cardiovascular-agents and Body-Weight

To derive recommendations for the dosing of commonly used medications in the morbidly obese patient in the ICU.. Articles were obtained through computerized searches involving MEDLINE. The bibliographies of retrieved publications and textbooks were reviewed for additional references.. All studies involving the pharmacokinetics or pharmacodynamics of medications in obese subjects or patients.. The emphasis was on studies involving morbidly obese patients but, in the absence of such data, investigations involving lesser forms of obesity were extracted.. There is a paucity of data upon which to make recommendations for dosing commonly used medications in the morbidly obese patient in the ICU, although recommendations were provided based on the available information.. There is clearly a need for more investigations involving dosing regimens of medications in the morbidly obese population. Until such studies are available, the clinician must try to derive the best dosing regimens for medications based on the limited pharmacokinetic data available for some agents and clinical judgement.

Topics: Analgesics, Opioid; Anti-Infective Agents; Anticoagulants; Anticonvulsants; Body Weight; Cardiovascular Agents; Critical Care; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Fibrinolytic Agents; Gastrointestinal Agents; Humans; Metabolic Clearance Rate; Obesity, Morbid; Practice Guidelines as Topic; Respiratory System Agents

Heart failure (HF) patients discharged from rural hospitals have higher 30-day readmission rates. Self-management (SM) reduces readmissions, but adherence to SM guidelines is low in the rural HF population. We tested a home-based intervention to enhance patient activation and lead to improved SM adherence.. In this two-group, repeated measures randomized control trial, the main outcomes were patient reported and clinical outcomes associated with SM adherence, and all-cause readmission at 30, 90 and 180 days.. The study included 100 HF patients discharged from a rural critical access hospital. The intervention group received a 12-week SM training and coaching program delivered by telephone and tailored on subjects' activation levels. At α = .10, the PATCH intervention showed significantly greater improvement compared to usual care in patient-reported SM adherence: weighing themselves, following a low-sodium diet, taking prescribed medication, and exercising daily (all p < .0005) at 3 and 6 months after discharge. In contrast, groups did not differ in physical activity assessed by actigraphy or in clinical biomarkers. Contrary to expectation, the 30-day readmission rate was significantly higher (p = .088) in the intervention group (19.6 %) than in the control group (6.1 %), with no differences at 90 or 180 days.. It is feasible to conduct a randomized controlled trial in HF patients discharged from rural critical access hospitals. Significantly higher patient-reported SM adherence was not accompanied by lower clinical biomarkers or readmission rates. Further research is needed to understand mechanisms that influence outcomes and healthcare utilization in this population.. ClinicalTrials.gov; NCT01964053 .

Topics: Adult; Aged; Aged, 80 and over; Body Weight; Cardiovascular Agents; Diet, Sodium-Restricted; Exercise; Female; Health Behavior; Health Knowledge, Attitudes, Practice; Heart Failure; Home Care Services, Hospital-Based; Humans; Male; Medication Adherence; Middle Aged; Patient Compliance; Patient Readmission; Program Evaluation; Rural Health Services; Self Care; Time Factors; Treatment Outcome

There are limited data comparing ultrafiltration with standard medical therapy as first-line treatment in patients with severe congestive heart failure (HF). We compared ultrafiltration and conventional therapy in patients hospitalized for HF and overt fluid overload.. Fifty-six patients with congestive HF were randomized to receive standard medical therapy (control group; n = 29) or ultrafiltration (ultrafiltration group; n = 27). The primary end point of the study was rehospitalizations for congestive HF during a 1-year follow-up. Despite similar body weight reduction at hospital discharge in the 2 groups (7.5 ± 5.5 and 7.9 ± 9.0 kg, respectively; P = .75), a lower incidence of rehospitalizations for HF was observed in the ultrafiltration-treated patients during the following year (hazard ratio 0.14, 95% confidence interval 0.04-0.48; P = .002). Ultrafiltration-induced benefit was associated with a more stable renal function, unchanged furosemide dose, and lower B-type natriuretic peptide levels. At 1 year, 7 deaths (30%) occurred in the ultrafiltration group and 11 (44%) in the control group (P = .33).. In HF patients with severe fluid overload, first-line treatment with ultrafiltration is associated with a prolonged clinical stabilization and a greater freedom from rehospitalization for congestive HF.

Topics: Aged; Aged, 80 and over; Body Weight; Cardiovascular Agents; Confidence Intervals; Diuretics; Dose-Response Relationship, Drug; Female; Furosemide; Heart Failure; Humans; Kidney Function Tests; Male; Monitoring, Physiologic; Natriuretic Peptide, Brain; Patient Readmission; Proportional Hazards Models; Severity of Illness Index; Treatment Outcome; Ultrafiltration

Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure.. To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure.. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment.. Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy.. Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema.. During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups.. Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity.. clinicaltrials.gov Identifier: NCT00071331

Topics: Administration, Oral; Aged; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Blood Urea Nitrogen; Body Weight; Cardiovascular Agents; Creatinine; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Quality of Life; Sodium; Tolvaptan

Several trials support the usefulness of disease management (DM) for improving clinical outcomes in heart failure (HF). Most of these studies are limited by small sample size; absence of concurrent, randomized controls; limited follow-up; restriction to urban academic centers; and low baseline use of effective medications.. We performed a prospective, randomized assessment of the effectiveness of HF DM delivered for 90 days across a diverse provider network in a heterogeneous population of 200 patients with high baseline use of approved HF pharmacotherapy. During a 90-day follow-up, patients randomized to DM experienced fewer hospitalizations for HF [primary end point, 0.55+/-0.15 per patient-year alive versus 1.14+/-0.22 per patient-year alive in control subjects; relative risk (RR), 0.48, P=0.027]. Intervention patients experienced reductions in hospital days related to a primary diagnosis of HF (4.3+/-0.4 versus 7.8+/-0.6 days hospitalized per patient-year; RR, 0.54; P<0.001), cardiovascular hospitalizations (0.81+/-0.19 versus 1.43+/-0.24 per patient-year alive; RR, 0.57; P=0.043), and days in hospital per patient-year alive for cardiovascular cause (RR, 0.64; P<0.001). Intervention patients showed a trend toward reduced all-cause hospitalizations and total hospital days. On long-term (mean, 283 days) follow-up, there was substantial attrition of the 3-month gain in outcomes, with sustained significant reduction only in days in hospital for cardiac cause.. In a population with high background use of standard HF therapy, a DM intervention, uniformly delivered across varied clinical sites, produced significant short-term improvement in HF-related clinical outcomes. Longer-term benefit likely requires more active chronic intervention, even among patients who appear clinically stable.

Topics: Academic Medical Centers; Aged; Aged, 80 and over; Body Weight; Cardiology; Cardiovascular Agents; Caregivers; Comorbidity; Diet, Sodium-Restricted; Disease Management; Female; Follow-Up Studies; Heart Failure; Hospitalization; Hospitals, Community; House Calls; Humans; Male; Massachusetts; Middle Aged; Patient Compliance; Patient Education as Topic; Private Practice; Rhode Island; Self Care; Severity of Illness Index; Single-Blind Method

The Women's Lifestyle Heart Trial was a small (N = 28) randomized controlled trial to evaluate the effects of a comprehensive lifestyle self-management program (very low-fat vegetarian diet, stress-management training, exercise, group support, and smoking cessation) on reduction of cardiovascular risk factors in postmenopausal women with coronary heart disease (CHD). Women assigned to the treatment condition (Prime Time) participated in a week-long retreat followed by twice-weekly 4-hour meetings. Endpoints were program adherence; changes in lipid profiles, body mass, blood pressure, hypolipidemic and antihypertensive medications; and quality of life. Risk factor and psychosocial evaluations were conducted at baseline and at 4, 12, and 24 months. Repeated measures analyses of covariance revealed that the dietary, stress management, and physical activity changes made by intervention women were dramatic and lasting. There were significantly greater improvements in the Prime Time condition compared to the usual care control group on body mass, angina symptoms, and quality of life, and a tendency for a greater reduction in blood pressure-lowering medications. Similar patterns were seen in lipids, blood pressure, and lipid-lowering medications, but did not reach significance. These results demonstrate that postmenopausal CHD women can make lasting lifestyle changes, and that these changes may reduce the need for cardiac medications and improve CHD risk factors and quality of life.

Topics: Aged; Blood Pressure; Body Weight; Cardiovascular Agents; Coronary Disease; Diet, Fat-Restricted; Exercise; Female; Humans; Life Style; Lipids; Middle Aged; Oregon; Postmenopause; Quality of Life; Risk Factors; Smoking Cessation; Social Support; Stress, Psychological; Survival Analysis; Treatment Outcome; Women's Health

Diabetes is a serious global health concern which severely affected public health as well as socio-economic growth worldwide. Scutellarin (SCU), a bioactive flavonoid, is known for its efficacious action against a range of ailments including cardiovascular problems. The present study was conducted to find out possible protective effect and its associated mechanisms of SCU on experimental type 2 diabetes-induced cardiac injury.. Type 2 diabetes was induced by treating animals with high fat diet for 4 weeks and a single intraperitoneal dose (35 mg/kg body weight) of streptozotocin and diabetic animals received SCU (10 or 20 mg/kg/day) for 6 weeks.. Scutellarin attenuated type 2 diabetes-induced hyperglycemia, bodyweight loss, hyperlipidaemia, cardiac functional damage with histopathological alterations and fibrosis. Scutellarin treatment to type 2 diabetic mice ameliorated oxidative stress, inflammatory status and apoptosis in heart. Furthermore, the underlying mechanisms for such mitigation of oxidative stress, inflammation and apoptosis in heart involved modulation of Nrf2/Keap1 pathway, TLR4/MyD88/NF-κB mediated inflammatory pathway and intrinsic (mitochondrial) apoptosis pathway, respectively.. The current findings suggest that SCU is effective in protecting type 2 diabetes-induced cardiac injury by attenuating oxidative stress and inflammatory responses and apoptosis, and it is also worth considering the efficacious potential of SCU to treat diabetic cardiomyopathy patients.

Topics: Animals; Apigenin; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Agents; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dose-Response Relationship, Drug; Gene Expression Regulation; Glucuronates; Heart Diseases; Inflammation; Lipids; Male; Mice; Oxidative Stress; RNA, Messenger

Topics: Body Weight; Cardiovascular Agents; Female; Heart Failure; Humans; Male; Sex Factors; Treatment Outcome

To describe the duration of time to achieve exclusive oral feeding in infants with single ventricle physiology and to identify risk factors associated with prolonged gastrostomy tube dependence.. Single center, retrospective study of infants with single ventricle physiology. The primary outcome was duration of time required to achieve oral feeding. Transition periods were defined as exclusive oral feeding by Glenn palliation (early), by 1 year of age (mid), or after 1 year of age (late).. Seventy-eight infants were analyzed; 46 (59%) were discharged to home with a gastrostomy tube after the initial hospitalization. Overall, 39 infants (50%) achieved early transition, 14 (18%) mid, and 18 (23%) late. The group who achieved early transition had a higher percentage of preoperative oral feeding (P < .01), greater weight-for-age z score at initial discharge (P = .03), shorter initial intensive care unit duration (P < .01), shorter initial hospital length of stay (P < .01), and greater weight-for-age z score at Glenn admission (P = .02). No preoperative oral feeding (OR = 0.12, P = .02) and greater number of cardiac medications at initial discharge (OR = 3.8, P = .03) were associated with failure to achieve early transition. No preoperative oral feeding (OR = 0.09, P = .01) and longer initial intensive care unit duration (OR = 1.1, P = .03) were associated with failure to achieve mid transition.. Preoperative oral feeding may potentially be a modifiable factor to help improve early transition to oral feeding.

Topics: Body Weight; Cardiovascular Agents; Cardiovascular Surgical Procedures; Enteral Nutrition; Female; Humans; Infant; Intensive Care Units, Pediatric; Length of Stay; Male; Oxygen; Preoperative Care; Retrospective Studies; Time Factors; Univentricular Heart

Increased sympathetic nerve activity and the activation of the central renin-angiotensin system are commonly associated with cardiovascular disease states such as hypertension and heart failure, yet the precise mechanisms contributing to the long-term maintenance of this sympatho-excitation are incompletely understood. Due to the established physiological role of neurotrophins contributing toward neuroplasticity and neuronal excitability along with recent evidence linking the renin-angiotensin system and brain-derived neurotrophic factor (BDNF) along with its receptor (TrkB), it is likely the two systems interact to promote sympatho-excitation during cardiovascular disease. However, this interaction has not yet been fully demonstrated, in vivo. Thus, we hypothesized that central angiotensin II (Ang II) treatment will evoke a sympatho-excitatory state mediated through the actions of BDNF/TrkB. We infused Ang II (20ng/min) into the right lateral ventricle of male Sprague-Dawley rats for twelve days with or without the TrkB receptor antagonist, ANA-12 (50ng/h). We found that ICV infusion of Ang II increased mean arterial pressure (+40.4mmHg), increased renal sympathetic nerve activity (+19.4% max activity), and induced baroreflex dysfunction relative to vehicle. Co-infusion of ANA-12 attenuated the increase in blood pressure (-20.6mmHg) and prevented the increase in renal sympathetic nerve activity (-22.2% max) and baroreflex dysfunction relative to Ang II alone. Ang II increased thirst and decreased food consumption, and Ang II+ANA-12 augmented the thirst response while attenuating the decrease in food consumption. We conclude that TrkB signaling is a mediator of the long-term blood pressure and sympathetic nerve activity responses to central Ang II activity. These findings demonstrate the involvement of neurotrophins such as BDNF in promoting Ang II-induced autonomic dysfunction and further implicate TrkB signaling in modulating presympathetic autonomic neurons during cardiovascular disease.

Topics: Angiotensin II; Animals; Azepines; Baroreflex; Benzamides; Blood Pressure; Body Weight; Cardiovascular Agents; Defecation; Drinking; Heart Rate; Hypertension; Kidney; Male; Organ Size; Rats, Sprague-Dawley; Receptor, trkB; Sympathetic Nervous System; Urination

To analyze how graft-weight-to-bodyweight ratio in pediatric liver transplant affects intraoperative and early postoperative hemodynamic and metabolic parameters.. We reviewed data from 130 children who underwent liver transplant between 2005 and 2015. Recipients were divided into 2 groups: those with a graft weight to body weight ratio > 4% (large for size) and those with a ratio ≤ 4% (normal for size). Data included demographics, preoperative laboratory findings, intraoperative metabolic and hemodynamic parameters, and intensive care follow-up parameters.. Patients in the large-graft-for-size group (>4%) received more colloid solution (57.7 ± 20.1 mL/kg vs 45.1 ± 21.9 mL/kg; P = .08) and higher doses of furosemide (0.7 ± 0.6 mg/kg vs 0.4 ± 0.7 mg/kg; P = .018). They had lower mean pH (7.1 ± 0.1 vs 7.2 ± 0.1; P = .004) and PO2 (115.4 ± 44.6 mm Hg vs 147.6 ± 49.3 mm Hg; P = .004) values, higher blood glucose values (352.8 ± 96.9 mg/dL vs 262.8 ± 88.2 mg/dL; P < .001), and lower mean body temperature (34.8 ± 0.7°C vs 35.2 ± 0.6°C; P = .016) during the neohepatic phase. They received more blood transfusions during both the anhepatic (30.3 ± 24.3 mL/kg vs 18.8 ± 21.8 mL/kg; P = .013) and neohepatic (17.7 ± 20.4 mL/kg vs 10.3 ± 15.5 mL/kg; P = .031) phases and more fresh frozen plasma (13.6 ± 17.6 mL/kg vs 6.2 ± 10.2 mL/kg; P = .012) during the neohepatic phase. They also were more likely to be hypotensive (P < .05) and to receive norepinephrine infusion more often (44% vs 22%; P < .05) intraoperatively. More patients in this group were mechanically ventilated in the intensive care unit (56% vs 31%; P = .035). There were no significant differences between the groups in postoperative acute renal dysfunction, graft rejection or loss, infections, length of intensive care stay, and mortality (P > .05).. High graft weight-to-body-weight ratio is associated with adverse metabolic and hemodynamic changes during the intraoperative and early postoperative periods. These results emphasize the importance of using an appropriately sized graft in liver transplant.

Topics: Adolescent; Age Factors; Biomarkers; Blood Transfusion; Body Weight; Cardiovascular Agents; Child; Child, Preschool; Female; Graft Rejection; Graft Survival; Hemodynamics; Hospital Mortality; Humans; Infant; Liver; Liver Failure; Liver Transplantation; Male; Organ Size; Patient Selection; Primary Graft Dysfunction; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

Traditional fermented cheese whey (TFCW), containing probiotics, has been used both as a dairy food with ethnic flavor and a medicine for cardiovascular disease, especially regulating blood lipid among Kazakh. We therefore investigated anti-atherosclerotic effects of TFCW in atherosclerotic rabbits and identified lactic acid bacteria (LAB) and yeasts in TFCW.. Atherosclerotic rabbits were induced by administration of atherosclerotic diet for 12 weeks and divided randomly into three groups and treated for 4 weeks with Simvastatin (20 mg/kg) or TFCW (25 mg/kg) and (50 mg/kg). In addition, a normal control group and an atherosclerotic group were used for comparison. All drugs were intragastrical administered once daily 10 mL/kg for 4 weeks. Body weight (BW), lipid profiles, C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were tested and theromatous plaques and the number of foam cells and infiltrating fibroblast cells in the thoracic aorta endothelium was evaluated by hematoxylin and eosin stainin. LAB and yeasts were isolated and purified by conventional techniques and identified using morphological and biochemical properties as well as gene sequences analysis.. After 4 weeks of treatment, high and low dose TFCW decreased serum TC, TG, LDLC, CRP, VCAM-1 and ICAM-1 (P < 0.05) compared to atherosclerotic group, and increased HDL-C (P < 0.05) compared to normal controls. Histological analysis showed TFCW reduced VCAM-1 expression and formation of atheromatous plaques on the aortic endothelium of atherosclerotic rabbits.. Seven classes of LBA from two different genera including Lactobacillus brevis, Lactobacillus kefianofaciens, Lactobacillus helveticus, Lactobacillus Casei, Lactobacillus plantarum, Lactobacillus kefiri and Lactococcus lactic as well as 2 classes of yeasts from two different genera including Saccharomyces unisporus and Issatchenkia orientalis were isolated and identified from TFCW. In summary, TFCW, containing 7 classes of LBA and 2 classes of yeasts, has significant anti-atherosclerotic potential in atherosclerotic rabbits and may modulate lipid metabolism and protect aorta in the atherosclerotic condition, which might be related to various probiotics acting through reducing the CRP, VCAM-1 and ICAM-1 levels and protecting the aortic endothelium.

Topics: Animals; Aorta; Atherosclerosis; Body Weight; C-Reactive Protein; Cardiovascular Agents; Cheese; Lipids; Male; Probiotics; Rabbits; Vascular Cell Adhesion Molecule-1; Whey

Two hundred patients at steady-state on long-term perhexiline were identified retrospectively. The ratio of maintenance dose to steady-state plasma concentration (dose:[Px]) was correlated with the following putative determinants via simple and multiple linear regression analyses: age, weight, left ventricular ejection fraction (LVEF), and creatinine clearance (CrCl, Cockroft-Gault formula). A Mann-Whitney U test was performed to determine if severe left ventricular systolic impairment affected maintenance dose.. Advanced age, left ventricular systolic impairment, and renal impairment were frequently encountered. Using simple linear regression, age was a negative correlate of dose:[P] (R = 0.23, P = 0.001), whereas weight (R = 0.27, P = 0.0001) and CrCl (R = 0.30, P < 0.0001) were positive correlates. Mann-Whitney U analysis showed no difference between dose: [Px] among patients with LVEF of less than 30% versus 30% or greater. Advancing age was strongly associated with decreasing weight (R = -0.45, P < 0.00001) and calculated CrCl varied directly with weight, as expected (R = 0.66, P < 0.0001). Stepwise multiple linear regression using age, LVEF, CrCl, and weight as potential predictors of dose:[P] yielded only weight as a significant determinant.. Perhexiline has become a "last-line" agent for refractory angina as a result of complex pharmacokinetics and potential toxicity. Use has increased predictably in the aged and infirm who have exhausted standard medical and surgical therapeutic options. Beyond genotype, the effect of patient characteristics on maintenance dose has not been explored in detail. In this study, dose requirement declined with age in a frail and wasting population as a result of weight-related pharmacokinetic factors. LVEF had no apparent effect on maintenance dose and should not be considered a contraindication to use.. A weight-adjusted starting dose may facilitate the safe and effective prescription of perhexiline and is calculated by 50 + 2 × weight (kg) mg/d, rounded to the closest 50 mg/day.

Topics: Aged; Aged, 80 and over; Aging; Angina Pectoris; Body Weight; Cardiovascular Agents; Creatinine; Humans; Middle Aged; Perhexiline; Renal Insufficiency; Retrospective Studies; Ventricular Dysfunction, Left

Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.. Three month old female mdx mice were exposed to the β(1) receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.. BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.. This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.

Topics: Adrenergic beta-Agonists; Analysis of Variance; Animals; Aortic Valve; Blood Pressure; Body Weight; Cardiomyopathies; Cardiovascular Agents; Collagen; Disease Models, Animal; Drug Administration Schedule; Dystrophin; Female; Fibrosis; Heart Rate; Injections, Intraperitoneal; Isoproterenol; Mice; Mice, Inbred mdx; Muscle Strength; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Myocardial Contraction; Myocardium; Poloxamer; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Pressure

Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine (TCM) formula, has been recognized as a clinical treatment for coronary heart disease (CHD) with qi deficiency and blood stasis syndrome. The effects of BYHWD on hemorheological disorders and energy metabolism in CHD with qi deficiency and blood stasis syndrome are still unclear.. To investigate whether the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are associated with the regulation of hemorheological disorders and energy metabolism.. The rats were lavaged with 25.68, 12.84 and 6.42 g/kg BYHWD (g weight of mixed crude drugs/kg body weight), respectively, once a day for 21 days. The body weight, exhaustive swimming time and tongue characters were observed and recorded. The whole blood viscosity and plasma viscosity were determined by hematology analyzer. The level of fibrinogen (Fbg) in plasma was determined by using Fbg assay kit. The platelet aggregation induced by adenosine diphosphatase was measured by semi-automatic whole blood platelet analyzer. The level of blood glucose (BG) was determined by LifeScan. The activity of Na(+)-K(+)-ATPase in heart tissues was detected by spectrophotometer.. BYHWD improved the exterior signs of qi deficiency and blood stasis syndrome in rats with CHD, including the body weight, exhaustive swimming time and tongue quality. The whole blood viscosity in rats treated with 25.68 g/kg BYHWD decreased at the shear rate of 10s(-1) (P<0.05) and the plasma viscosity decreased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.05). The plasma Fbg level and the platelet aggregation decreased in rats treated with 25.68 g/kg BYHWD (P<0.01). The results also revealed that the BG level decreased and the Na(+)-K(+)-ATPase activity in heart tissues increased in rats treated with 25.68 and 12.84 g/kg BYHWD (P<0.01).. The results suggest that the ameliorative effects of BYHWD on CHD rats with qi deficiency and blood stasis syndrome are mediated by the improvement of hemorheological disorders and energy metabolism.

Topics: Animals; Biomarkers; Blood Glucose; Blood Viscosity; Body Weight; Cardiovascular Agents; Coronary Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Energy Metabolism; Female; Fibrinogen; Hemorheology; Male; Myocardium; Physical Endurance; Platelet Aggregation; Qi; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase; Swimming; Time Factors; Tongue

Topics: Body Weight; Cardiovascular Agents; Coronary Disease; Diet, Reducing; Humans; Randomized Controlled Trials as Topic; Religion; Risk Factors; Sedentary Behavior; Television

This study aimed to find the effects of heparin on atherosclerosis and the production of matrix metalloproteinase (MMP)-2 in low-density lipoprotein receptor-deficient (LDLr(-/-)) mice.. Sixteen 7-week-old LDLr(-/-) mice were randomized to receive sterile water or heparin. The levels of total cholesterol, high-density lipoprotein cholesterol, triglyceride and homocysteine were measured. Mean lesions area was calculated as the total atherosclerotic lesions area and expressed as a percentage of total luminal surface area. The lesions area was measured blindly by the same person using computer-assisted image analysis. The expression and localization of the MMP-2 was examined by immunohistochemistry.. All mice exhibited atherosclerotic lesions in the aortic sinus and aortic surface. Total cholesterol was decreased, while high-density lipoprotein cholesterol was increased in heparin compared with that in control group (P=0.001 and 0.002). Triglyceride was not significantly different between the two groups (P=0.92). The amount of atherosclerotic lesions in the aortic surface was 40.5% lower in heparin group than that in the control group (P<0.001). The mean area of atherosclerotic lesions in the aortic sinus was also less in the heparin group than that in the control group. Coincidently, the expression of MMP-2 in the atherosclerotic lesions in the heparin group was 49.3% lower than that in the control group (P<0.001).. Heparin can inhibit the production of MMP-2 in the atherosclerotic lesions and improve the atherosclerotic lesions in LDLr(-/-) mice.

Topics: Animals; Aorta; Atherosclerosis; Biomarkers; Body Weight; Cardiovascular Agents; Cholesterol; Cholesterol, HDL; Disease Models, Animal; Eating; Heparin; Homocysteine; Immunohistochemistry; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL; Triglycerides

We explored the effect of hydrogen sulfide (H(2)S) on atherosclerotic progression, particularly on intracellular adhesion molecule-1 (ICAM-1) in apolipoprotein-E knockout (apoE(-/-)) mice and human umbilical vein endothelial cells (HUVECs).. ApoE(-/-) mice were treated with sodium hydrosulfide (NaHS) or DL-propargylglycine (PPG); HUVECs were pretreated with NaHS. Compared with control mice, apoE(-/-) mice showed decreased plasma H(2)S level and aortic H(2)S production but increased plasma ICAM-1 and aortic ICAM-1 protein and mRNA. Compared with apoE(-/-) mice, apoE(-/-)+NaHS mice showed increased plasma H(2)S level, but decreased size of atherosclerotic plaque and plasma and aortic ICAM-1 levels, whereas apoE(-/-)+PPG mice showed decreased plasma H(2)S level but enlarged plaque size and increased plasma and aortic ICAM-1 levels. NaHS suppressed ICAM-1 expression in tumor necrosis factor (TNF)-alpha-treated HUVECs. NaHS inhibited IkappaB degradation and NF-kappaB nuclear translocation in HUVECs treated with TNF-alpha.. The vascular CSE/H(2)S pathway was disturbed in apoE(-/-) mice. H(2)S exerted an antiatherogenic effect and inhibited ICAM-1 expression in apoE(-/-) mice. H(2)S inhibited ICAM-1 expression in TNF-alpha-induced HUVECs via the NF-kappaB pathway.

Topics: Active Transport, Cell Nucleus; Alkynes; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Weight; Cardiovascular Agents; Cells, Cultured; Cystathionine gamma-Lyase; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Inhibitors; Foam Cells; Glycine; Humans; Hydrogen Sulfide; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; NF-kappa B; RNA, Messenger; Sulfides; Tumor Necrosis Factor-alpha

Premature neonates are frequently administered indomethacin, ibuprofen and gentamicin during the period of active glomerulogenesis. These drugs are known to have nephrotoxic effects, but the morphological effect of these drugs is unknown. The purpose of this study was to determine whether administration of these drugs during the late stages of glomerulogenesis in the rat has an effect on glomerular endowment. Rat pups were given, intraperitoneally, indomethacin, ibuprofen or indomethacin and gentamicin for the first 5 days of their postnatal life. The pups were killed at 14 days of age at completion of glomerulogenesis. The total number of glomeruli in the left kidney was determined by the physical disector/fractionator stereological technique. There was no difference between treatment groups in total number of glomeruli per kidney (P = 0.45). There were significantly fewer glomeruli per gram of kidney in those rat pups that had received indomethacin or ibuprofen (P < 0.0001). The reduction in the number of glomeruli per gram of kidney may indicate augmented growth of nephron tubules and/or collecting ducts, and/or be a consequence of oedema secondary to drug exposure. Further study is required to determine whether reduced glomerular number is seen in older animals or following exposure to these drugs at different time-points in kidney development.

Topics: Analgesics, Non-Narcotic; Animals; Animals, Newborn; Anti-Bacterial Agents; Body Weight; Cardiovascular Agents; Drug Combinations; Female; Gentamicins; Ibuprofen; Indomethacin; Kidney Glomerulus; Nephrons; Organ Size; Pregnancy; Rats; Rats, Sprague-Dawley

Mildronate is a cardioprotective drug that improves cardiac function during ischaemia and functions by lowering l-carnitine concentration in body tissues and modulating myocardial energy metabolism. The aim of the present study was to characterise cardiovascular function and liver condition after long-term mildronate treatment in rats. In addition, changes in the plasma lipid profile, along with changes in the concentration of mildronate, l-carnitine and gamma-butyrobetaine were monitored in the rat tissues. Wistar rats were perorally treated daily with a mildronate dose of either 100, 200 or 400 mg/kg for 4, 8 or 12 weeks. The l-carnitine-lowering effect of mildronate was dose-dependent. However, the carnitine levels reached a plateau after about four weeks of treatment. During the additional weeks of treatment, the carnitine levels were not considerably changed. The obtained results provide evidence that even a high dose of mildronate does not alter cardiovascular parameters and the function of isolated rat hearts. Furthermore, the histological evaluation of liver tissue cryosections and measurement of biochemical markers of hepatic toxicity showed that all the measured values were within the normal reference range. Our results provide evidence that long-term mildronate administration induces significant changes in carnitine homeostasis, but it is not associated with cardiac impairment or disturbances in liver function.

Topics: Animals; Betaine; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Glucose; Heart; Hemodynamics; Lipids; Liver; Liver Glycogen; Male; Methylhydrazines; Myocardium; Rats; Rats, Wistar; Time Factors; Toxicity Tests, Chronic

Topics: Biomarkers; Blood Pressure; Body Weight; Cardiovascular Agents; Cardiovascular Diseases; Diabetic Angiopathies; Diagnostic Imaging; Europe; Evaluation Studies as Topic; Evidence-Based Medicine; Exercise; Health Policy; Heart Rate; Humans; Life Style; Lipids; Metabolic Syndrome; Nutritional Status; Obesity; Pedigree; Risk Assessment; Sex Factors; Smoking Prevention

Mildronate is a fatty acid oxidation inhibitor approved as an antianginal drug in parts of Europe. We carried out the first study to determine whether a 10-day course of mildronate could reduce myocardial infarct size (IS) during acute myocardial ischemia. Sprague Dawley rats received 200 mg/kg/d of mildronate (treated group, n = 16) or sterile water (control group, n = 14) subcutaneously for 10 days before ischemia-reperfusion. Rats were then subjected to 45 minutes of left coronary artery occlusion and 2 hours of reperfusion. The 2 groups had identical areas at risk: treated 38 +/- 3%; controls 38 +/- 2%. The amount of necrosis was smaller in the mildronate group at 16 +/- 2% of the left ventricle versus controls, 22 +/- 2% (P = 0.05); and for any amount of risk >25%, necrosis was smaller in the treated group (P = 0.0035). Myocardial IS (% of risk zone) was 43+/-3% in the mildronate-treated rats, and 57+/-4% in controls (P = 0.004). During occlusion, there were no differences between the 2 groups in heart rate (216 +/- 12 bpm, mildronate and 210 +/- 9 bpm, control), in mean arterial pressure (60 +/- 2 mm Hg, mildronate and 64 +/- 3 mm Hg, control) or in the frequency of arrhythmias. Our study for the first time demonstrated that a 10-day treatment with mildronate reduced myocardial IS in an experimental model of acute myocardial ischemia, without any effect on hemodynamics.

Topics: Angina Pectoris; Animals; Blood Pressure; Body Weight; Cardiovascular Agents; Fatty Acids; Female; Heart Rate; Methylhydrazines; Myocardial Infarction; Oxidation-Reduction; Rats; Rats, Sprague-Dawley

The ICH S7B guideline specifically requests the evaluation of the QT interval in in vivo models as an accepted risk factor for fatal tachyarrythmias. While it recommends correcting the QT interval for heart rate (HR), it also concedes that such corrections can yield misleading results. Data acquired from 40 cynomolgus monkeys (CM) and 66 Beagle dogs (BD) on 64 and 166 episodes, respectively, of 25-h ECG data collection in healthy control group animals were analyzed for this publication. The total number of ECGs evaluated was 10,761 (CM) and 24,882 (BD). The two species appear to have some difference in cardiac repolarization regulatory mechanisms. CM are more subject to diurnal fluctuations of autonomic nervous tone, which leads to dramatic variation of QT interval duration (up to 12.7%) at the same HR (60 to 70 bpm) in different light cycles. BD do not have such a variation. Different species require different QT correction formulas. Van de Water's correction provides optimal results in BD; Bazett's correction presents optimal results in CM. Fundamental behavioral differences (domesticated vs wild animals) may require individual approaches in the interpretation of the safety pharmacology studies in various species.

Topics: Animals; Body Weight; Cardiovascular Agents; Diet; Dogs; Drug Evaluation, Preclinical; Electrocardiography; Environment; Heart Rate; Macaca fascicularis; Photoperiod; Physical Conditioning, Animal; Reference Standards; Species Specificity; Telemetry; Water Supply

Bofutsushosan (BOF), a traditional Chinese formulation (Kampo formulation in Japanese), is widely used for patients with obesity and hyperlipidemia resulting from long-term inappropriate lifestyles. Since atherosclerosis, a lifestyle-related disease, is accompanied by an abnormal accumulation of vascular smooth muscle cells (VSMCs) in the intimal area of the artery, we investigated the preventive effect of BOF on intimal thickening. Oral administration of BOF extracts 3 d before and 7 d after balloon endothelial denudation dose dependently suppressed the intimal thickening and proliferation of VSMCs in the intimal area in rat carotid arteries. This model has a similar pathologic process to atherosclerosis and is considered to be an "accelerated atherosclerosis" model. BOF extract also dose dependently inhibited the migration of cultured VSMCs. BOF extract suppressed serum lipid levels, which are a major risk factor for atherosclerosis. These findings clarified the usefulness of BOF in cardiovascular risk-reduction therapy.

Topics: Animals; Aorta, Thoracic; Blood Vessels; Body Weight; Cardiovascular Agents; Carotid Arteries; Catheterization; Cell Movement; Cell Proliferation; Cells, Cultured; Drugs, Chinese Herbal; Eating; Endothelium, Vascular; Lipids; Male; Muscle, Smooth, Vascular; Rats

Topics: Animals; Anthracyclines; Body Weight; Cardiovascular Agents; Disease Models, Animal; Heart Failure; Heart Rate; Models, Cardiovascular; Razoxane; Stroke Volume

Cardiac toxicity associated with chronic administration of anthracycline (ANT) antibiotics represents a serious complication of their use in anticancer chemotherapy, but can also serve as a useful experimental model of cardiomyopathy and congestive heart failure.. In this study, a model of chronic ANT cardiotoxicity induced by repeated i.v. daunorubicin (DAU) administration to rabbits was tested.. Three groups of animals were used: (1) control group-10 animals received i.v. saline; (2) 11 animals received DAU (3 mg/kg, i.v.); (3) 5 animals received the model cardioprotective agent dexrazoxane (DEX, 60 mg/kg, i.p.), 30 min prior to DAU. All substances were administered once weekly, for 10 weeks. The DAU-induced heart damage and protective action of DEX were determined and quantitated with the use of histopathology, invasive haemodynamic measurements (e.g. left ventricular pressure changes-dP/dt(max), dP/dt(min)), non-invasive systolic function examinations (left ventricular ejection fraction, PEP/LVET index) and biochemical analysis of cardiac troponin T plasma concentrations.. All the employed methods showed unambiguously pronounced heart impairment in the DAU group, with the development of both systolic and diastolic heart failure, as well as significant reduction of DAU-cardiotoxicity in DEX-pretreated animals. Other toxicities were acceptable.. The presented model has been approved to be consistent and reliable and it can serve as a basis for future determinations and comparisons of chronic cardiotoxic effects of various drugs, as well as for the evaluation of potential cardioprotectants.

Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Body Weight; Cardiovascular Agents; Daunorubicin; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Erythrocyte Indices; Heart Failure; Heart Rate; Heart Ventricles; Male; Models, Cardiovascular; Myocardium; Myocytes, Cardiac; Rabbits; Razoxane; Stroke Volume; Time Factors

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Blood Pressure; Body Weight; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Fibrosis; Male; Muscle Cells; Myocardial Infarction; Myocardium; Neprilysin; Organ Size; Pyridines; Rats; Rats, Wistar; Thiazepines; Ventricular Remodeling

Ghrelin is a novel growth hormone (GH)-releasing peptide which was isolated from the stomach. We have reported that ghrelin causes vasorelaxation in rats through GH-independent mechanisms. We investigated whether ghrelin improves endothelial dysfunction. Ghrelin was subcutaneously administered to GH-deficient rats for three weeks. After isolation of the thoracic aorta, aortic ring tension was measured to evaluate vasorelaxation. Acetylcholine-induced vasorelaxation was impaired in GH-deficient rats given placebo compared to that in normal rats given placebo. GH-deficient rats treated with ghrelin, however, showed a significant increase in the maximal relaxation as compared with those given placebo. This improvement by ghrelin was inhibited by N(G)-nitro-L-arginine methyl ester, a nonselective nitric oxide synthase (NOS) inhibitor. Western blot analysis demonstrated that treatment with ghrelin increased endothelial NOS (eNOS) expression in the aorta of GH-deficient rats. These results suggest that administration of ghrelin improves endothelial dysfunction and increases eNOS expression in rats through GH-independent mechanisms.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arteriosclerosis; Blood Pressure; Blotting, Western; Body Weight; Cardiovascular Agents; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Ghrelin; Growth Hormone; Heart Rate; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Peptide Hormones; Placebos; Rats; Rats, Sprague-Dawley

To evaluate whether the elevated blood pressure induced by chronic treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) contributes to an impairment of endothelium-dependent relaxation (EDR), the effects of chronic treatment of Wistar rats with L-NAME on systolic blood pressure, pulmonary arterial blood pressure and EDR of the pulmonary arteries were studied and compared with those of stroke-prone spontaneously hypertensive rats (SHRSP). While the systolic blood pressure (SBP) of Wistar rats was increased above that of controls by chronic treatment with L-NAME, it was still significantly lower than that of SHRSP. Chronic treatment with L-NAME did not affect pulmonary arterial blood pressure. On the other hand, the pulmonary arterial blood pressure of SHRSP was slightly but significantly higher than that of the control normotensive Wistar Kyoto rats (WKY). EDR in response to acetylcholine in the pulmonary artery of L-NAME-treated rats was significantly smaller than that in control Wistar rats. The EDR markedly increased in the presence of L-arginine and completely disappeared in the presence of N(omega)-nitro-L-arginine. Indomethacin hardly affected EDR. In preparations from SHRSP, the EDR was not different from that in those from WKY. Relaxation induced by sodium nitroprusside was identical in all preparations. Elevation of SBP and the impairment of EDR observed in L-NAME-treated rats recovered two weeks following cessation of treatment. These results suggest that the impaired EDR in the pulmonary artery of L-NAME-treated rats is not due to an L-NAME-induced increase in blood pressure but due to the inhibition of nitric oxide synthase by the drug remaining in the endothelium.

Topics: Animals; Arginine; Blood Pressure; Body Weight; Cardiovascular Agents; Endothelium, Vascular; Enzyme Inhibitors; Genetic Predisposition to Disease; Hypertension; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Donors; Nitroarginine; Nitroprusside; Pulmonary Artery; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Wistar; Stroke; Vasodilation

Pregnancy is associated with a substantial increase in uterine artery blood flow, which may in part result from dilation in response to vascular endothelial growth factor (VEGF). Uterine blood flow is reported to be reduced in globally diet-restricted pregnant rats. Both global and protein dietary restriction in pregnancy produce programmed effects in offspring. In this study we hypothesized that protein restriction in pregnancy impairs maternal uterine artery responses to VEGF. Vascular responses to VEGF were determined in isolated uterine arteries of pregnant (18 or 19 d of gestation) Wistar rats fed a diet containing either 18% or 9% casein throughout pregnancy. For comparison, responses to phenylephrine, potassium chloride, and acetylcholine were determined. In addition, the response of the mesenteric artery to VEGF was studied in the same animals. A significant reduction of the maximal relaxation to VEGF (p = 0.041) and in the overall response (p = 0.004) to VEGF was found in uterine arteries of the 9% compared with the 18% group, but responses to all other agonists were similar. The VEGF response was reduced by cyclooxygenase inhibition (indomethacin) in both groups. In the 18%, but not the 9%, group it was further reduced by nitric oxide synthase inhibition (Nomega-nitro-L-arginine methyl ester). VEGF was shown to dilate the mesenteric artery but this effect was not significantly altered by the low-protein diet. These results show an attenuated uterine artery vasodilator response to VEGF produced by a low-protein diet in pregnancy, partly because of a reduction of the nitric oxide component of VEGF-mediated relaxation.

Topics: Acetylcholine; Animals; Arteries; Body Weight; Cardiovascular Agents; Caseins; Dietary Proteins; Dose-Response Relationship, Drug; Endothelial Growth Factors; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Indomethacin; Intercellular Signaling Peptides and Proteins; Lymphokines; NG-Nitroarginine Methyl Ester; Potassium Chloride; Pregnancy; Protein Deficiency; Random Allocation; Rats; Rats, Wistar; Regional Blood Flow; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasodilation; Vasodilator Agents

Flow (shear stress)-mediated dilation (FMD) plays a key role in the local control of vascular diameter and blood flow supply. Although vasodilator treatments improve FMD in diverse models of hypertension, FMD may also change in situations where systemic blood pressure is not affected. In pathological situations such as ischemia, local blood flow and vascular density are increased by vasodilators not affecting systemic blood pressure. As the mechanisms involved remain obscure, we studied FMD in resistance arteries from mice treated chronically (1 month) with hydralazine (200 mg/L in drinking water). Blood flow in mesenteric arteries of mice treated with hydralazine was significantly increased (130 +/- 15 to 169 +/- 27 microl/min, n = 10/group), whereas mean arterial blood pressure was not affected (79 +/- 5 vs 82 +/- 3 mm Hg in controls). Mesenteric resistance arteries (90 microm internal diameter, 75 mm Hg) were isolated and mounted in vitro in an arteriograph. Pressure (myogenic tone)-, phenylephrine-, and KCl-induced contractions, as well as acetylcholine- and sodium nitroprusside-induced dilations, were unaffected by hydralazine. Flow-mediated dilation in arteries from hydralazine-treated mice was significantly increased, especially for low flow values (up to sevenfold). L-NAME-sensitive and indomethacin-sensitive FMD were both increased by hydralazine. Passive arterial diameter increased and arterial wall thickness decreased after chronic hydralazine. This is the first functional evidence that flow (shear stress)-mediated dilation in resistance arteries is improved by a chronic treatment with a nonselective vasodilator. This arteriolar adaptation to a chronic increase in blood flow might be of importance in the pathophysiology of ischemic diseases.

Topics: Acetylcholine; Animals; Blood Flow Velocity; Body Weight; Cardiovascular Agents; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Hydralazine; Indomethacin; Male; Mesenteric Arteries; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Pressure; Stress, Mechanical; Vasodilator Agents

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits gamma-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction. Congestive heart failure was produced by left coronary artery ligation in rats. MET-88 at 100 mg/kg/day was orally administered from the 2nd day after surgery. We performed a survival study for 181 days, and measured ventricular remodeling, cardiac function, and myocardial high-energy phosphate levels after treatment for 20 days. MET-88 prolonged survival with a median 50% survival of 103 days compared to 79 days for the heart-failure control rats. The expansion of the left ventricular cavity (ventricular remodeling) in heart-failure rats was prevented by treatment with MET-88, and the effect of MET-88 was similar to that of captopril at 20 mg/kg. MET-88 attenuated the rise in right atrial pressure in heart-failure rats and augmented cardiac functional adaptability against an increased load. Also, MET-88 improved the myocardial energy state in heart-failure rats. The present results indicate that MET-88 improves the pathosis in rats with heart failure induced by myocardial infarction.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Body Weight; Cardiovascular Agents; gamma-Butyrobetaine Dioxygenase; Heart Failure; Heart Ventricles; Hemodynamics; Lactic Acid; Male; Methylhydrazines; Mixed Function Oxygenases; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Survival Rate

We examined endothelium-dependent relaxation in the aortas and renal arteries of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus, in comparison with non-diabetic Long-Evans Tokushima Otsuka rats as controls. Acetylcholine-induced relaxation in both arteries was attenuated, and the attenuation was restored to the control level by indomethacin. The relaxation was inhibited completely in the aortas, but only partially in renal arteries by N(G)-nitro-L-arginine methyl ester, and the degree of the latter inhibition was greater in OLETF rats than in the controls. The relaxation was inhibited by aminoguanidine in both arteries of OLETF rats but not in the controls. Serum NO(2) plus NO(3) levels significantly increased in OLETF rats. These results suggest that impairment of relaxation in OLETF rat arteries is due to increased release of contractile factors but not decreased release of nitric oxide.

Topics: Acetylcholine; Animals; Aorta; Biological Factors; Blood Glucose; Body Weight; Cardiovascular Agents; Charybdotoxin; Diabetes Mellitus, Type 2; Drug Interactions; Endothelium, Vascular; Enzyme Inhibitors; Guanidines; In Vitro Techniques; Indomethacin; Lipids; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitrites; Rats; Rats, Inbred OLETF; Renal Artery; Vasodilation

Hyperthyroidism was induced by subcutaneous injections of L-thyroxine (T(4)) (500 mg/kg/day) for 3 days in order to study whether adrenergic and muscarinic receptor-mediated vascular responses alter at an early stage of the disease. T(4) treatment was sufficient to induce a significant degree of thyroid weight loss, tachycardia, cardiac hypertrophy, and an elevation in serum T(4) levels. The tension of aortic ring preparations isolated from rats was measured isometrically to investigate the influence of acute hyperthyroidism. The contractions induced by norepinephrine (NE) were significantly suppressed in aortic rings from rats treated with T(4) compared with control rats. N(G)-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase (NOS), significantly enhanced NE-induced contraction in aortic rings from both control and T(4)-treated rats, and the enhancement was greater in rats treated with T(4) than control rats. The relaxations induced by either acetylcholine (ACh) or sodium nitroprusside (SNP) were also significantly enhanced by T(4) treatment. L-NOARG abolished the relaxation induced by ACh in aortic rings from both control and T(4)-treated rats. L-NOARG shifted SNP-induced relaxation curves of aortic rings from those of control rats to the left, but not with rats treated with T(4). T(4) treatment showed no influence on the amount of endothelial NOS (eNOS) protein. These results suggest that vascular responses alter at an early stage of hyperthyroidism and that it may be due to a modification in the NO system which is independent from the amount of eNOS protein.

Topics: Acetylcholine; Acute Disease; Animals; Aorta; Blood Pressure; Blotting, Western; Body Weight; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Rate; Hyperthyroidism; Male; Muscle Relaxation; Myocardial Contraction; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Norepinephrine; Rats; Rats, Wistar; Stimulation, Chemical; Thyroxine; Triiodothyronine; Vasoconstriction

We examined the effects of MET-88 on haemodynamics and cardiac hypertrophy in rats with an aortocaval shunt (A-V shunt). On the day of surgery, an A-V shunt was produced by using an 18-gauge needle in Wistar rats as described by Garcia and Diebold. MET-88 and captopril were orally administered to rats 1 week after surgery, and the administration was continued for 3 weeks. Four weeks after the surgery, A-V shunt-operated rats had biventricular hypertrophy and higher right atrial pressure (RAP) and left ventricular end-diastolic pressure (LVEDP) than sham-operated rats. Compared with untreated A-V shunt rats, those treated with MET-88 showed significant attenuation of the development of left ventricular (LV) hypertrophy and of the increased LVEDP. Captopril-treated A-V shunt rats also failed to show increases in LV weight and LVEDP. In in vitro studies, MET-88 had no effect on renin and angiotensin-converting enzyme (ACE) activities in the plasma of normal rats. These results suggest that MET-88 improved LV hypertrophy and LV dysfunction in rats with an A-V shunt. Furthermore, the data indicate that the beneficial effects of MET-88 may be attributed to some pathway, not involving the renin-angiotensin system, such as myocardial energy metabolism, venous return, etc. We conclude that MET-88 may be a novel agent for the therapy of chronic heart failure.

Topics: Animals; Body Weight; Cardiac Volume; Cardiomegaly; Cardiovascular Agents; Heart; Hemodynamics; Male; Methylhydrazines; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Renin; Ventricular Dysfunction, Left

Changes in cholinesterases activities in daunorubicin cardiomyopathy and in dexrazoxane (DRZX)-treated daunorubicin cardiomyopathy were investigated in rabbits. Acetyl- and butyrylcholinesterase (AChE and BuChE) were determined using Ellman's method. In the serum, a significant decrease of BuChE was observed in the daunorubicin group (9.05 at the beginning and 7.15 microcat/l at the end of the experiment). After DRZX, no significant changes were found and a significant increase in BuChE was observed in the control group (10.26-12.38 microcat/l). AChE activity in the left and right cardiac ventricles was not significantly different between the groups while in the septum there was a significantly lower AChE activity found in the daunorubicin group only. BuChE activity was significantly decreased in the left (15.64 ncat/g) and right (19.27 ncat/g) heart ventricles, in the septum and in the liver in the daunorubicin group. A significant decrease in serum total protein and albumin was demonstrated only in the daunorubicin group. Our results support the hypothesis about the influence of daunorubicin on protein (and enzyme) synthesis in the liver and heart. A protective effect of DRZX on cholinesterases activity was observed. The changes in cholinesterase activities may thus reflect their possible role in cardiomyopathy.

Topics: Acetylcholinesterase; Animals; Antibiotics, Antineoplastic; Body Weight; Butyrylcholinesterase; Cardiomyopathies; Cardiovascular Agents; Daunorubicin; Heart; Male; Myocardium; Rabbits; Razoxane; Ventricular Function, Left

Oxyradicals have been implicated as a possible cause of reperfusion-arrhythmias (RA). However, the use of diverse exogenous oxyradical scavengers designed to reduce RA has given contradictory results. The aim of the present study was to determine whether enhancing the activity of the main endogenous enzyme involved in peroxide elimination in cardiac cells, namely glutathione peroxidase, may limit RA in isolated heart preparations by increasing their antioxidant status. For this purpose, a group of 15 male Wistar rats received a selenium enriched diet for ten weeks (1.5 mg Se/kg diet). Control animals (n = 15) received a standard diet containing 0.05 mg Se/kg diet. The incidence of early ventricular arrhythmias was investigated during the reperfusion period following 10 min regional ischemia induced ex-vivo by left coronary artery ligation. Our results show that selenium-supplementation significantly increased the global selenium status of the animals. In the isolated heart preparations, the selenium supplementation induced a significant reduction of the severity of RA as assessed by the arrhythmia score and the limitation of the incidence of both ventricular tachycardia (control: 91% vs selenium: 36%, p < 0.05) and irreversible ventricular fibrillation (control: 45% vs selenium: 0%, p < 0.05). These effects were associated with a significant increase in cardiac mitochondrial and cytosolic glutathione peroxidase activities in both the left and the right ventricles. These results illustrate the potential protective effect of selenium against ischemia-reperfusion injury and suggest that peroxides might play a key role in the genesis of some aspects of the reperfusion syndrome.

Topics: Administration, Oral; Animals; Arrhythmias, Cardiac; Body Weight; Cardiovascular Agents; Coronary Circulation; Dietary Supplements; Erythrocytes; Free Radicals; Glutathione Peroxidase; Heart; Heart Rate; Male; Myocardial Reperfusion Injury; Myocardium; Organ Size; Rats; Rats, Wistar; Reactive Oxygen Species; Selenium

In laboratory animals, histology is most commonly used to study doxorubicin-induced cardiotoxicity. However, for monitoring during treatment, large numbers of animals are needed. Recently we developed a new method to measure ECG values in freely moving mice by telemetry. With this model we investigated the effect of chronic doxorubicin administration on the ECG of freely moving BALB/c mice and the efficacy of ICRF-187 as a protective agent. The ST interval significantly widened from 15.0 +/- 1.5 to 56.8 +/- 11.8 ms in week 10 (7 weekly doses of 4 mg/kg doxorubicin given i.v. plus 3 weeks of observation). The ECG of the control animals did not change during the entire study. After sacrifice the hearts of doxorubicin-treated animals were enlarged and the atria were hypertrophic. As this schedule exerted more toxicity than needed to investigate protective agents, the protection of ICRF-187 was determined using a dose schedule with lower general toxicity (6 weekly doses of 4 mg/kg doxorubicin given i.v. plus 2 weeks of observation). On this schedule, the animals' hearts appeared normal after sacrifice and ICRF-187 (50 mg/kg given i.p. 1 h before doxorubicin) provided almost full protection. These data were confirmed by histology. The results indicate that this new model is very sensitive and enables monitoring of the development of cardiotoxicity with time. These findings result in a model that allows the testing of protectors against doxorubicin-induced cardiotoxicity as demonstrated by the protection provided by ICRF-187.

Topics: Analysis of Variance; Animals; Antineoplastic Agents, Alkylating; Behavior, Animal; Body Weight; Cardiomyopathies; Cardiovascular Agents; Doxorubicin; Drug Interactions; Electrocardiography; Heart; Heart Atria; Heart Rate; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Razoxane; Telemetry

Topics: Anesthesia; Body Weight; Cardiac Surgical Procedures; Cardiovascular Agents; Child; Humans; Infusion Pumps; Syringes

Topics: Aged; Amyloidosis; Antihypertensive Agents; Arrhythmias, Cardiac; Body Weight; Cardiac Glycosides; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular System; Coronary Circulation; Coronary Disease; Heart Valve Diseases; Hemodynamics; Humans; Hypertension; Myocardial Contraction; Organ Size

Narcotised mongrel dogs were used to examine the effect of coronary drugs on the cerebrospinal fluid pressure (CFP). An increase in CFP, although of varying degree, was observed for all compounds tested. The reason for this effect is suggested to be a direct dilatation of the cerebral blood vessels, leading to an increase in intracranial blood volume. It could be established that the increase in CFP is not due to changes in cardiac or circulation parameters, nor to effects of the volume or osmolarity of the test substance solutions. Thus, the headaches which occur following treatment with dipyridamole or organic nitrates cannot be explained in terms of an increase in CFP.

Topics: Animals; Blood Pressure; Body Weight; Carbon Dioxide; Cardiovascular Agents; Coronary Vessels; Dogs; Female; Heart Rate; Injections, Intravenous; Intracranial Pressure; Male; Osmotic Pressure

The calculations necessary to allow infusion of a known drug dosage at micrograms per kilogram of body weight per minute are time-consuming and error prone. A simpler method entails multiplication of the patient's weight in kilograms by the factor 15. The resultant figure represents the number of milligrams of drug to be placed in 250 ml of infusate vehicle. The solution, which is delivered through a microdrip chamber (60 gtt per milliliter), will contain 1 microgram per kilogram in each drop. One is thus permitted to define dosage by setting up the solution to have 1 gtt = 1 microgram/kg.

Topics: Body Weight; Cardiovascular Agents; Humans; Infusions, Parenteral; Mathematics; Methods

Topics: Body Weight; Cardiovascular Agents; Claviceps; Ergot Alkaloids; Oxytocics; Poaceae