were divided into four groups, groups S-1 to S-4 and W-1 to W-4, respectively. Groups S-1 and W-1 were untreated as control. Groups S-2 and W-2 were treated with V1 antagonist, groups S-3 and W-3 received V2 antagonist, and groups S-4 and W-4 were treated with both of V1 and V2 antagonists. V1 and/or V2 antagonists did not affect degree of blood pressure of W-2, W-3, and W-4 rats, and V1 antagonist, alone or combined with V2 antagonist, slightly reduced increases in blood pressure of S-2 and S-4 rats without significance. However, V2 antagonist induced significantly massive and hyposmolar urine in W-3 rats compared with that in S-3 rats. In conclusion, in SHR, circulating vasopressin contributes to increases in blood pressure via either V1 or V2 receptors less than expected from previous studies with antibodies or peptide antagonists.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Pressure; Hypertension; Male; Osmolar Concentration; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Vasopressin; Urine; Vasopressins

The present study compared the extent and duration of MAO inhibition by the selective and reversible MAO-A inhibitor brofaromine with the selective and irreversible MAO-A inhibitor clorgyline using amine pressor tests and excretion of urinary amine metabolites (MHPG, tryptamine). The pharmacological characterization of clorgyline as an irreversible and brofaromine as a reversible MAO-A inhibitor in clinically effective doses was confirmed in humans.

Topics: Administration, Oral; Adult; Blood Pressure; Clorgyline; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Hypertension; Infusions, Intravenous; Male; Methoxyhydroxyphenylglycol; Monoamine Oxidase; Norepinephrine; Piperidines; Reference Values; Tryptamines; Tyramine

It is well known that peripheral vasopressin (VP) is essential for the development and maintenance of DOC-salt hypertension. It is, however, still unclear whether central VP is involved in this type of hypertension. Therefore, the aim of this study was to clarify the role of central VP in the regulation of blood pressure in DOC-salt hypertension. In order to examine this issue, three series of investigations were performed. First, a novel vasopressin V1 antagonist (OPC21268) was administered intravenously to DOC-salt hypertensive rats, and mean arterial blood pressure (MABP) and heart rate (HR) were recorded. Second, the concentration of VP in the perfusate of microdialysis of cerebrospinal fluid (CSF) was determined in DOC-salt hypertensive and control rats. Finally, intracerebroventricular (i.c.v.) administration of a V1 antagonist was performed in DOC-salt hypertensive rats to determine the central mechanism of hypertension. Intravenous administration of a V1 antagonist had no effect on MABP and HR. There was no difference in VP in the perfusate of CSF between DOC-salt hypertensive and control rats. I.c.v. administration of a V1 antagonist significantly decreased MABP and HR in a dose-dependent manner in DOC-salt hypertensive rats (P < 0.05-0.01). These results suggest that central VP is involved in the maintenance of DOC-salt hypertension, and the mechanism is, in part, mediated by upregulation of the V1 receptor.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Cardiac Output; Desoxycorticosterone; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Injections, Intravenous; Injections, Intraventricular; Male; Microdialysis; Piperidines; Quinolones; Rats; Rats, Wistar

The present study was undertaken to evaluate the effects of R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl)- N-methyl-2-benzothiazolamine) (Fig. 1) on postischemic ventricular function, an inhibitor of the Na+/Ca2+ overload, in the working heart preparation of the rat. The hearts were paced at 5 Hz and perfused with Tyrode solution of 37 degrees C at a physiological pH. After 15 min of pretreatment with R 56865, low-flow ischemia (30 min) was induced by reducing the perfusion pressure from 51.5 mmHg to 11.0 mmHg and R 56865 was infused simultaneously. The hemodynamic effects of R 56865 were evaluated in the concentration range [10(-8)-3.10(-6) M]. The five parameters measured were: LVP (Left Ventricular Pressure), +dP/dtmax (maximal rate of pressure increase), AO (Aortic Output), CF (Coronary Flow) and CO (Cardiac Output). They were determined in the working heart mode after 15 min of equilibration and at the end of the experiment. From these data the recovery percentages were calculated. The recovery percentages for the LVP, +dP/dtmax, AO, CF and CO for the control hearts (3.3%, 0.0%, 7.9%, 10.4% and 8.5%, respectively) differed significantly from those at 10(-7) M (39.6%, 40.8%, 25.0%, 41.8% and 29.9% respectively). The recovery percentage were the highest at 10(-6) M (79.6%, 82.1%, 54.7%, 92.7% and 67.2%, respectively). The concentration of 10(-7) M was associated with a smaller reduction in LVP (12.9%) than at 10(-6) M (25.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzothiazoles; Blood Glucose; Blood Pressure; Body Weight; Calcium Channel Blockers; Cardiac Output; Coronary Circulation; Diabetes Mellitus, Experimental; Heart; Heart Ventricles; Hypertension; In Vitro Techniques; Male; Myocardial Ischemia; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Thiazoles; Ventricular Function; Ventricular Pressure

We studied the contribution of vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the nonpeptide orally effective vasopressin V1 receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasopressin V1 receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140 +/- 4 mm Hg (n = 12) in DOCA-salt rats compared with 111 +/- 2 mm Hg in salt control rats (n = 18). Acute oral OPC-21268 (30 mg/kg) significantly (P < .01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24 +/- 3 mm Hg occurring at 2.5 +/- 0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178 +/- 2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P < .01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal decrease of 27 +/- 5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120 +/- 1 mm Hg, n = 20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC-21268 (30 mg/kg twice daily for 7 days) hepatic V1 receptor binding was significantly reduced for up to 10 hours (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Binding Sites; Blood Pressure; Desoxycorticosterone; Female; Hypertension; Kinetics; Mesenteric Arteries; Piperidines; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Sodium Chloride; Systole; Vascular Resistance

We studied the hypotensive effects of OPC-21268, an orally effective nonpeptide vasopressin V1 receptor antagonist, in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). OPC-21268 was given intravenously to conscious, freely moving SHR and SHRSP. We used young and aged animals to examine the contribution of vasopressin to the development and maintenance of hypertension in both types of rats. In SHR, hypertension was fully established at 38 weeks of age, and intravenous injection of OPC-21268 produced slight hypotensive effects at either 38 or 70 weeks of age. In SHRSP, hypertension developed at 25 weeks of age, and blood pressure was sustained at a high level (approximately 250 mm Hg systolic blood pressure) thereafter. Intravenous administration of OPC-21268 did not cause hypotensive effects in young rats at 15 weeks, but at 25 weeks a significant decrease in blood pressure was observed. Furthermore, in the malignant state of SHRSP (35 to 41 weeks), OPC-21268 significantly decreased mean blood pressure by 32.4 +/- 7.9 mm Hg (mean +/- SEM) at 3 mg/kg IV, and the decrease was dose dependent (0.3 to 3.0 mg/kg). Plasma vasopressin concentrations were increased in a more malignant phase of SHRSP at 45 weeks of age, whereas at other ages of SHRSP or in SHR, plasma vasopressin levels were not increased. These results suggest that vasopressin plays an important role through V1 receptors in the maintenance of hypertension, at least in the malignant phase of SHRSP, and OPC-21268 may be therapeutically useful in the treatment of some types of hypertension.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Blood Pressure; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

1-(2-[(6-Methoxyl)-naphthylmethyl)])-1-methyl-N-piperidinylacethyl -6,7- dimethoxyl-1,2,3,4-tetrahydroisoquinoline (CPU-23), a substituted tetrahydroisoquinoline, reduced the voltages of P wave and J point, prolonged PR interval, and slowed sinus rhythm of ECG in spontaneously hypertensive rats (SHR) and age-matched normotensive WKY rats. The effects of CPU-23 on cardiac electric activity were stronger in SHR than in WKY rats (P < 0.05 or P < 0.01). The results suggest that CPU-23 have a calcium antagonistic activity on rat hearts and that calcium antagonists may exert a stronger inhibition of the cardiac electric activity in hypertensive rats than in normotensive rats.

Topics: Animals; Calcium Channel Blockers; Electrocardiography; Heart Rate; Hypertension; Isoquinolines; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrahydroisoquinolines

The nature of the muscarinic (M) receptor subtype mediating endothelium-dependent vasodilation was investigated in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).. Characterization of the muscarinic receptor mediating vasodilation and the possible hypertension-induced effects on the nature of this receptor, which have both received little attention in resistance vessels of the SHR.. After a methoxamine-induced vasoconstriction, the vessels were dilated with acetyl-beta-metacholine (MCh). The MCh-induced vasodilation was analysed by means of the M1-selective antagonist pirenzepine, the M2-selective antagonists AF-DX116 and AQ-RA 741 and the M3-selective antagonists 4-DAMP and p-FHHSiD. The potency of these compounds was quantified by means of pA2 values. Atropine, a non-selective muscarinic antagonist, was used for comparison.. The rank order of potency for the muscarinic receptor antagonists in preparations taken from SHR and WKY rats appears to be atropine > 4-DAMP > p-FHHSiD > pirenzepine > AQ-RA 741 > AF-DX 116. This rank order corresponds to that found in isolated conduit arteries.. The pA2 values for the various compounds were not significantly different in SHR and WKY rat preparations, indicating that the nature of this receptor is not influenced by hypertension. The high potency of the M3-selective drugs and the weak activity of pirenzepine and the M2-selective antagonists suggest a major role of M3-receptors in the cholinergic vasodilation in the perfused mesenteric vascular bed both in SHR and WKY rat preparations.

Topics: Animals; Atropine; Benzodiazepinones; Endothelium, Vascular; Hypertension; Male; Mesenteric Artery, Superior; Muscarinic Antagonists; Parasympatholytics; Piperidines; Pirenzepine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Muscarinic; Vasodilation

To determine the roles of vasopressin, the renin-angiotensin system and sex in the pathogenesis of salt-sensitive hypertension in the Dahl rat.. The effects of 12 days' treatment with a non-peptide, orally effective V1 antagonist (OPC-21,268) and captopril, individually or together, were compared in male and female Dahl salt-sensitive rats after 10 days on a high-salt diet.. OPC-21,268 was given in the food, and captopril was administered with osmotic pumps implanted subcutaneously.. Systolic blood pressure (SBP) reached a higher level in untreated males than in untreated females. V1 blockade in males prevented any further increase in SBP during the first week of treatment, but SBP rose thereafter towards the levels found in the untreated males. In females OPC-21,268 had no effect. In males captopril prevented any further increase in SBP. There was no effect of captopril in females during the first week of treatment, but SBP fell to pretreatment levels during the second week. Combined treatment with OPC-21,268 and captopril in males had a smaller antihypertensive effect than either drug alone. In females combined treatment prevented any further increase in SBP.. These findings suggest that both vasopressin and the renin-angiotensin system contribute to the pathogenesis of Dahl salt-sensitive hypertension, but that other factors, possibly including the sympathetic nervous system, are also involved. Sex also affects the severity of this form of hypertension and influences the relative roles of vasopressin and the renin-angiotensin system. It is likely that the gonadal steroid hormones modulate the activity of the pathogenetic factors in this form of hypertension at a central or peripheral level.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Captopril; Circadian Rhythm; Diet; Female; Hypertension; Male; Piperidines; Quinolones; Rats; Rats, Mutant Strains; Renin-Angiotensin System; Sex Characteristics; Sodium Chloride; Vasopressins

The muscarinic receptors in the aorta of the normo- and hypertensive rats were characterised with tritiated acetylcholine (3H-ACh) and various muscarinic receptor antagonists. The binding of 3H-ACh to the endothelial membranes of the normotensive Wistar Kyoto rats (WKY) and the spontaneously hypertensive rats (SHR) was displaceable by nanomolar range of scopolamine but only by micromolar range of atropine and homatropine. The reverse was observed with the muscle binding sites, i.e. the 3H-ACh was displaceable by nanomolar range of atropine and homatropine but only by micromolar range of scopolamine. Pirenzepine and 4-diphenyl-acetoxy-N-methyl-piperidine metobromide (4-DAMP) displaced the binding of 3H-ACh from both tissues in the nano to micromolar range, with the displacement from the endothelial binding sites occurring at lower concentration range of the ligands. The apparent IC50 values of both compounds for the smooth muscle were 9 and 16 times greater than those for the endothelial binding sites respectively. When saturated with guanylyl-imididiphosphate (GppNHp), conversion of high to low-affinity binding site occurred in both tissues of the WKY but only in the smooth muscle of the SHR. GppNHp had no apparent effect on the binding of 3H-ACh to the endothelial binding sites confirming that the high-affinity site for 3H-ACh was missing in the endothelium of the SHR.

Topics: Acetylcholine; Animals; Aorta; Atropine; Binding, Competitive; Endothelium, Vascular; Guanylyl Imidodiphosphate; Hypertension; In Vitro Techniques; Kinetics; Muscle, Smooth, Vascular; Parasympatholytics; Piperidines; Pirenzepine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Muscarinic; Scopolamine; Tropanes

1. A series of substituted tetrahydroisoquinolins derived from the cleavage products of tetrandrine were found to inhibit [3H]-nitrendipine binding to rat cerebral cortical membranes. Those compounds which displaced [3H]-nitrendipine binding were also able to inhibit high KCl-induced contraction of rat aorta in vitro. 2. There was a significant correlation between the ability of these tetrahydroisoquinolines to inhibit [3H]-nitrendipine binding and KCl-induced contraction (r = 0.99, P less than 0.001). 3. CPU-23 (1-(1-[(6-methoxy)-naphth-2-yl])-propyl-2-(1-piperidine)-acetyl- 6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline), one of the most potent compounds identified in this series, behaved as a simple competitive inhibitor at the [3H]-nitrendipine binding site and reduced the apparent affinity but not the maximal number of binding sites in saturation analysis. 4. In contrast to nifedipine which caused hypotension and tachycardia, CPU-23 induced both hypotension and bradycardia in a dose-dependent manner in pentobarbitone-anaesthetized Sprague-Dawley rats, spontaneously hypertensive and age-matched normotensive WKY rats. 5. It is suggested that CPU-23 may exert its cardiovascular effects via interaction with the dihydropyridine binding site on the L-type calcium channel.

Topics: Alkaloids; Animals; Aorta; Benzylisoquinolines; Blood Pressure; Calcium Channels; Cerebral Cortex; Dose-Response Relationship, Drug; Female; Heart Rate; Hypertension; Isoquinolines; Male; Nitrendipine; Piperidines; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Rats, Wistar; Tetrahydroisoquinolines; Vasoconstriction

We have examined a series of novel dihydropyrimidine calcium channel blockers that contain a basic group attached to either C5 or N3 of the heterocyclic ring. Structure-activity studies show that a 1-(phenylmethyl)-4-piperidinyl carbamate moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart potent and long-acting antihypertensive activity in vivo. One of these compounds (11) was identified as a lead, and the individual enantiomers 12a (R) and 12b (S) were synthesized. Two key steps of the synthesis were (1) the efficient separation of the diastereomeric ureido derivatives 29a/29b and (2) the high-yield transformation of 2-methoxy intermediates 30a/30b to the (p-methoxybenzyl)thio intermediates 31a/31b. Chirality was demonstrated to be a significant determinant of biological activity, with the dihydropyridine receptor recognizing the enamino ester moiety (12a) but not the carbamate moiety (12b). Dihydropyrimidine 12a is equipotent to nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine. Dihydropyrimidine 12a has the potential advantage of being a single enantiomer.

Topics: Amlodipine; Animals; Antihypertensive Agents; Calcium Channel Blockers; Crystallization; Hypertension; Male; Molecular Structure; Nifedipine; Piperidines; Pyrimidines; Rabbits; Rats; Rats, Inbred SHR; Stereoisomerism; Structure-Activity Relationship; Vasodilation; X-Ray Diffraction

The cardiovascular and renal responses to AHR-16303B, a novel antagonist of 5-hydroxytryptamine (5-HT2) receptors and calcium channels, were examined in spontaneously hypertensive (SHR) and normotensive rats (NTR) and compared with verapamil and ritanserin. In SHR, AHR-16303B (10-300 mg/kg orally, p.o.) produced dose-related reductions in mean arterial blood pressure (MABP), accompanied by modest isokaliuretic diuresis and unchanged heart rate (HR). In NTR, 10-30 mg/kg p.o. AHR-16303B had no effect on MABP or renal excretory function; 100 and 300 mg/kg reduced MABP but had only transient effects on HR; 100 mg/kg produced antidiuresis in NTR. Both strains of rats tolerated doses of AHR-16303B as high as 300 mg/kg. In both SHR and NTR, verapamil (10-100 mg/kg p.o.) produced dose-related reductions in MABP, antinatriuresis at 60 and 100 mg/kg, and variable effects on HR. Oral ritanserin had no effect on MABP of SHR or NTR at 3 or 10 mg/kg. AHR-16303B is unique in that it simultaneously antagonizes 5-HT2 receptors and produces safe and effective reduction of elevated BP without altering HR or triggering renal compensatory antidiuresis. At effective 5-HT2/calcium antagonistic doses, AHR-16303B has no effect on cardiorenal homeostasis in normotensive animals.

Topics: Administration, Oral; Animals; Blood Pressure; Calcium Channel Blockers; Cardiovascular System; Dose-Response Relationship, Drug; Heart Rate; Hypertension; Injections, Intravenous; Kidney; Male; Piperidines; Propiophenones; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Verapamil

A series of 4-(diarylmethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds were synthesized as calcium-channel blockers and antihypertensive agents. Compounds were evaluated for calcium-channel-blocking activity by determining their ability to antagonize calcium-induced contractions of isolated rabbit aortic strips. The most potent compounds were those with fluoro substituents in the 3- and/or 4-positions of both rings of the diphenylmethyl group. Bis(4-fluorophenyl)acetonitrile analogue 79 was similar in potency to bis(4-fluorophenyl)methyl compound 1. The methylene analogue of 1 (78) and derivatives of 1 that contained a hydroxyl (76), carbamoyl (80), amino (81), or acetamido (82) substituent on the methyl group were less potent. In most cases, substituents on the phenoxy ring, changes in the distance between the aryloxy group and the piperidine nitrogen, and the substitution of S, N(CH3), or CH2 for the oxygen atom of the aryloxy group had only a small to moderate effect on the potency. The best compounds in this series were more potent than verapamil, diltiazem, flunarizine, and lidoflazine, but were less potent than nifedipine. Compounds were evaluated for antihypertensive activity in spontaneously hypertensive rats (SHR) at an oral dose of 30 mg/kg. Of the 55 compounds tested, only nine produced a statistically significant (p less than 0.05) reduction in blood pressure greater than 20%; all of these compounds had fluoro substituents in both rings of the diphenylmethyl group. One of the most active compounds in the SHR at 30 mg/kg was 1-[4-[3-[4-[bis(3,4-difluorophenyl)methyl]-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (63), which produced a 35% reduction in blood pressure and was similar in activity to nifedipine. At lower doses, however, 4-[bis(4-fluorophenyl)methyl]-1-[3-(4-chlorophenoxy)propyl]piperidine (93) was one of the most effective antihypertensive agents, producing reductions in blood pressure of 17 and 11% at oral doses of 10 and 3 mg/kg, respectively; 63 was inactive at 10 mg/kg.

Topics: Animals; Antihypertensive Agents; Aorta; Calcium; Calcium Channel Blockers; Hypertension; Male; Molecular Structure; Muscle Contraction; Piperidines; Rabbits; Rats; Rats, Inbred SHR; Structure-Activity Relationship

Healthy ambulatory subjects took 6 different MAO inhibitors (MAOIs) orally for 2 to 4 weeks. The new reversible MAO-A inhibitors brofaromine and moclobemide were compared with the irreversible MAOIs clorgyline, selegiline, phenelzine and tranylcypromine. Pressor responsiveness to oral tyramine was assessed before, during and after treatment. In unmedicated subjects, doses of tyramine to raise systolic blood pressure by at least 30 mmHg (PD30) ranged between 200 and 800 mg. During treatment with MAOIs, the PD30 decreased. The ratio of median effective doses (ED50) of tyramine (pre- vs post-treatment) was: selegiline 5, moclobemide 7, brofaromine 10, clorgyline 10, phenelzine 13 and tranylcypromine 55. Pressor responsiveness normalized within 8 days after stopping the reversible MAOIs and 30 days after tranylcypromine. The increased sensitivity after phenelzine persisted for longer than 8 weeks and after clorgyline for longer than 15 weeks. The results suggest that the two reversible MAO-A inhibitors moclobemide and brofaromine carry a much reduced liability to tyramine-related hypertensive reactions.

Topics: Administration, Oral; Adult; Benzamides; Blood Pressure; Female; Humans; Hypertension; Male; Moclobemide; Monoamine Oxidase Inhibitors; Piperidines; Risk Factors; Tyramine

Acute as well as chronic treatment with ketanserin but not with ritanserin reduced the blood pressure in the spontaneously hypertensive rat, indicating that 5-HT2-receptor blockade alone does not have antihypertensive properties. Whereas the blood pressure reduction to acute administration of ketanserin was directly related to its ability to shift the dose-response curve of phenylephrine (alpha 1-adrenergic blockade), the same relationship was not apparent following chronic treatment with ketanserin. This suggests that the 5-HT2- and alpha 1-blockade may complement each other in reducing the blood pressure, a conclusion supported by the observation that in the conscious rat, 5-HT2-receptor blockade by ritanserin enhanced the hypotensive response to prazosin. However, ritanserin did not influence the ability of prazosin to antagonize pressor responses to phenylephrine in the pithed rat.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Hypertension; Ketanserin; Male; Phenylephrine; Piperidines; Prazosin; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha; Receptors, Serotonin; Ritanserin; Serotonin; Sympathetic Nervous System

Ketanserin suppresses baroreflex-mediated tachycardia following the administration of hypotensive doses of sodium nitroprusside in conscious spontaneously hypertensive rats (SHR). The purpose of this study was to compare the baroreflex effects of ketanserin with those of the more selective S2-serotonergic receptor antagonist ritanserin and the alpha 1-blocker prazosin. In conscious SHR, both ketanserin (3 mg/kg) and prazosin (0.01 and 0.1 mg/kg) caused a significant reduction in blood pressure. Ritanserin (3 mg/kg) and the combination of a low dose of prazosin (0.01 mg/kg) and ritanserin (3 mg/kg) did not lower blood pressure significantly. Baroreflex responses were determined by measuring the maximal changes in heart period (HP = 60,000/HR) after administration of 20 to 100 micrograms/kg sodium nitroprusside. Whereas saline and prazosin lacked an effect on changes in HPmax, ketanserin reversed the decrease in delta HPmax into a significant increase. Ritanserin alone caused a slight but insignificant inhibition, whereas the combination of ritanserin and prazosin blocked the sodium nitroprusside-induced reflex tachycardia. Ritanserin, in contrast to prazosin or ketanserin, lowered resting heart rate values. We conclude that the interference of ketanserin with the baroreflex in SHR is a unique property of this agent, related to its simultaneous effects on serotonin (5-HT) S2-receptors and alpha 1-adrenoceptors.

Topics: Animals; Blood Pressure; Heart Rate; Hypertension; Ketanserin; Male; Piperidines; Prazosin; Pressoreceptors; Rats; Rats, Inbred SHR; Ritanserin; Serotonin Antagonists

Topics: Anesthesia; Animals; Blood Pressure; Hypertension; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Serotonin Antagonists

1. In previous studies, exogenous serotonin (5-HT), administered intravenously, caused dose-related increases in mean arterial pressure and heart rate in conscious sheep. The 5-HT2 antagonist ketanserin (0.1 mg/kg per h, i.v.) was shown to lower blood pressure in the conscious sheep primarily through antagonism of alpha-adrenoceptors. 2. A newer 5-HT2 antagonist, ritanserin, is a more selective antagonist in vivo, as it attenuated or abolished pressor responses to exogenous 5-HT, but not to phenylephrine. 3. When infused alone, ritanserin (0.1 mg/kg per h, i.v.) failed to produce a decrease in blood pressure, suggesting that 5-HT antagonistic properties are not sufficient by themselves to lower blood pressure. 4. Ritanserin displayed a different metabolic profile to ketanserin, with a markedly decreased water intake. The mechanism of this effect is unresolved, but may imply a permissive role for 5-HT in the modulation of drinking responses in the sheep. 5. Ritanserin did not modify ACTH-induced hypertension in sheep.

Topics: Animals; Blood Pressure; Cardiac Output; Heart Rate; Hypertension; Ketanserin; Phenylephrine; Piperidines; Ritanserin; Serotonin; Serotonin Antagonists; Sheep; Water-Electrolyte Balance

Topics: Acute Kidney Injury; Aminopyrine; Analgesics; Benzophenones; Child; Dipyrone; Drug Combinations; Humans; Hypertension; Male; Piperidines; Seizures

Ketanserin is a pure antagonist of serotonin S2-receptors, in blood vessels, platelets and bronchial tissue. Ketanserin has been suggested as hypotensive drug in man, but it shows as well a specific activity on platelet aggregation. An increased incidence of hypertension, of unknown origin, has been found in patients with chronic alcoholism: hypotheses have been made upon an increased incretion of catecholamines and a greater sensitivity of blood vessels' receptors to their action. The data from the present study of eleven patients show that these subjects had an increased platelet activity and ketanserin administration was effective in allowing both the blood pressure levels and platelet activity to resume their normal range. This drug is thus suggested, for its pharmacological properties, as an elective medication for hypertensive patients with chronic alcoholism.

Topics: Adult; Alcoholism; Antihypertensive Agents; Blood Pressure; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Time Factors

Topics: Animals; Humans; Hypertension; Ketanserin; Piperidines; Serotonin; Serotonin Antagonists

Postoperative hypertension following coronary artery bypass grafting is usually treated with vasodilating agents like nitroprusside. In recent studies ketanserin, a 5-hydroxytryptamine type 2 antagonist, appeared to be effective in the treatment of this clinical syndrome. In 20 patients, divided into two comparable groups, nitroprusside and ketanserin were compared with respect to their haemodynamic and ventilatory profiles. The study showed that both agents were equally effective in decreasing the raised systolic blood pressure, but that ketanserin was more advantageous with respect to the absence of reflex tachycardia and the unchanged shunt fraction.

Topics: Blood Pressure; Coronary Artery Bypass; Female; Ferricyanides; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Nitroprusside; Piperidines; Postoperative Complications; Pulmonary Artery; Vascular Resistance

Serotonin has complex effects on the cardiovascular system. In the intact animal it may cause increases or decreases of blood pressure and in isolated blood vessels contraction or relaxation depending on the species and vascular bed studied, the route of administration and the dosage used. Contractions evoked by the monoamine are mediated mainly by S2-serotonergic receptors on vascular smooth muscle; in addition, serotonin may act indirectly by amplifying the response to norepinephrine and other agonists, by displacing norepinephrine from adrenergic nerve terminals or releasing constrictor substance(s) from the endothelium. Dilatation in response to serotonin is mediated by endothelial and prejunctional S1-serotonergic receptors which pharmacologically resemble 5-HT1-binding sites. In hypertension, constrictor responses to serotonin are augmented, while the vasodilator effects of the monoamine are decreased. The constrictor response to serotonin is increased more than those to other agonists, suggesting a functional rather than a structural adaptation of the hypertensive blood vessel wall. In hypertension the turnover of circulating platelets, the major source of peripheral serotonin, is accelerated and the mechanisms for the removal of the monoamine are impaired. The functional changes of the blood vessel wall and platelets could play a role in the maintenance of the increased peripheral vascular resistance in chronic hypertension, and they could be involved in the pathogenesis of complications of the hypertensive process. The concept that serotonin plays a role in chronic hypertension is further supported by the antihypertensive properties of the S2-serotonergic antagonist, ketanserin.

Topics: Animals; Blood Platelets; Heart; Hypertension; Ketanserin; Muscle, Smooth, Vascular; Piperidines; Rats; Rats, Inbred SHR; Serotonin; Vasoconstriction; Vasodilation

Topics: Cardiovascular Diseases; Drug Therapy, Combination; Humans; Hypertension; Ketanserin; Piperidines; Serotonin

The effects of maintenance treatment with ketanserin 40 mg twice daily on renal haemodynamics were studied in 13 essential hypertensives. To establish whether activation of the renin system modifies the response to ketanserin the patients were studied under three conditions: on a sodium restricted diet combined with hydrochlorothiazide, on a sodium restricted diet without hydrochlorothiazide and on a liberal sodium diet. Blood pressure fell in a proportion of the patients on all three regimens. Neither effective renal plasma flow (ERPF; clearance of 131I-hippuran) nor glomerular filtration rate (GFR; clearance of 125I-iothalamate) was significantly altered by ketanserin on either regimen. Neither the blood pressure response nor the renal response was modified by renin stimulation. The renal response was not related to the fall in blood pressure observed in some patients. Therefore ketanserin probably does not affect renal autoregulation.

Topics: Adult; Angiotensins; Female; Glomerular Filtration Rate; Humans; Hypertension; Ketanserin; Kidney; Male; Middle Aged; Piperidines; Renin

The serotonin (S2) antagonist, ketanserin was given to 16 patients with essential hypertension on a single-blind basis. Ten patients were treated for 3 years with ketanserin 40-80 mg daily on a once or twice daily regimen. In this group supine blood pressure fell from 164 +/- 4/101 +/- 2 mmHg on placebo to 152 +/- 5/91 +/- 3 mmHg (NS/P less than 0.01) after 3 years of therapy. During treatment, total serum cholesterol remained essentially unchanged while serum triglycerides were significantly reduced. No side-effects were seen except for dry mouth or slight nasal congestion reported by two patients. In six patients regional haemodynamics were assessed by forearm plethysmography. After 3 months of ketanserin, resting vascular resistance was significantly reduced from 58.3 +/- 12 units on single-blind placebo to 47.0 +/- 12 units (P less than 0.005) on single-blind ketanserin, 40 mg twice daily. We conclude that ketanserin is an effective antihypertensive agent during long-term therapy with some beneficial effects on serum lipids. The antihypertensive effect seems to be mediated chiefly by a decrease in vascular resistance.

Topics: Female; Hemodynamics; Humans; Hypertension; Ketanserin; Long-Term Care; Male; Middle Aged; Piperidines

This report describes the successful use of ketanserin, a 5-HT2 receptor antagonist, for the acute control of systemic blood pressure in a patient with the carcinoid syndrome, undergoing hepatic artery embolisation. Serial measurements of plasma 5-hydroxyindoles, platelet 5-hydroxytryptamine and plasma catecholamines are also given.

Topics: Aged; Antihypertensive Agents; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Hypertension; Intraoperative Period; Ketanserin; Malignant Carcinoid Syndrome; Piperidines

Ketanserin was administered intravenously as either 20 or 10 mg boluses to 16 patients with severe preeclampsia in labor. The fetal heart rate was monitored with a scalp electrode and the uterine contractions were evaluated with a fluid-filled catheter connected to a physiologic pressure transducer. A 10-minute recording before every administration of ketanserin was compared to the same period immediately afterward. Ketanserin lowered the systolic and diastolic blood pressure significantly (p less than 0.005, paired Student's t test). Maternal heart rate was unchanged but the mean fetal heart rate increased by 4.6 bpm. Long-term beat-to-beat variability and acceleration patterns were not affected. On four occasions an improvement in variable decelerations of the fetal heart, due to a reduction in uterine activity, was seen. Changes in the amplitude of contractions were not statistically significant. The frequency of contractions, however, was significantly reduced from 3.6 to 2.4 per 10 minutes (p less than 0.005). No serious adverse effects occurred.

Topics: Blood Pressure; Female; Fetal Heart; Heart Rate; Humans; Hypertension; Ketanserin; Obstetric Labor Complications; Piperidines; Pre-Eclampsia; Pregnancy; Uterine Contraction

CGP 6085 A, [4-(5,6-dimethyl-2-benzofuranyl)piperidine HCl], has been found to be a mild to moderately potent hypotensive agent. One hour following CGP 6085 A administration (10 mg/kg, i.p.), a maximal reduction in blood pressure of approximately 20-30 mm Hg is observed in spontaneously hypertensive rats. The maximal reduction in blood pressure was observed at a dose of 3 mg/kg. CGP 6085 A blocks 5-HT uptake in the brainstem when assessed in vivo by use of the serotonin depletor, H 75/12 (3-hydroxy-4-methyl-alpha-ethyl-phenylethylamine). The maximal inhibitory effect on 5-HT uptake occurred at 10 mg/kg CGP 6085 A. The reduction in blood pressure correlates well with the ability of the drug to inhibit 5-HT uptake as assayed by H 75/12, with a correlation coefficient of 0.71 for SH rats. However, since the drug has not been widely characterized, alternate explanations for the cardiovascular pharmacological properties of CGP 6085 A are also proposed.

Topics: Amphetamines; Animals; Blood Pressure; Brain Stem; Heart Rate; Hydroxyindoleacetic Acid; Hypertension; Male; Nitroprusside; Piperidines; Rats; Rats, Inbred SHR; Serotonin

In the spontaneously hypertensive rat (SHR), ketanserin and the ketanserin analogues R56413 and ritanserin were studied with regard to their ability to reduce the blood pressure in conscious rats and shift the dose-response curves for phenylephrine and serotonin (5-HT) in pithed rats after acute administration. There was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine-induced pressor responses. 5-HT2-receptor blockade alone by ritanserin did not influence the blood pressure but it potentiated the hypotensive response to alpha 1-adrenoceptor blockade by prazosin. Thus, following acute administration in the SHR, the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but the 5-HT2-receptor blockade may contribute.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Hypertension; Ketanserin; Male; Piperidines; Prazosin; Rats; Rats, Inbred SHR; Time Factors

The similarity between the metabolic pathways of serotonin in platelets and serotoninergic nerve endings has often been emphasized. The turnover of serotonin was therefore investigated in two diseases: hypertension (as central serotoninergic neurones appear to modulate central sympathetic nervous activity) and depression (as a central 5-HT-deficiency and a low 3H-imipramine binding on platelets have been described in patients with endogenous depression). Mean platelet 5-HT level was significantly lower in essential hypertensives than in controls. A reduction in platelet 5-HT level was also observed in depression and was more marked in women than in men. Serotonin level was only weakly related to the severity of the diseases. In some hypertensive patients, administration of ketanserin resulted in a reduction of blood pressure without affecting 5-HT level. In depressive patients, maprotiline and chlorimipramine acted differently on 5-HT level but both improved the clinical symptoms.

Topics: Adult; Antidepressive Agents; Blood Platelets; Depressive Disorder; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Serotonin; Serotonin Antagonists; Sex Factors

This study examined the effects of the serotonergic (5-HT2) antagonist ketanserin in sheep on haemodynamic responses to infused serotonin (5-HT), development of adrenocorticotrophin (ACTH)-induced hypertension, and the effect of ACTH on in vivo pressor responsiveness to 5-HT. Serotonin produced a dose-related increase in mean arterial pressure and heart rate. These increases in mean arterial pressure were attenuated or abolished by ketanserin, but increases in heart rate were enhanced. Ketanserin modified the pressure response to the alpha-adrenergic agonist phenylephrine, and did not further lower mean arterial pressure in sheep pretreated with the alpha-antagonist prazosin. Thus, ketanserin exhibits alpha-adrenergic antagonism in sheep. Ketanserin infusion lowered mean arterial pressure in normal sheep but did not affect the pressor response to ACTH infusion. There was no difference in pressor responsiveness to 5-HT (0.1-30 micrograms/kg) before and after ACTH treatment. Thus, 5-HT raises mean arterial pressure in sheep in a dose-related fashion, but there is no evidence of a role for 5-HT in ACTH-induced hypertension.

Topics: Adrenergic alpha-Antagonists; Adrenocorticotropic Hormone; Animals; Blood Pressure; Female; Heart Rate; Hypertension; Ketanserin; Phenylephrine; Piperidines; Prazosin; Serotonin; Serotonin Antagonists; Sheep

The relationship between the acute blood pressure lowering effect of ketanserin with age was investigated in 57 patients ranging from 25 to 90 years (mean 61 years). There was a highly significant correlation between the degree of reduction of systolic and diastolic blood pressure and age, independent of the starting blood pressure. The fact that the acute blood pressure-lowering effect of ketanserin increases with age may suggest a role for serotonin in blood pressure regulation, particularly in elderly patients.

Topics: Adult; Aged; Aging; Antihypertensive Agents; Blood Pressure; Female; Humans; Hypertension; Injections, Intravenous; Ketanserin; Male; Middle Aged; Piperidines

Ketanserin is a serotonin antagonist with high affinity for S2-serotonergic receptors, which mediate the vasoconstrictor effects of serotonin. It does not block the vasodilator effects of this monoamine, and it is devoid of agonist activity and serious central side effects. Ketanserin, however, also binds to alpha 1-adrenoceptors. The compound (10 mg i.v.) was given to 30 patients with essential hypertension and four normotensive patients with chronic autonomic failure, owing to an efferent sympathetic lesion. Ketanserin lowered systolic and diastolic arterial pressure by about 20%. The effects on cardiac output, cardiac filling pressures, forearm blood flow, renal blood flow, and glomerular filtration rate revealed a hemodynamic pattern compatible with dilatation of both resistance and capacitance vessels. These vasodilator effects were accompanied by moderate reflex stimulation of the heart. The drug did not alter the pressor effect of bolus injections of the alpha 1-adrenoceptor agonist phenylephrine, which contrasted with the competitive antagonism exerted by the alpha 1-adrenoceptor antagonist prazosin. Baroreflex-mediated bradycardia after phenylephrine also was not affected by ketanserin. The drug had a distinct hypotensive effect in patients with autonomic failure, despite the fact that these patients did not respond to the nonselective alpha-adrenoceptor antagonist phentolamine, 20 mg i.v. Thus, ketanserin is capable of lowering arterial pressure independently of alpha 1-adrenoceptor blockade. The results are therefore indirect evidence supporting a role of serotonin in hypertension.

Topics: Aldosterone; Blood Pressure; Female; Hemodynamics; Humans; Hypertension; Ketanserin; Male; Middle Aged; Norepinephrine; Phentolamine; Phenylephrine; Piperidines; Regional Blood Flow; Renal Circulation; Renin; Serotonin; Serotonin Antagonists; Time Factors

Ketanserin is a serotonin (S2) blocker that reduces blood pressure (BP) in patients with essential hypertension preferentially by a reduction of peripheral vascular resistance. Heart rate is generally not affected or slightly reduced. When given in monotherapy on a 40 mg b.i.d. regimen, ketanserin reduces diastolic BP as effectively as metoprolol 100 mg b.i.d. or hydrochlorotiazide 25 mg b.i.d. The incidence of adverse reactions is low and comparable to these reference drugs. A satisfactory BP control is provided over a 24-h interval on a 40 mg b.i.d. dosage schedule, and the effect is maintained on a long-term basis, i.e., greater than 2 years. The response seems to be more marked in older patients, which may be due to an augmented platelet serotonin release and a vascular hypersensitivity in this age group. The future usefulness of ketanserin, as well as any other antihypertensive agent, will depend on its ability to prevent organ damage, as well as its ability to provide "quality of life" for the patient.

Topics: Adrenergic beta-Antagonists; Adult; Blood Pressure; Diuretics; Female; Humans; Hypertension; Ketanserin; Male; Piperidines; Serotonin Antagonists; Time Factors

Ketanserin is a 5-HT2 antagonist with alpha-adrenoreceptor blocking activity. This study examines the efficacy and safety of ketanserin in the control of severe primary and secondary hypertension, including renal hypertension. Patients with uncontrolled hypertension were admitted to hospital and entered the study if the supine diastolic blood pressure phase V (SDBP) was greater than 110 mm Hg after 2 h continuous BP monitoring (Dynamap). Ketanserin was administered as an intravenous (i.v.) 5 mg bolus every 60 s until SDBP fell greater than 15 mm Hg or maximum dose (30 mg) was reached, then by i.v. infusion at 4-20 mg/h to maintain SDBP fall greater than 15 mm Hg over 6 h. Twenty five patients were monitored and 20 (seven men, 13 women, ages 14-65 years) fulfilled the entry criteria. Seventeen of 20 were on antihypertensive medication, and 14 had underlying renal disease. Preinjection mean BP was 188/123 mm Hg for the 20 patients, falling at 5 min to 175/103 mm Hg. Supine diastolic blood pressure fell greater than 15 mm Hg in 16 of 20 patients. In these patients, BP remained satisfactorily controlled over the 6-h ketanserin infusion. Heart rate was unchanged. The four patients who did not respond were receiving the alpha-blocker prazosin, but seven other patients on high-dose prazosin did respond. We conclude that i.v. ketanserin is effective in the acute management of severe hypertension, including hypertension secondary to renal disease.

Topics: Adolescent; Adult; Blood Pressure; Creatinine; Female; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Renin; Serotonin Antagonists; Time Factors

Ketanserin, a new selective 5-HT2-serotonergic antagonist, was used to: confirm its hypotensive efficacy in acute and long-term treatment, determine its influence on the influence on the metabolism of serotonin (5-HT) and catecholamines, and elucidate their mutual relationship. Ketanserin was given intravenously to 10 patients with hypertensive crisis or resistant hypertension and orally to 15 patients with mild to severe hypertension for 1 year. Blood pressure, heart rate, 24-h urinary excretion of vanilmandelic acid (VMA; the major endproduct of catecholamines) and of 5-hydroxyindoleacetic acid (HIAA; the endproduct of serotonin metabolism), and platelet aggregation were measured. In doses normalizing blood pressure and platelet aggregation, ketanserin administered to hypertensive patients either intravenously in acute treatment or orally in chronic treatment caused: (a) decreased HIAA excretion (more marked in chronic than in acute treatment) and (b) simultaneous decrease in VMA excretion. It is concluded that the decisive sites of ketanserin action are the 5-HT2 receptors of platelets. The compound reduces platelet aggregation and the release of 5-HT, its metabolism, and, hence, the excretion of HIAA. The action of ketanserin on 5-HT2 receptors of vascular smooth muscle participates in the hypotensive effect of the drug but does not explain the decreased excretion of HIAA and VMA.

Topics: Adult; Blood Pressure; Female; Heart Rate; Humans; Hydroxyindoleacetic Acid; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Platelet Aggregation; Serotonin; Serotonin Antagonists; Time Factors; Vanilmandelic Acid

Serotonin is a vasoactive substance that acts on blood vessels and platelets but whose primary action lies in its role as an amplifier for other agents. The aim of this work was to study the effects on blood platelets and erythrocytes of the S2-serotonergic receptor antagonist ketanserin. Twenty-seven patients with untreated hypertension and/or intermittent claudication received a bolus intravenous (i.v.) injection of 10 mg ketanserin followed by 2 mg/h during 3 h i.v. infusion. Platelet function and erythrocyte filterability were studied before and 30 min, 3 h, and 24 h after the bolus injection. The results showed decreases of plasma beta-thromboglobulin and platelet factor 4 levels (p less than 0.001) and platelet aggregation induced by epinephrine plus serotonin (p less than 0.001), whereas ADP-induced aggregation remained unchanged 30 min and 3 h after ketanserin administration. Red cell filterability was decreased (p less than 0.01). There was a tendency toward lower mean arterial blood pressure but heart rate remained unchanged. The dual effect of ketanserin on platelet function and erythrocyte filterability might be of great clinical value in hypertension and peripheral vascular disease in which microcirculatory flow is altered.

Topics: Adult; Aged; Blood Platelets; Erythrocyte Deformability; Erythrocytes; Female; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Platelet Aggregation; Serotonin Antagonists; Vascular Diseases

We evaluated the long-term antihypertensive effects of ketanserin, a selective serotonin2-receptor blocker with weak adrenergic receptor blocker properties. Ketanserin was given alone, 40 mg o.d. or b.i.d., for 2 years to 12 patients with essential hypertension. Systolic and diastolic blood pressures (BPs) were significantly reduced 14 days after the start of therapy and remained lowered during the 2-year follow-up period. In a larger group of patients who received ketanserin monotherapy for 2 to 3 months, the response to therapy varied considerably between subjects, with an overall response rate (BP less than 165/95 mm Hg) of 60% to 75%. During steady-state conditions, the maximum and minimum ketanserin plasma concentrations varied from threefold to fourfold between subjects and did not correlate with individual reductions in BP, but for each individual there was a positive correlation between BP reduction and ketanserin plasma concentration throughout a study day. In combination with beta-blockers, ketanserin effectively reduced BP in the supine and standing positions. The plasma concentration profile was not altered as much during combination therapy as when ketanserin was given alone. Side effects were few and tolerable. Ketanserin effectively reduces BP both alone and in combination with beta-blockers and may be still another drug useful in the treatment of essential hypertension.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Blood Pressure; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Serotonin Antagonists

Topics: Adrenergic beta-Antagonists; Blood Pressure; Diuretics; Drug Therapy, Combination; Humans; Hypertension; Ketanserin; Piperidines

Chronic oral treatment (8 weeks) with the selective 5-hydroxytryptamine2 (5-HT2)-receptor blocking agent, ritanserin, did not reduce blood pressure in the spontaneously hypertensive rat (SHR) during basal conditions or during stress (jet air). In pithed rats the pressor responses to 5-HT but not to phenylephrine or sympathetic stimulation of the sympathetic outflow were completely antagonized. These observations indirectly suggests that the 5-HT2-receptor blocking properties of the antihypertensive agent ketanserin cannot alone account for the antihypertensive effects in SHR that are observed during chronic treatment with this agent.

Topics: Animals; Blood Pressure; Decerebrate State; Dose-Response Relationship, Drug; Electric Stimulation; Heart Rate; Hypertension; Ketanserin; Male; Phenylephrine; Piperidines; Prazosin; Rats; Rats, Inbred SHR; Receptors, Serotonin; Ritanserin; Time Factors

Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT2-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced. It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Electric Stimulation; Hypertension; Ketanserin; Phenylephrine; Piperidines; Prazosin; Pyrimidines; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha; Ritanserin; Sympathetic Nervous System

Intravenous administration of ketanserin--a selective antagonist of serotonin receptors--to hypertensive patients resulted in an immediate marked drop of blood pressure accompanied by a decreased excretion of vanilmandelic acid and 5-hydroxy-3-indolylacetic acid. The drug was well tolerated by all patients without any serious complaints.

Topics: Adult; Blood Pressure; Drug Evaluation; Female; Humans; Hydroxyindoleacetic Acid; Hypertension; Ketanserin; Male; Middle Aged; Piperidines; Serotonin Antagonists; Vanilmandelic Acid

Topics: Antihypertensive Agents; Humans; Hypertension; Ketanserin; Piperidines

The effects of chronic oral treatment with the 5-hydroxytryptamine (serotonin) receptor blocking agent ketanserin (17 mg/100 g dry food) on blood pressure, heart weight, peripheral vascular reactivity, baroreceptor sensitivity, central cardiovascular reactivity and central catecholamine turnover were investigated in the spontaneously hypertensive rat. Blood pressure measurements were performed in conscious rats 24 h after insertion of catheters. After 6 weeks treatment basal blood pressure was reduced (16%) compared to control rats (given identical food, except for ketanserin). Both heart weight and body weight were reduced (both to 93% of control values) leaving heart weight/body weight ratio unchanged. Pressor responses to phenylephrine and depressor responses to isoprenaline (after pretreatment with reserpine and atropin) were not different while the blood pressure increase to 5-hydroxytryptamine was inhibited, indicating that after 6 weeks treatment the blood pressure reduction is not directly related to alpha-adrenoceptor blockade. Cardiovascular response to stress (jet air), baroreceptor sensitivity (bradycardia to phenylephrine) and central catecholamine synthesis rates (accumulation of 5-hydroxytryptophan and dihydroxyphenylalanine after synthesis inhibition) were unchanged supporting earlier evidence that central mechanisms probably do not contribute to the hypotensive effects of ketanserin.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Heart Rate; Hypertension; Ketanserin; Piperidines; Rats; Rats, Inbred SHR; Receptors, Serotonin; Serotonin Antagonists

The effect of ketanserin on the action of 5-hydroxytryptamine (5-HT) and noradrenaline has been studied using the rat isolated perfused mesentery preparation. Both 5-HT and noradrenaline produced constriction in the mesenteric vessels. The responses to 5-HT and noradrenaline were greater in tissues from hypertensive animals. Responses to 5-HT were abolished by 1 nM ketanserin. Ketanserin was found to be a competitive antagonist of the noradrenaline-induced constrictions (pA2 = 7.5). In partially constricted tissues, 5-HT induced vasoconstriction and vasodilation. In the presence of ketanserin the vasoconstriction was reduced and the 5-HT-induced vasodilation was potentiated. The amount of potentiation of the 5-HT-induced vasodilation by ketanserin was similar in tissues from normotensive and hypertensive rats. It is suggested that the 5-HT-induced vasoconstriction is mediated by activation of 5-HT2 receptors. In the presence of ketanserin, the 5-HT2 receptor mediated vasoconstriction is antagonized, unmasking a 5-HT-induced vasodilation.

Topics: Amidines; Animals; Antihypertensive Agents; Blood Pressure; Hypertension; In Vitro Techniques; Ketanserin; Male; Norepinephrine; Piperidines; Rats; Serotonin; Serotonin Antagonists; Vasoconstriction; Vasodilation

Some of the presynaptic and postsynaptic excitatory and inhibitory actions of 5-hydroxytryptamine (5-HT) in the rat mesenteric arteries were reexamined with particular reference to the genetic hypertensive rat model. Mesenteric arteries were perfused and the perfusion pressure monitored in the presence or absence of 5-HT, norepinephrine or periarterial sympathetic nerve stimulation. The vasoconstrictor response to 5-HT was resistant to prazosin but effectively inhibited by cyproheptadine and ketanserin. The vasoconstrictor responses to norepinephrine and nerve stimulation were markedly potentiated by 5-HT, and this potentiation was blocked by ketanserin at concentrations which inhibited the 5-HT-induced vasoconstriction, while much higher concentrations were required for cyproheptadine. No significant difference was found in these regards between mesenteric arteries from the spontaneously hypertensive rats (SHR) and those from the normotensive Kyoto Wistar rats (WKY). 5-HT significantly increased the nerve stimulation-evoked 3H overflow in [3H]norepinephrine-treated mesenteric arteries of SHR, but reduced the 3H overflow in the WKY preparations. These results suggest that ketanserin-sensitive 5-HT2 receptors are involved in the potentiating effect of 5-HT in the rat mesenteric arteries, and that an increase in transmitter release by 5-HT may contribute to its potentiation of nerve stimulation-induced vasoconstriction in SHR.

Topics: Animals; Blood Pressure; Cyproheptadine; Drug Synergism; Hypertension; In Vitro Techniques; Ketanserin; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Norepinephrine; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin; Synapses

Topics: Adult; Antihypertensive Agents; Delivery, Obstetric; Female; Humans; Hydralazine; Hypertension; Infant, Newborn; Ketanserin; Piperidines; Pre-Eclampsia; Pregnancy; Serotonin Antagonists; Time Factors; Vascular Resistance

In patients developing hypertension following coronary artery bypass surgery (CABG) the possible role of 5-hydroxytryptamine (5-HT; serotonin) was investigated by injecting ketanserin, a specific 5-HT2-receptor antagonist. Ketanserin was administered intravenously when intraarterial systolic blood pressure (SAP) exceeded 150 mm Hg either as a 10-mg bolus (group 1, N = 15), or as a 10-mg bolus followed by infusion of 4 mg/h for either 2.5 h (group 2, N = 15) or for 1 h (group 3, N = 10). In 33 patients (82.5%), SAP and diastolic arterial pressure decreased significantly within 5 min after the 10-mg bolus. In group 1, SAP gradually increased after 30-50 min but in groups 2 and 3 SAP remained normal. The triple index (TI) decreased significantly in all groups. Heart rate decreased slightly but significantly in groups 2 and 3. Central venous and left atrial pressures did not change substantially in any of the three groups. Cardiac output increased significantly (0.51 +/- 0.158 L/min); hence, systemic vascular resistance (SVR) decreased significantly (452.1 +/- 50.57 dyn . s . cm-5--group 3). No rebound increase in SAP occurred after terminating the infusions (groups 2 and 3). These findings indicate that 5-HT plays a role in the majority of patients who develop hypertension following CABG. The decrease of SVR without reflex tachycardia is a favorable effect of ketanserin.

Topics: Coronary Artery Bypass; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Infusions, Parenteral; Injections, Intravenous; Ketanserin; Male; Middle Aged; Piperidines; Postoperative Complications; Serotonin Antagonists

The possible role of 5-hydroxytryptamine (serotonin) in patients developing hypertension following coronary artery bypass surgery was investigated by intravenous administration of ketanserin, a specific 5-hydroxytryptamine-receptor antagonist. Our findings in the preliminary study indicate that 5-hydroxytryptamine might not play a role in the hypertension seen after coronary artery bypass surgery.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Coronary Artery Bypass; Humans; Hypertension; Ketanserin; Middle Aged; Piperidines; Postoperative Care; Postoperative Complications

Topics: Female; Humans; Hypertension; Intraoperative Complications; Ketanserin; Malignant Carcinoid Syndrome; Middle Aged; Piperidines; Serotonin Antagonists

Blood pressure and heart rate, supine and standing, were studied in patients with essential hypertension during 8 weeks of oral therapy with two dosage schedules of ketanserin, 40 mg once and twice daily. Ketanserin caused significant reductions in both supine and standing blood pressure but no significant alterations in heart rate in both groups of patients. Measurements of blood pressure and heart rate over a 24 h period during steady state conditions revealed that maximal blood pressure reduction was correlated with time to peak plasma concentrations. Steady state plasma concentrations of ketanserin were significantly higher in the patients receiving 40 mg twice daily compared to 40 mg once daily. In the group with once daily treatment, tmax was 1.2 +/- 0.17 h, Css 13 +/- 4.3 ng/ml, Cmax 137 +/- 19.6 ng/ml and t1/2, z h. 9.6 +/- 1.27 h.

Topics: Adult; Aged; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Ketanserin; Kinetics; Male; Middle Aged; Piperidines; Serotonin Antagonists

The role of alpha 1-adrenoceptors in the hypotensive response to ketanserin was studied in conscious normotensive (sham-operated) and Page hypertensive (two-kidney, two wrapped) rabbits. Ketanserin (0.01, 0.1 and 1 mg/kg i.v.) was administered at 30 min intervals on four experimental days: no pretreatment; after prazosin 1 mg/kg and infusion; after pharmacological 'total' autonomic effector block (TAB) and with repeated three point methoxamine dose-response lines. Only the highest dose (1 mg/kg) of ketanserin lowered blood pressure and dilated the iliac vascular bed (Doppler flowmeter) in both wrap and sham-operated rabbits. Prazosin pretreatment and TAB prevented these effects. Ketanserin (1 mg/kg) also caused significant alpha 1-adrenoceptor antagonism as measured by a 2.5-fold shift in the methoxamine dose-response lines. In separate experiments prazosin (0.01-0.1 mg/kg i.v. bolus) caused similar falls in blood pressure and alpha 1-adrenoceptor block as ketanserin 0.3 and 1 mg/kg. The only difference observed between prazosin and ketanserin was the substantial reflex tachycardia to prazosin that was absent after ketanserin. These results suggest that in normotensive rabbits and in rabbits with Page hypertension the hypotensive response to ketanserin can be explained by alpha 1-adrenoceptor antagonism.

Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Hemodynamics; Hypertension; Ketanserin; Male; Methoxamine; Piperidines; Prazosin; Quinazolines; Rabbits; Receptors, Serotonin; Serotonin Antagonists

The long-term haemodynamic effects of ketanserin, a new serotonin-antagonist, was examined in 13 patients of both sexes (age range 24-62 years) with mild and moderate essential hypertension (EH). Cardiac output (CO) and intra-arterial blood pressure (BP) were measured at rest and during exercise before and after nine months of therapy. On ketanserin the mean casual BP was lowered by 15/21 mmHg to 152/91 mmHg and five of the 13 patients became 'normotensive' (BP less than 140/90 mmHg). The intra-arterial systolic pressure fell by 5-8% and the diastolic pressure by 5-11% from pretreatment levels at rest supine, sitting and during 50, 100 and 150 W exercise. The fall in BP was associated with a reduction in CO at rest while during exercise both a fall in CO and in total peripheral resistance contributed to the hypotensive effect. The fall in CO was due to a reduction in heart rate (average: -4 to 8 beats/min). The stroke volume remained unchanged in all settings and oxygen consumption was not affected by the drug. Body weight and body fluid volumes did not change significantly. Eight patients complained of drowsiness and lack of concentration. It is concluded that in mild and moderate EH ketanserin induces a moderate BP reduction associated with a fall in CO. There is no large vasodilating effect after long-term ketanserin treatment either at rest or during exercise. Ketanserin does not influence body fluid balance. The incidence of side-effects is high.

Topics: Adult; Blood Pressure; Body Fluids; Body Weight; Cardiac Output; Female; Heart Rate; Hemodynamics; Humans; Hypertension; Ketanserin; Male; Middle Aged; Oxygen Consumption; Physical Exertion; Piperidines; Rest; Time Factors; Vascular Resistance

Topics: Chromatography, High Pressure Liquid; Humans; Hypertension; Ketanserin; Piperidines; Time Factors

A series of 4'-substituted spiro[4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-ones was prepared and evaluated for antihypertensive activity in the spontaneously hypertensive rat (SHR). The basic ring system was prepared in one step by condensation of dilithiated (tert-butoxycarbonyl)aniline (3) with (tert-butoxycarbonyl)piperidinone. Deprotection afforded 6, which was condensed with expoxides or alkyl halides to furnish the title compounds. The most active compound was dl-erythro-4'-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]spiro [4H-3,1-benzoxazine-4,4'-piperidin]-2(1H)-one (9), and various modifications of this compound were made in order to elucidate the structure-activity relationships in the series. Preliminary indications are that 9 may act by both central and peripheral mechanisms.

Topics: Animals; Hypertension; Male; Oxazines; Piperidines; Piperidones; Rats; Spiro Compounds; Structure-Activity Relationship; Systole

Topics: Cardiovascular System; Humans; Hypertension; Ketanserin; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists

The new selective 5-HT2 receptor blocking agent ketanserin was given in a dose of 10 mg intravenously to 12 patients with essential hypertension. It caused a distinct fall in supine systemic arterial, right atrial, pulmonary artery, and pulmonary capillary "wedge" pressures. Cardiac output, renal blood flow, and glomerular filtration rate showed no persistent changes. Thus 5-HT2 receptor blockade caused dilatation of both resistance and capacitance vessels and of the renal vascular bed. Heart rate and plasma concentrations of renin and noradrenaline rose after ketanserin. These data suggest that 5-HT may have a role in maintaining high blood pressure.

Topics: Adult; Aged; Cardiac Output; Female; Heart Rate; Humans; Hypertension; Ketanserin; Kidney; Male; Middle Aged; Norepinephrine; Piperidines; Receptors, Serotonin; Vascular Resistance

Eleven patients undergoing coronary or aortic valve surgery received ketanserin (3 X 10 mg i.v.). When surgery was finished hemodynamic measurements were performed prior to and after cessation of nitrous oxide. The results were compared with those of a control group (n = 30), reported in a previous study. At the end of operation the ketanserin treated patients had significantly lower heart rate (84 +/- 16 vs. 96 +/- 14 min-1; Mean +/- S.D.), lower mean arterial pressure (75 +/- 12 vs. 84 +/- 10 mmHg) and higher skin temperature (31.9 +/- 1.3 vs. 27.7 +/- 2.3 degrees C). However, postoperative hypertension after the withdrawal of nitrous oxide was not prevented: similarly as in the control group blood pressure rose and systemic vascular resistance increased. As the last dose of ketanserin was given 60 minutes before the end of anesthesia it is likely that the effect of ketanserin had already worn off.

Topics: Adult; Aged; Anesthesia; Aortic Valve; Coronary Artery Bypass; Heart Valve Prosthesis; Hemodynamics; Humans; Hypertension; Injections, Intravenous; Ketanserin; Middle Aged; Nitrous Oxide; Piperidines; Postoperative Complications; Serotonin Antagonists

The intravenous injection of ketanserin (0.63-0.31-0.16 mg/kg) to aged, spontaneously hypertensive dogs produces a dose- and time-dependent reduction of mean arterial blood pressure. Concomitantly the whole blood viscosity at shear rates between 11.5 to 450 sec-1 is reduced in parallel with the reduction of packed cell volume (PCV), red blood cell (RBC) number and whole blood haemoglobin content. Plasma viscosity and plasma fibrinogen levels are slightly reduced after the highest dose of ketanserin only, while plasma osmolarity is not affected. Packed RBC viscosity and RBC deformability as measured by a filtration technique are not consistently changed by such a treatment. The reduction of PCV, possibly subsequent to plasma volume expansion during whole blood pressure reduction, is the major cause for the decrease in whole blood viscosity. Such a rheological effect of ketanserin may contribute to the reduction of peripheral vascular resistance and the maintenance of microcirculatory flow despite the decrease of capillary perfusion pressure during blood pressure reduction.

Topics: Aging; Animals; Blood Cell Count; Blood Pressure; Blood Viscosity; Dogs; Erythrocyte Membrane; Hypertension; Ketanserin; Piperidines; Serotonin Antagonists; Vascular Resistance

The serotonergic receptor antagonist 3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4-[1H,3H]quinazolinedione Ketanserin (R 41 468) caused a dose-dependent inhibition on the contractile responses to 5-hydroxytryptamine of isolated rat caudal artery, canine basilar, carotid, coronary and gastrosplenic arteries, canine gastrosplenic veins (threshold 10(-10)-10(-9) M) and canine saphenous veins (threshold 10(-8) M). In concentrations up to 2.5 X 10(-5) M, it did not have agonistic properties. From 10(-8) M on, R 41 468 inhibited the contractions of rat caudal arteries and canine saphenous veins caused by postjunctional alpha adrenergic activation. In the rat caudal artery, R 41 468, in concentrations which did not affect the contractile response to norepinephrine, abolished the amplifying effect of low concentrations of 5-hydroxytryptamine on alpha adrenergic activation. In the canine saphenous vein, R 41 468 did not affect the prejunctional inhibitory effect of 5-hydroxytryptamine during sympathetic nerve stimulation. In the perfused guinea-pig stomach, R 41 468 depressed and in certain experiments reversed the vasoconstrictor response to 5-hydroxytryptamine. In isolated perfused kidneys from both normotensive and spontaneously hypertensive rats, R 41 468, in concentrations which did not depress vasoconstrictor responses to exogenous norepinephrine, inhibited those to 5-hydroxytryptamine. The compound caused a dose-related reduction in aortic blood pressure in unanesthetized spontaneously hypertensive rats, which was larger and occurred at lower concentrations, than in control animals. These results demonstrate that R 41 468 is a potent antagonist of the vasoconstrictor effects of 5-hydroxytryptamine, in particular of its amplifying effect on threshold amounts of norepinephrine, which may help explain its antihypertensive properties.

Topics: Adrenergic alpha-Agonists; Animals; Arteries; Blood Pressure; Calcium; Dogs; Guinea Pigs; Hypertension; In Vitro Techniques; Ketanserin; Kidney; Male; Muscle, Smooth, Vascular; Norepinephrine; Organ Specificity; Piperidines; Rats; Serotonin Antagonists; Species Specificity; Stomach; Vasoconstriction; Veins

Topics: Angina Pectoris; Aniline Compounds; Arrhythmias, Cardiac; Calcium; Cardiomegaly; Diuretics; Heart Diseases; Heart Failure; Humans; Hypertension; Indapamide; Nifedipine; Perhexiline; Piperidines; Pyridines; Verapamil

The synthesis and antihypertensive activity of several piperidinebenzenesulfenamides related to the previously reported potent hypotensive agents 1 and a series of 1-arypiperazine-4-benzenesulfenamides 7 are described. A number of the latter compounds exhibit marked antihypertensive properties. The most interesting of these compounds, 7a and 7k, have been evaluated in several other animal models. In addition, benzenesulfinamides 9a and 9b and benzensulfonamides 10a and 10b have been prepared for comparison purposes.

Topics: Animals; Antihypertensive Agents; Dogs; Hypertension; Piperazines; Piperidines; Rats; Structure-Activity Relationship; Sulfenic Acids

The synthesis of a series of 1-aralkyl-4-ureidopiperidines is reported. These compounds are related to the benzamidopiperidines exemplified by indoramin. Some of the ureidopiperidines are more potent antihypertensive agents than their benzamidopiperidine counterparts. Two examples, 1-(2-thenoyl)-3-[1-[2-(3-indolyl)ethyl]piperid-4-yl]urea and 1-(2-thenoyl)-3-[1-[4-(4-fluorophenyl)-4-oxobutyl]piperid-4-yl]urea (19 and 58), emerged as the most potent antihypertensive agents in this series.

Topics: Animals; Antihypertensive Agents; Desoxycorticosterone; Hypertension; Hypertension, Renal; Piperidines; Rats; Structure-Activity Relationship

Topics: Animals; Anisoles; Blood Pressure; Desipramine; Dioxolanes; Guanethidine; Heart Rate; Hypertension; Piperidines; Rats; Serotonin Antagonists; Time Factors

The synthesis and antihypertensive and diuretic activity of several N-sulfur derivatives of 3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] are reported. Benzenesulfenamide 3 possessed marked, species-specific diuretic and antihypertensive activity in rats.

Topics: Animals; Antidepressive Agents; Antihypertensive Agents; Central Nervous System; Depression, Chemical; Diuretics; Dogs; Female; Haplorhini; Hypertension; Macaca mulatta; Piperidines; Rats; Sodium; Structure-Activity Relationship

A series of 3-[2-(phenoxypiperidyl)-ethyl]indoles was synthesized and evaluated for hypotensive activity in the spontaneous hypertensive rat. Maximum hypotensive activity appeared when the phenoxy substituent was para substituted and occupied the 4 position of the piperidine ring.

Topics: Animals; Antihypertensive Agents; Drug Evaluation, Preclinical; Hypertension; Indoles; Piperidines; Rats

Topics: Antihypertensive Agents; Diuretics; Edema; Female; Humans; Hypertension; Male; Piperidines; Thiazoles

Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (etozolin, Gö 687, Elkapin) is a diuretic with a new chemical structure. Animal experiments with etozolin showed low toxicity, potent diuretic and saluretic properties with a mild onset of action. A marked antihypertensive effect was found in long-term experiments in hypertensive rats. In investigations concerning general pharmacology etozolin showed no effects which stand against its use as a diuretic.

Topics: Animals; Bile; Blood Pressure; Diuresis; Diuretics; Dogs; Gallbladder; Hypertension; Piperidines; Rats; Thiazoles; Water-Electrolyte Balance

In anaesthetized dogs, electrical stimulation of the median posterior hypothalamus provoked hypertension accompanied by a decrease of renal blood flow and an increase of femoral blood flow. Similar hypothalamic reactions occurred after bilateral cervical vagotomy or after atropine, 2 mg/kg i.v. During reflexogenic hypertension induced by bilateral carotid occlusion in bivagotomized dogs, the renal and femoral blood flows were not significantly modified. The decrease of the renal blood flow and the increase of the femoral blood flow, during hypothalamic stimulation were greatly reduced or reversed after R 28935 equals erythro-1-(1--e12-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidaxolinone, 80 mug/kg i.v., but not after clonidine, 5 mug/kg i.v.

Topics: Animals; Antihypertensive Agents; Atropine; Benzimidazoles; Blood Flow Velocity; Carotid Sinus; Clonidine; Dioxanes; Dogs; Electric Stimulation; Femoral Artery; Hypertension; Hypothalamus; Kidney; Piperidines; Pressoreceptors; Vagotomy

The alpha-blocker indoramin had only modest hypotensive action in the normotensive anaesthetised, paralysed patient undergoing major surgical intervention but had a greater effect in the hypertensive patient. The absence of deleterious cardiac effects even with intravenous doses as high as 1 mg/kg. supports previous findings as to the safety of this compound. It is possible that indoramin potentiates the hypotensive action of halothane but there is no evidence to suggest that an adverse interaction might arise when halothane is used to anaesthetise a patient receiving indoramin treatment.

Topics: Adrenergic alpha-Antagonists; Adult; Aged; Anesthesia, General; Arthroplasty; Benzazepines; Blood Pressure; Female; Halothane; Heart Rate; Hemorrhage; Humans; Hypertension; Hypotension, Controlled; Indoles; Male; Mastectomy; Middle Aged; Nephrectomy; Piperidines; Premedication; Prostatectomy; Spinal Fusion; Urinary Bladder

Topics: Antihypertensive Agents; Benzamides; Blood Pressure; Female; Heart Rate; Humans; Hypertension; Indoles; Male; Middle Aged; Piperidines; Proteinuria

Topics: Adolescent; Adult; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Brain Diseases; Cerebrovascular Disorders; Child; Epilepsy; Humans; Hypertension; Hypnotics and Sedatives; Intracranial Arteriosclerosis; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Seizures

Topics: Adult; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiomegaly; Diuretics; Electrocardiography; Female; Heart; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Minoxidil; Nephrectomy; Piperidines; Posture; Propranolol; Pyrimidines; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Blood Pressure; Evaluation Studies as Topic; Female; Follow-Up Studies; Furosemide; Guanethidine; Heart Rate; Humans; Hydralazine; Hydrochlorothiazide; Hypertension; Hypertrichosis; Hypotension, Orthostatic; Kidney Failure, Chronic; Male; Methyldopa; Middle Aged; Minoxidil; Nausea; Piperidines; Pyrimidines

Topics: Amides; Animals; Dogs; Humans; Hypertension; Indoles; Phenoxybenzamine; Piperidines; Propranolol; Vascular Resistance

Topics: Acetylcholine; Amitriptyline; Animals; Antidepressive Agents; Behavior, Animal; Biogenic Amines; Blood Pressure; Brain Chemistry; Central Nervous System; Diazepam; Electroshock; Ethanol; Hexobarbital; Hypertension; Hypothermia, Induced; Imipramine; Iproniazid; Methamphetamine; Mice; Nialamide; Physostigmine; Piperidines; Reserpine; Tremorine

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Body Weight; Cardiac Output; Female; Furosemide; Heart Rate; Humans; Hydralazine; Hydrochlorothiazide; Hypertension; Imines; Kidney; Male; Middle Aged; Piperidines; Propranolol; Pyrimidines; Renin; Sodium

Topics: Amides; Antihypertensive Agents; Clopamide; Diuretics; Drug Combinations; Ergoloid Mesylates; Humans; Hypertension; Piperidines; Potassium; Reserpine; Sodium

Topics: Adult; Aged; Amides; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Child; Child, Preschool; Clopamide; Depression, Chemical; Diabetes Complications; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Hyperthyroidism; Infant; Liver Function Tests; Male; Middle Aged; Piperidines; Potassium; Reserpine; Urine

Topics: Aged; Blood Pressure; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Aged; Amides; Clopamide; Diuretics; Drug Synergism; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Ambulatory Care; Amides; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Ambulatory Care; Amides; Benzoates; Clopamide; Diuretics; Drug Synergism; Female; Humans; Hypertension; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular; Reserpine

Topics: Adult; Amides; Clopamide; Diuretics; Humans; Hypertension; Middle Aged; Piperidines

Topics: Angiotensin II; Antihypertensive Agents; Electrocardiography; Ergoloid Mesylates; Ergotamine; Female; Heart Failure; Humans; Hypertension; Hypotension, Orthostatic; Methyldopa; Middle Aged; Norepinephrine; Phytotherapy; Piperidines; Plants, Medicinal; Pulmonary Edema; Rauwolfia; Sympatholytics

Topics: Adrenergic alpha-Antagonists; Adult; Aldosterone; Antihypertensive Agents; Blood Pressure; Cardiac Output; Female; Forearm; Glomerular Filtration Rate; Heart; Heart Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Norepinephrine; Piperidines; Posture; Propranolol; Pyrimidines; Sodium; Valsalva Maneuver; Vanilmandelic Acid; Vascular Resistance; Vasodilator Agents

Topics: Aged; Ambulatory Care; Amides; Blood Urea Nitrogen; Clopamide; Creatinine; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Potassium; Reserpine

Topics: Adult; Aged; Amides; Blood Pressure; Clopamide; Diuresis; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Potassium Deficiency; Reserpine; Water-Electrolyte Balance

Topics: Amides; Clopamide; Diuretics; Ergoloid Mesylates; Humans; Hypertension; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Clopamide; Diuretics; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Animals; Cardiac Output; Dogs; Hypertension; Kidney; Piperidines; Pyrimidines; Vascular Resistance; Vasodilator Agents

Topics: Cardiac Output; Heart Rate; Hypertension; Kidney; Piperidines; Pyrimidines; Vasodilator Agents

Topics: Humans; Hydralazine; Hypertension; Piperidines; Propranolol; Pyrimidines; Vasodilator Agents

Topics: Humans; Hydralazine; Hypertension; Piperidines; Propranolol; Pyrimidines; Vasodilator Agents

Topics: Adult; Aged; Ambulatory Care; Amides; Antihypertensive Agents; Arteriosclerosis; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Amides; Ammonia; Clopamide; Diuretics; Female; Humans; Hypertension; Lymphedema; Male; Middle Aged; Migraine Disorders; Piperidines

Topics: Androstanes; Atropine; Body Weight; Histamine Release; Humans; Hypertension; Hypothermia, Induced; Intubation; Muscles; Neostigmine; Neuromuscular Junction; Peripheral Nerves; Piperidines; Stimulation, Chemical

Topics: Aged; Albuminuria; Amides; Brain; Clopamide; Diuresis; Diuretics; Ergoloid Mesylates; Fundus Oculi; Headache; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Obesity; Piperidines; Sodium; Vertigo

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adolescent; Adult; Amides; Clopamide; Diuretics; Drug Synergism; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Amides; Clopamide; Diuretics; Female; Humans; Hypertension; Male; Middle Aged; Piperidines

Topics: Adolescent; Adult; Aged; Amides; Clopamide; Diuretics; Edema; Humans; Hypertension; Middle Aged; Piperidines

Topics: Adult; Ambulatory Care; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Male; Piperidines; Reserpine

Topics: Aged; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Humans; Hypertension; Hypnotics and Sedatives; Phenothiazines; Piperazines; Piperidines; Reserpine; Sympatholytics

Topics: Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adolescent; Adult; Aged; Amides; Blood Pressure; Clopamide; Diuretics; Drug Synergism; Ergoloid Mesylates; Female; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Piperidines; Reserpine

Topics: Aged; Amides; Antihypertensive Agents; Blood Pressure; Clopamide; Diuretics; Ergoloid Mesylates; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Amides; Clopamide; Diuretics; Ergoloid Mesylates; Hypertension; Piperidines; Reserpine

Topics: Adult; Age Factors; Aged; Ergoloid Mesylates; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Amides; Clopamide; Diuretics; Edema; Female; Humans; Hypertension; Piperidines; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Adrenal Cortex Hormones; Adult; Amides; Body Weight; Clopamide; Coronary Disease; Diabetes Insipidus; Diuretics; Edema; Female; Heart Valve Diseases; Humans; Hypertension; Male; Middle Aged; Obesity; Piperidines; Pulmonary Heart Disease

Topics: Aged; Amides; Clopamide; Diuretics; Drug Synergism; Ergot Alkaloids; Female; Humans; Hypertension; Male; Piperidines; Reserpine

Topics: Adult; Aged; Amides; Blood Pressure Determination; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Male; Middle Aged; Piperidines; Reserpine

Topics: Adult; Amides; Antihypertensive Agents; Clopamide; Diuretics; Ergot Alkaloids; Female; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Piperidines; Potassium; Reserpine

Topics: Amides; Clopamide; Diuretics; Ergot Alkaloids; Hypertension; Hypertension, Renal; Hypokalemia; Piperidines; Reserpine

Topics: Animals; Blood Pressure; Carotid Arteries; Cats; Epinephrine; Female; Hexamethonium Compounds; Hypertension; In Vitro Techniques; Intestines; Male; Muscle, Smooth; Nictitating Membrane; Norepinephrine; Piperidines; Rats; Sympathetic Nervous System; Sympathomimetics; Tachyphylaxis; Trachea; Uterus; Vas Deferens

Topics: Ganglionic Blockers; Humans; Hypertension; Piperidines

Topics: Amides; Arteries; Clopamide; Diuretics; Ergoloid Mesylates; Humans; Hypertension; Middle Aged; Piperidines; Reserpine

Topics: Amides; Clopamide; Diuretics; Ergoloid Mesylates; Humans; Hypertension; Ischemic Attack, Transient; Piperidines

Topics: Amides; Clopamide; Diuretics; Edema; Female; Humans; Hypertension; Piperidines; Pregnancy; Pregnancy Complications

Topics: Amines; Animals; Blood Pressure; Cats; Chemistry, Organic; Dogs; Ganglia, Autonomic; Heart Rate; Hypertension; Nictitating Membrane; Organic Chemistry Phenomena; Piperidines; Pyrrolidines; Rats; Respiration

Topics: Adult; Aged; Anxiety Disorders; Biliary Tract Diseases; Cardiovascular Diseases; Depression; Dysautonomia, Familial; Female; Gastrointestinal Diseases; Humans; Hypertension; Lung Diseases; Male; Middle Aged; Neoplasms; Piperidines; Tranquilizing Agents

Topics: Clopamide; Diuretics; Heart Failure; Humans; Hypertension; Liver Cirrhosis; Obesity; Piperidines

Topics: Animals; Atropine; Blood Circulation; Blood Pressure; Blood Pressure Determination; Chloralose; Cyproheptadine; Diphenhydramine; Dogs; Endotoxins; Hemorrhage; Histamine H1 Antagonists; Histamine Release; Humans; Hypertension; Hypertension, Portal; Isoproterenol; Morphine; p-Methoxy-N-methylphenethylamine; Pharmacology; Phenothiazines; Phenoxybenzamine; Piperidines; Research; Reserpine; Shigella; Shock, Septic; Splenic Artery; Sympatholytics; Vasodilator Agents

Topics: Animals; Antihypertensive Agents; Cats; Dogs; Guanidines; Hypertension; Hypertension, Renal; Kidney; Pharmacology; Piperidines; Rats; Research

Topics: Alkaloids; Hypertension; Hypertension, Renal; Piperidines; Research; Solanine; Spectrophotometry

Topics: Antitubercular Agents; Hypertension; Pempidine; Piperidines

Topics: Antihypertensive Agents; Hypertension; Monitoring, Physiologic; Pempidine; Piperidines; Professional Practice

When chlorothiazide is given to hypertensive patients who are receiving pempidine a rise in plasma pempidine concentration occurs and this is proportionately greater than the additional fall in blood pressure. After pempidine has been added to human whole blood in vitro or in vivo the ratio of the pempidine concentration in the red cells to that in the plasma falls in the course of 1 hr from an initial value greater than 2 to about 1.2. If chlorothiazide is present also, however, the ratio remains constant at 0.7. Changes in the plasma pempidine concentration in vivo probably result from the binding of pempidine to plasma protein in the presence of chlorothiazide. This has been observed in vitro by a dialysis technique.

Topics: Antihypertensive Agents; Blood Pressure; Body Fluids; Chlorothiazide; Erythrocytes; Humans; Hypertension; Hypotension; Male; Pempidine; Piperidines

Topics: Hypertension; Pempidine; Piperidines; Reserpine

Topics: Hypertension; Pempidine; Piperidines

Topics: Humans; Hypertension; Pempidine; Piperidines

Topics: Hypertension; Pempidine; Piperidines

Topics: Hypertension; Pempidine; Piperidines

Topics: Autonomic Agents; Hypertension; Piperidines; Quaternary Ammonium Compounds

Topics: Antihypertensive Agents; Central Nervous System Stimulants; Hypertension; Piperidines; Reserpine; Secologanin Tryptamine Alkaloids; Sympatholytics

Topics: Blood Pressure; Blood Pressure Determination; Hypertension; Piperidines