piperidines and Myocardial-Ischemia

Topics: Animals; Delayed Rectifier Potassium Channels; Humans; Membrane Potentials; Myocardial Ischemia; Pilocarpine; Piperidines; Receptor, Muscarinic M3; Signal Transduction

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 morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD).. Prospective randomised controlled trial.. University hospital.. 26 patients with stable CAD.. Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well.. Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion.. Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB.. We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response.. NCT00427232.

Topics: Adult; Aged; Angina Pectoris; Antihypertensive Agents; Coronary Angiography; Coronary Artery Disease; Endothelin Receptor Antagonists; Endothelin-1; Female; Fractional Flow Reserve, Myocardial; Humans; Male; Middle Aged; Myocardial Ischemia; Oligopeptides; Peptides, Cyclic; Piperidines; Prospective Studies; Protein Precursors; Young Adult

To test the hypothesis that the choice of anesthesia technique for coronary artery surgery influences the degree and magnitude of the subsequent inflammatory response and its consequences.. Prospective, randomized, comparative study.. Major university teaching hospital.. Sixty patients undergoing elective surgery.. Patients were randomized into an alfentanil group, a high-dose remifentanil group, a low-dose remifentanil group, or a thoracic epidural group, in combination with a propofol target-controlled infusion. The study was blinded for the opioid, except in the epidural group. Tight control of perioperative hemodynamic parameters was maintained, and the postoperative management was strictly standardized. Bactericidal permeability-increasing protein as an indicator of the polymorphonuclear neutrophil response, interleukin-6 as an inducer of the acute-phase response, and lipopolysaccharide-binding protein and C-reactive protein as parameters of the acute phase response were determined at regular intervals. Ventilator dependency and analgesia were evaluated as clinical outcome measures.. Interleukin-6 levels increased in all groups. Plasma levels in the epidural group were significantly higher at all time points than in the other groups. The increase in the plasma levels of bactericidal permeability-increasing protein, lipopolysaccharide-binding protein, and C-reactive protein showed the same pattern in all groups, and no significant differences among the 4 groups were observed.. Supplementation of a fast-track anesthetic technique with epidural analgesia preserves hemodynamic stability and is associated with faster extubation times (p = 0.003) and less postoperative pain (p = 0.045). Thoracic epidural analgesia was associated with significantly higher levels of IL-6 throughout the study period as compared with the total intravenous anesthesia groups. The exact clinical relevance of this finding remains unclear.

Topics: Acute-Phase Proteins; Alfentanil; Analgesics, Opioid; Anesthesia; Anesthesia, Epidural; Antimicrobial Cationic Peptides; Biomarkers; Blood Bactericidal Activity; Blood Proteins; C-Reactive Protein; Cardiopulmonary Bypass; Carrier Proteins; Coronary Artery Bypass; Dose-Response Relationship, Drug; Elective Surgical Procedures; Enzyme-Linked Immunosorbent Assay; Follow-Up Studies; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Lipopolysaccharides; Membrane Glycoproteins; Membrane Proteins; Middle Aged; Myocardial Ischemia; Piperidines; Prospective Studies; Remifentanil

Unstable coronary artery disease is in most cases associated with plaque rupture, activation of the coagulation system and subsequent intracoronary thrombus formation which may cause myocardial cell damage. The aim of the present analysis was to assess the relation between troponin T, markers of coagulation activity, i.e. prothrombin fragment 1+2, thrombin-antithrombin complex, soluble fibrin and D-dimer, and ischemic events, i.e. death, myocardial (re-)infarction or refractory angina. 320 patients with unstable coronary artery disease were randomized to 72 hours infusion with inogatran, a low molecular weight direct thrombin inhibitor, or unfractionated heparin. Patients with elevated troponin levels had higher levels of prothrombin fragment 1+2, soluble fibrin and D-dimer before, during, and at 24 hours after cessation of anticoagulant treatment. These troponin-positive patients tended to have worse short-term clinical outcome, without relation to markers of coagulation activity. Troponin-negative patients with unchanged or early increased thrombin generation during treatment had a cluster of ischemic events within 24 hours after cessation of the study drug. The 30-day ischemic event rate was 19 % in troponin-negative patients with unchanged or early increased prothrombin fragment 1+2, and 5.7 % in patients with decreased prothrombin fragment 1+2, p=0.006, and similarly 15 % in troponin-negative patients with unchanged or early increased thrombin-antithrombin complex and 4.5 % in patients with decreased thrombin-antithrombin complex, p=0.02. In conclusion, in unstable coronary artery disease a troponin elevation indicates higher risk and higher coagulation activity. However, among the troponin negative patients, with a lower risk and lower coagulation activity, a part of the patients seem to be non-responders to treatment with a thrombin inhibitor expressed as unchanged or raised coagulation activity and a raised risk of ischemic events early after cessation of treatment.

Topics: Adult; Aged; Biomarkers; Blood Coagulation; Coronary Artery Disease; Glycine; Heparin; Humans; Middle Aged; Myocardial Ischemia; Piperidines; Predictive Value of Tests; Risk Factors; Thrombin; Thrombophilia; Treatment Failure; Treatment Outcome; Troponin T

This study compares remifentanil/propofol (remi/prop) with isoflurane/fentanyl (iso/fen) anesthesia to determine which provides the greater hemodynamic stability, lesser myocardial ischemia, and morbidity with better postoperative outcomes after carotid endarterectomy. Sixty patients undergoing unilateral carotid endarterectomy were randomized to receive either a remi/prop or iso/fen anesthetic. Hemodynamic variables were recorded during the surgical procedure. In addition, transesophageal echocardiography was used to assess evidence of intraoperative regional wall motion abnormalities suggestive of cardiac ischemia. Emergence and extubation times, recovery from anesthesia, hemodynamic instability, nausea, vomiting, and pain in post anesthesia recovery, discharge delays, ICU admittance, hospital discharge, and preoperative and postoperative troponin levels were compared using appropriate statistical methods with P < 0.05 considered significant. The groups were demographically alike. Hemodynamic variables were similar during intubation and throughout surgery. Twenty-two percent of patients receiving iso/fen developed intraoperative regional wall motion abnormalities suggestive of ischemia, whereas no remi/prop patients had changes (P < 0.05). There was no difference in ST-T wave changes after surgery, and no patient had an elevation in troponin I levels. Postoperative variables were similar except that patients who received iso/fen had lower Stewart recovery scores during the first 15 minutes after post anesthesia care unit admission and a higher incidence of nausea and vomiting the day after surgery, whereas patients receiving remi/prop had discharge delays secondary to hypertension. ICU admittance, time to first void, oral intake, and time to hospital discharge were similar between the groups. At 9 times the cost of an iso/fen anesthesia technique, remi/prop offers little advantage over inhalational anesthesia for carotid endarterectomy.

Topics: Aged; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Carotid Artery Diseases; Endarterectomy, Carotid; Female; Fentanyl; Hemodynamics; Humans; Intraoperative Complications; Isoflurane; Male; Myocardial Ischemia; Piperidines; Postoperative Complications; Propofol; Remifentanil

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

We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

Topics: Acute Disease; Aspirin; Causality; Coronary Disease; Coronary Thrombosis; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Postoperative Complications; Stents; Syndrome

The first Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) trial showed no benefit of 2 doses of sibrafiban over aspirin for secondary prevention after acute coronary syndromes. In 2nd SYMPHONY, we compared low-dose sibrafiban plus aspirin (LDS+A), high-dose sibrafiban (HDS), and aspirin alone.. When the first SYMPHONY results became known, enrollment in 2nd SYMPHONY was stopped prematurely at 6671 patients who had been treated for a median of 90 days. The primary end point of death, myocardial (re)infarction (MI), or severe recurrent ischemia did not differ significantly between aspirin (9.3%) and LDS+A (9.2%; OR, 0.98; 95% CI, 0.80 to 1.20) or HDS (10.5%; OR, 1.14; 95% CI, 0.9 to 1.39) patients. Secondary end points did not differ significantly between aspirin and LDS+A patients. Death or MI occurred significantly more often with HDS (OR, 1.43; 95% CI, 1.14 to 1.80), as did mortality alone (OR, 1.83; 95% CI, 1.17 to 2.88) and MI (OR, 1.32; 95% CI, 1.03 to 1.69). Major bleeding was significantly more frequent in LDS+A patients (5.7%) versus aspirin alone (4.0%) but not in HDS patients (4.6%).. Combining aspirin with LDS did not improve outcomes after acute coronary syndromes and caused more bleeding compared with aspirin alone. There was a trend toward increased mortality in this group and a significant increase in the high-dose arm.

Topics: Aged; Aspirin; Cause of Death; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Hemorrhage; Hospitalization; Humans; Male; Middle Aged; Myocardial Ischemia; Neovascularization, Physiologic; Oximes; Piperidines; Treatment Failure

Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.. Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.. The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

Topics: Administration, Oral; Adolescent; Arterial Occlusive Diseases; Benzodiazepines; Double-Blind Method; Drug Evaluation; Female; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Myocardial Ischemia; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Research Design; Secondary Prevention; Stroke

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

Thrombin has been suggested as one of the main pharmacologic targets in unstable coronary syndromes. Electrocardiographic signs of ischemia during continuous monitoring convey prognostic information in these patients. This study assessed the anti-ischemic and clinical effects of the novel low-molecular weight thrombin inhibitor inogatran in patients with unstable angina and non-Q-wave infarction without persistent ST-segment elevation on hospital admission. Within 24 hours of the last episode of chest pain, 324 patients were randomized to 72 hours of treatment with inogatran or heparin. Continuous ST-segment analysis with computerized vectorcardiography was used to monitor ischemia for 24 hours. The occurrence of cardiac events during the first 7 days were studied and compared with ischemic episodes during the initial 24 hours. The heparin-treated patients had less episodes of ischemia (ST vector magnitude [ST-VM]: 1 +/- 2.6 vs 2 +/- 4.5, p < 0.001 and ST change vector magnitude [STC-VM]: 3 +/- 4.7 vs 6 +/- 7.6, p < 0.001) than the patients receiving inogatran. This was paralleled by a lower incidence of the combined end point of death, nonfatal infarction, refractory or recurrent angina during the first 7 days for the heparin-treated patients (35%) compared with the inogatran-treated patients (50%) (p < 0.05). Patients who had episodes of ischemia in spite of anti-ischemic therapy were at increased risk of all events studied. Heparin is more effective than inogatran in suppressing myocardial ischemia and clinical events at short-term follow-up. Continuous ST-segment monitoring with vectorcardiography identifies nonresponders who are at an increased level of risk.

Topics: Adult; Aged; Aged, 80 and over; Angina, Unstable; Anticoagulants; Antithrombins; Double-Blind Method; Electrocardiography, Ambulatory; Female; Follow-Up Studies; Glycine; Heparin; Humans; Male; Middle Aged; Myocardial Ischemia; Piperidines; Prospective Studies; Recurrence; Thrombin; Vectorcardiography

To test whether KMUP-1 (7-[2-[4-(2-chlorophenyl) piperazinyl]ethyl]-1,3-dimethylxanthine) prevents myocardial ischemia-induced apoptosis, we examined KMUP-1-treated H9c2 cells culture. Recent attention has focused on the activation of nitric oxide (NO)-guanosine 3', 5'cyclic monophosphate (cGMP)-protein kinase G (PKG) signaling pathway triggered by mitogen-activated protein kinase (MAPK) family, including extracellular-signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 in the mechanism of cardiac protection during ischemia-induced cell-death. We propose that KMUP-1 inhibits ischemia-induced apoptosis in H9c2 cells culture through these pathways. Cell viability was assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and apoptotic evaluation was conducted using DNA ladder assay and Hoechst 33342 staining. The level of intracellular calcium was detected using - Fura2-acetoxymethyl (Fura2-AM) staining, and mitochondrial calcium with Rhod 2-acetoxymethyl (Rhod 2-AM) staining under fluorescence microscopic observation. The expression of endothelium NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase α1 (sGCα1), PKG, Bcl-2/Bax ratio, ERK1/2, p38, and JNK proteins were measured by Western blotting assay. KMUP-1 pretreatment improved cell viability and inhibited ischemia-induced apoptosis of H9c2 cells. Calcium overload both in the intracellular and mitochondrial sites was attenuated by KMUP-1 pretreatment. Moreover, KMUP-1 reduced intracellular reactive oxygen species (ROS), increased plasma NOx (nitrite and nitrate) level, and the expression of eNOS. Otherwise, the iNOS expression was downregulated. KMUP-1 pretreatment upregulated the expression of sGCα1 and PKG protein. The ratio of Bcl-2/Bax expression was increased by the elevated level of Bcl2 and decreased level of Bax. In comparison with the ischemia group, KMUP-1 pretreatment groups reduced the expression of phosphorylated extracellular signal-regulated kinases ERK1/2, p-p38, and p-JNK as well. Therefore, KMUP-1 inhibits myocardial ischemia-induced apoptosis by restoration of cellular calcium influx through the mechanism of NO-cGMP-MAPK pathways.

Topics: Animals; Apoptosis; Calcium; Cell Line; Cyclic GMP; MAP Kinase Signaling System; Mitochondria; Models, Biological; Myocardial Ischemia; Myocytes, Cardiac; Nitric Oxide; Piperidines; Rats; Xanthines

Myocardial infarction due to ischemia accounts for majority of deaths among cardiovascular disorders. Isoproterenol (ISO) induced myocardial infarction and the protection offered by piperine was investigated in the present report. Lipid profile analysis by determining the levels of cholesterol, phospholipids, triglycerides and lipoproteins in serum and heart tissues showed anti-dyslipidemic action of piperine against ISO induced myocardial injury by modulating the ISO induced altered lipid profiles, maintaining to near control values. ISO treatment increased TBARS levels, PCC, serum markers of heart, depleted antioxidant status (GSH, SOD, CAT, GPx and GST) in tissues and, total, protein- and non-protein-sulfhydryl levels in serum and heart tissues. Piperine pre-treatment decreased the levels of serum markers, lipid peroxidation and PCC with increased antioxidant status in the heart tissues of ISO administered rats. Increased levels of the glycoprotein components in serum and decreased levels in heart tissues upon ISO administration were restored to near normal levels by piperine pre-treatment. Our present reports also showed the modulatory effect of piperine on membrane bound ATPase's showing protection against ISO induced changes in membrane fluidity. The present study proved piperine as a potent therapeutic agent with its antioxidant and anti-dyslipidemic action against ISO induced myocardial infarction.

Topics: Alkaloids; Animals; Antioxidants; Benzodioxoles; Biomarkers; Heart; Isoproterenol; Lipid Peroxidation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Wistar

To evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD).. Administrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use.. Mean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30 days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78-1.05) or repaglinide use (aHR 0.80; 95% CI 0.63-1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome.. In older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae.

Topics: Aged; Aged, 80 and over; Alberta; Blue Cross Blue Shield Insurance Plans; Carbamates; Cardiovascular Diseases; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Female; Gliclazide; Glyburide; Hospitalization; Humans; Hypoglycemic Agents; Male; Myocardial Ischemia; Piperidines; Proportional Hazards Models; Retrospective Studies; Risk; Universal Health Insurance

Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.

Topics: Adiponectin; Administration, Oral; AMP-Activated Protein Kinases; Animals; Apoptosis; Cardiotonic Agents; Heart Ventricles; Hypoglycemic Agents; Male; Mice, Knockout; Mice, Transgenic; Mutant Proteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Oxidative Stress; Piperidines; Random Allocation; Receptors, Adiponectin; Signal Transduction

Reverse-mode of the Na(+)/Ca(2+) exchanger (NCX) stimulation provides cardioprotective effects for the ischemic/reperfused heart during ischemic preconditioning (IP). This study was designed to test the hypothesis that pretreatment with an inhibitor of cardiac delayed-rectifying K(+) channel (IKr), E4031, increases reverse-mode of NCX activity, and triggers preconditioning against infarct size (IS) and arrhythmias caused by ischemia/reperfusion injury through mitoKCa channels.. In the isolated perfused rat heart, myocardial ischemia/reperfusion injury was created by occlusion of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion. Two cycles of coronary occlusion for 5 min and reperfusion were performed, or pretreatment with E4031 or sevoflurane (Sevo) before the 30 min occlusion with the reversed-mode of NCX inhibitor (KB-R7943) or not.. E4031 or Sevo preconditioning not only markedly decreased IS but also reduced arrhythmias, which was significantly blunted by KB-R7943. Furthermore, these effects of E4031 preconditioning on IS and arrhythmias were abolished by inhibition of the mitoKCa channels. Similarly, pretreatment with NS1619, an opener of the mitoKCa channels, for 10 min before occlusion reduced both the infarct size and arrhythmias caused by ischemia/reperfusion. However, these effects weren't affected by blockade of the NCX with KB-R7943.. Taken together, these preliminary results conclude that pretreatment with E4031 reduces infarct size and produces anti-arrhythmic effect via stimulating the reverse-mode NCX, and that the mitoKCa channels mediate the protective effects.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Ischemic Preconditioning; Male; Mitochondria; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Piperidines; Potassium Channels, Calcium-Activated; Pyridines; Rats; Rats, Sprague-Dawley; Sodium-Calcium Exchanger

Myocardial infarction as the most severe clinical manifestation of coronary atherosclerosis is the major cause of death in western countries. Although rupture of an atherosclerotic plaque is generally causal for this event, in recent years differential diagnoses have been discussed to further optimize diagnosis and treatment of myocardial ischemia. The "universal definition of myocardial infarction" defines five subtypes of myocardial infarction: in particular, type 2 myocardial infarction includes other diseases related to myocardial ischemia such as hyper- or hypotension, coronary artery spasms, arrhythmia, etc. Some medications for the acute therapy of migraine like triptans can lead to myocardial infarction.

Topics: Combined Modality Therapy; Drug Substitution; Female; Humans; Middle Aged; Migraine Disorders; Myocardial Infarction; Myocardial Ischemia; Piperidines; Self Medication; Substance-Related Disorders; Tryptamines

Anandamide, one of the endocannabinoids, has been reported to exhibit cardioprotective properties, particularly in its ability to limit the damage produced by ischemia reperfusion injury. However, the mechanisms underlying the effect are not well known. This study is to investigate whether anandamide alter Na(+)/Ca(2+) exchanger and the intracellular free Ca(2+) concentration ([Ca(2+)]i).. Na(+)/Ca(2+) exchanger current (I(NCX)) was recorded and analysed by using whole-cell patch-clamp technique and [Ca(2+)]i was measured by loading myocytes with the fluorescent Ca(2+) indicator Fura-2/AM.. We found that I(NCX) was enhanced significantly after perfusion with simulated ischemic external solution; [Ca(2+)]i was also significantly increased by simulated ischemic solution. The reversal potential of I(NCX) was shifted to negative potentials in simulated ischemic external solution. Anandamide (1-100 nM) failed to affect I(NCX) and [Ca(2+)]i in normal solution. However, anandamide (1-100 nM) suppressed the increase in INCX in simulated ischemic external solution concentration-dependently and normalized INCX reversal potential. Furthermore, anandamide (100 nM) significantly attenuated the increase in [Ca(2+)]i in simulated ischemic solution. Blocking CB1 receptors with the specific antagonist AM251 (500 nM) failed to affect the effects of anandamide on I(NCX) and [Ca(2+)]i in simulated ischemic solution. CB2 receptor antagonist AM630 (100 nM) eliminated the effects of anandamide on I(NCX) and [Ca(2+)]i in simulated ischemic solution, and CB2 receptor agonist JWH133 (100 nM) simulated the effects of anandamide that suppressed the increase in I(NCX) and [Ca(2+)]i in simulated ischemic solution. In addition, pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX, 500 ng/ml) eliminated the effects of anandamide and JWH133 on I(NCX) in simulated ischemic solution.. Collectively, these findings suggest that anandamide suppresses calcium overload through inhibition of I(NCX) during perfusion with simulated ischemic solution; the effects may be mediated by CB2 receptor via PTX-sensitive Gi/o proteins. This mechanism is importantly involved in the anti-ischemia injury caused by endocannabinoids.

Topics: Aniline Compounds; Animals; Arachidonic Acids; Calcium; Cannabinoids; Cell Separation; Endocannabinoids; GTP-Binding Protein alpha Subunits, Gi-Go; Heart Ventricles; Indoles; Intracellular Space; Ion Channel Gating; Male; Myocardial Ischemia; Myocytes, Cardiac; Pertussis Toxin; Phenyl Ethers; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Sodium-Calcium Exchanger; Solutions

Diabetes increases cardiac damage after myocardial ischaemia. Cannabinoids can protect against myocardial ischaemia/reperfusion injury. The aim of this study was to examine the cardioprotective effect of the cannabinoid agonist WIN 55,212-2 (WIN) against ischaemia/reperfusion injury in an experimental model of type 2 diabetes. We performed these experiments in the Zucker diabetic fatty rat, and focused on the role of cannabinoid receptors in modulation of cardiac inducible nitric oxide synthase (iNOS)/endothelial-type nitric oxide synthase (eNOS) expression.. Male 20-week-old Zucker diabetic fatty rats were treated with vehicle, WIN, the selective CB1 or CB2 receptor antagonists AM251 and AM630, respectively, AM251 + WIN or AM630 + WIN. Hearts were isolated from these rats, and the cardiac functional response to ischaemia/reperfusion injury was evaluated. In addition, cardiac iNOS and eNOS expression were determined by western blot.. WIN significantly improved cardiac recovery after ischaemia/ reperfusion in the hearts from Zucker diabetic fatty rats by restoring coronary perfusion pressure and heart rate to preischaemic levels. Additionally, WIN decreased cardiac iNOS expression and increased eNOS expression after ischaemia/reperfusion in diabetic hearts. WIN-induced cardiac functional recovery was completely blocked by the CB2 antagonist AM630. However, changes in NOS isoenzyme expression were not affected by the CB antagonists.. This study shows a cardioprotective effect of a cannabinoid agonist on ischaemia/reperfusion injury in an experimental model of a metabolic disorder. The activation mainly of CB2 receptors and the restoration of iNOS/eNOS cardiac equilibrium are mechanisms involved in this protective effect. These initial studies have provided the basis for future research in this field.

Topics: Animals; Benzoxazines; Cannabinoids; Cardiotonic Agents; Coronary Vessels; Diabetes Mellitus, Type 2; Heart; Heart Rate; Indoles; Male; Morpholines; Myocardial Ischemia; Myocardial Reperfusion Injury; Naphthalenes; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Piperidines; Pyrazoles; Rats; Rats, Zucker; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Role of 2-Deoxy-D-glucose (2-DG) in reversing the Indian red scorpion (Mesobuthus tamulus concanesis Pocock, MBT) venom-induced toxicity was examined. Femoral arterial pressure, ECG and respiratory movements were recorded in urethane anesthetized rats. Plasma glucose and serum insulin levels were also estimated. Intravenous injection of 5 mg/kg MBT venom produced immediate decrease in mean arterial pressure, heart rate and respiratory frequency followed by an increase and subsequent progressive decrease. ECG pattern exhibited ischaemic changes. There was hyperinsulinemia after venom without corresponding decrease in plasma glucose. The animals died within 37 +/- 9 min and demonstrated significant increase in pulmonary water content. 2-DG pretreatment (0.5 g/kg, iv) improved the cardiopulmonary abnormalities induced by venom and the animals survived for nearly 120 min. There was no hyperinsulinemia and increased pulmonary water content in these animals. In insulin (2 IU/kg) treated rats, the MBT venom-induced cardiopulmonary abnormalities were attenuated and ECG abnormalities were reversed. The pulmonary water content in these animals exhibited a decreasing trend and the animals survived for 120 min. Repaglinide (10 microg/kg, iv) pretreatment failed to reverse the venom-induced cardiopulmonary changes including the increased pulmonary water content. The survival time was similar to venom only group. The present results reveal that 2-DG reverses the venom-induced cardiopulmonary toxicity probably by restoring insulin sensitivity.

Topics: Anesthesia; Animals; Blood Glucose; Carbamates; Cardiovascular Abnormalities; Deoxyglucose; Hyperglycemia; India; Insulin; Lung Diseases; Myocardial Ischemia; Piperidines; Pulmonary Edema; Rats; Respiration; Scorpion Venoms; Ultrasonography

Rimonabant (SR141716) is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro- and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg.kg(-1).day(-1), 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction.

Topics: Animals; Biomarkers; Blood Vessels; Body Weight; Cannabinoid Receptor Antagonists; Disease Models, Animal; Eating; Inflammation; Insulin Resistance; Intestinal Mucosa; Kidney Diseases; Kidney Glomerulus; Lipid Metabolism; Male; Metabolic Syndrome; Myocardial Ischemia; Piperidines; Prediabetic State; Pyrazoles; Rats; Rats, Mutant Strains; Renal Circulation; Rimonabant; Sclerosis; Thrombosis

the time for 1.0 mm ST-segment depression (T-1.0mm) adopted to characterize ischemic preconditioning (IPC) in sequential exercise tests is consistent and reproducible; however, it has several limitations.. to apply an electrocardiographic score of myocardial ischemia in sequential exercise tests, comparing it to the conventional T-1.0 mm index.. sixty one patients with mean age of 62.2 ± 7.5 years were evaluated; 86.9% were males. A total of 151 tests were analyzed, 116 of which were from patients who completed two assessment phases. The first phase comprised two sequential exercise tests for the documentation of IPC; the second phase, initiated one week later, comprised two more tests carried out under the effect of repaglinide. Two observers who were blind to the tests applied the score.. Perfect inter and intraobserver agreement was found (Kendall tau-b = 0.96, p < 0.0001, and Kendall tau-b = 0.98, p < 0.0001, respectively). Values of sensitivity and specificity, negative predictive value, positive predictive value and accuracy were 72.41%, 89.29%, 75.8%, 87.5% and 81.0%, respectively.. the ischemic score is a consistent and reproducible method for the documentation of IPC, and is a feasible alternative to T-1.0 mm.

Topics: Carbamates; Diabetes Mellitus; Double-Blind Method; Electrocardiography; Ergometry; Female; Humans; Hypoglycemic Agents; Ischemic Preconditioning; Male; Middle Aged; Myocardial Ischemia; Observer Variation; Piperidines; Predictive Value of Tests

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Blood Pressure; Carbamates; Cyclohexanes; Disease Models, Animal; Drug Interactions; Endotoxemia; Glyburide; Heart Atria; Heart Conduction System; Lipopolysaccharides; Male; Myocardial Ischemia; Nateglinide; Phenylalanine; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Tetraethylammonium; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

This study determined the role of the reverse mode Na(+)/Ca(2+) exchanger (NCX) in cardioprotection of metabolic inhibition preconditioning in isolated ventricular myocyctes. Activity of the reverse mode NCX was assessed by changes of [Ca(2+)](i) upon withdrawal of extracellular Na(+). [Ca(2+)](i) was measured by spectrofluorometry, using Fura-2 as Ca(2+) indicator. The amplitude of contraction and exclusion of trypan blue by myocytes served as indices of contractile function and viability, respectively. Firstly, NCX activity significantly decreased during simulated reperfusion after severe metabolic inhibition (index ischaemia) in myocytes subjected to metabolic inhibition preconditioning. This inhibitory effect on NCX activity correlated with the enhancing effect of metabolic inhibition preconditioning on cell viability following ischaemic insult. Treatment myocytes with E4031, an activator of reverse mode NCX, during index ischaemia and reperfusion attenuated the enhancing effects of metabolic inhibition preconditioning on cell contraction and viability. Secondly, NCX activity was significantly higher at the end of metabolic inhibition preconditioning. More importantly, E4031 pretreatment mimicked the beneficial effects of metabolic inhibition preconditioning in myocytes and ischaemic preconditioning in the isolated perfused heart, respectively, and these effects were abolished by KB-R7943, an inhibitor of reverse mode NCX. The results indicate that increased reverse mode NCX activity during preconditioning triggered cardioprotection, and reduced reverse mode NCX activity during reperfusion after index ischaemia conferred cardioprotection.

Topics: Animals; Anti-Arrhythmia Agents; Calcium; Cell Survival; Fura-2; Ischemic Preconditioning, Myocardial; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Sodium-Calcium Exchanger; Spectrometry, Fluorescence; Thiourea; Ventricular Function

A paradoxical microcirculatory constriction has been observed in hearts of patients with ischemia, secondary to coronary stenosis. Here, using the isolated mouse heart (Langendorff), we examined the mechanism of this response, assuming involvement of nitric oxide (NO) and endothelin-1 (ET-1) systems. Perfusion pressure was maintained at 65 mmHg for 70 min (protocol 1), or it was reduced to 30 mmHg over two intervals, between the 20- and 40-min marks (protocol 2) or from the 20-min mark onward (protocol 3). In protocol 1, coronary resistance (CR) remained steady in untreated heart, whereas it progressively increased during treatment with the NO synthesis inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (2.7-fold) or the ET(A) antagonist BQ-610 (2.8 fold). The ET(B) antagonist BQ-788 had instead no effect by itself but curtailed vasoconstriction to BQ-610. In protocol 2, hypotension raised CR by 2.2-fold. This response was blunted by reactive oxygen species (ROS) scavengers (mannitol and superoxide dismutase plus catalase) and was converted into vasodilation by l-NAME, BQ-610, or BQ-788. Restoration of normal pressure was followed by vasodilation and vasoconstriction, respectively, in untreated and treated preparations. In protocol 3, CR progressively increased with hypotension in the absence but not presence of L-NAME or BQ-610. We conclude that the coronary vasculature is normally relaxed by two concerted processes, a direct action of NO and ET-1 curtailing an ET(B2)-mediated tonic vasoconstriction through ET(A) activation. The negative feedback mechanism on ET(B2) subsides during hypotension, and the ensuing vasoconstriction is ascribed to ET-1 activating ET(A) and ET(B2) and reactive nitrogen oxide species originating from ROS-NO interaction.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Stenosis; Coronary Vessels; Endothelins; Enzyme Inhibitors; Hemodynamics; Hypotension; Mice; Mice, Inbred C57BL; Microcirculation; Models, Cardiovascular; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oligopeptides; Piperidines; Reactive Oxygen Species; Vasoconstriction; Vasodilation; Vasomotor System

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Disease Models, Animal; Endocardium; Endothelin B Receptor Antagonists; Endothelin-1; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oligopeptides; Pericardium; Piperidines; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Fibrillation; Viper Venoms

Opioid receptors mediate cardiac ischemic preconditioning. Remifentanil is a new, potent ultra-short-acting phenylpiperidine opioid used in high doses for anesthesia. The authors hypothesize that pretreatment with this drug confers cardioprotection.. Male Sprague-Dawley rats were anesthetized and the chest was opened. All animals were subjected to 30 min of occlusion of the left coronary artery and 2 h of reperfusion. Before the 30-min occlusion, rats received either preconditioning by ischemia (ischemic preconditioning, 5-min occlusion, 5-min reperfusion x 3) or pretreatment with remifentanil, performed with the same regime (3 x 5-min infusions) using 0.2, 0.6, 2, 6, or 20 microg.kg.min intravenously. The experiment was repeated with naltrindole (a selective Delta-opioid receptor antagonist, 5 mg/kg), norbinaltorphimine (a selective kappa-OR antagonist, 5 mg/kg), or CTOP (a selective mu-opioid receptor antagonist, 1 mg/kg) administered before remifentanil-induced preconditioning or ischemic preconditioning, respectively. Infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining.. There was a dose-related reduction in infarct size/area at risk after treatment with remifentanil that was similar to that seen with ischemic preconditioning. This effect was prevented or significantly attenuated by coadministration of a mu, kappa, or Delta-opioid antagonist. The infarct-sparing effect of ischemic preconditioning was abolished by blockade of kappa-opioid receptors or Delta-opioid receptors but not by mu-opioid receptors.. Remifentanil mimics cardioprotection via all three opioid receptors. This differs from ischemic preconditioning, which confers cardioprotection via kappa- and Delta-, but not mu-opioid receptors. Part of the protective effect of remifentanil may be produced by mu-agonist activity outside the heart.

Topics: Animals; Dose-Response Relationship, Drug; Ischemic Preconditioning, Myocardial; Male; Myocardial Ischemia; Myocardial Reperfusion; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Remifentanil

Decreasing heart rate might be beneficial for improvement of myocardial energetics and could reduce the severity of myocardial ischemia. We examined the contribution of heart rate reduction by cilobradine (DK-AH 269), a direct sinus node inhibitor, on left ventricular function and peripheral vasomotion in anesthetized rabbits with experimental myocardial infarction. The rabbits were randomized to receive either placebo (n=10) or cilobradine (n=7). Cilobradine decreased significantly heart rate from 163 +/- 33 to 131 +/- 13 bpm, p< 0.05, without any inotopic or vascular effects. After 60 min coronary occlusion and 30 min reperfusion, both systolic and diastolic ventricular function were more reduced in the cilobradine group; i.e. maximal left ventricular pressure significantly decreased to 62 +/- 11 mmHg, p < 0.05 (placebo: 77 +/- 9 mmHg); dP/dt(min) significantly decreased to -904 +/- 247 mmHg, p < 0.05 (placebo: -1106 +/- 242 mmHg). However, infarct size in the cilobradine group was significantly smaller compared with the placebo group. In conclusion, cilobradine reduced heart rate without any negative inotropic effect and reduced infarct size. On that account, this bradycardic agent might open a promising therapeutical avenue to treat postischemic dysfunction.

Topics: Animals; Benzazepines; Bradycardia; Heart Rate; Myocardial Ischemia; Piperidines; Rabbits

1 The purpose of this study was to determine whether endocannabinoids can protect the heart against ischaemia and reperfusion. 2 Rat isolated hearts were exposed to low-flow ischaemia (0.5-0.6 ml min(-1)) and reperfusion. Functional recovery as well as CK and LDH overflow into the coronary effluent were monitored. Infarct size was determined at the end of the experiments. Phosphorylation levels of p38, ERK1/2, and JNK/SAPK kinases were measured by Western blots. 3 None of the untreated hearts recovered from ischaemia during the reperfusion period. Perfusion with either 300 nM palmitoylethanolamide (PEA) or 300 nM 2-arachidonoylglycerol (2-AG), but not anandamide (up to 1 micro M), 15 min before and throughout the ischaemic period, improved myocardial recovery and decreased the levels of coronary CK and LDH. PEA and 2-AG also reduced infarct size. 4 The CB(2)-receptor antagonist, SR144528, blocked completely the cardioprotective effect of both PEA and 2-AG, whereas the CB(1)-receptor antagonist, SR141716A, blocked partially the effect of 2-AG only. In contrast, both ACEA and JWH015, two selective agonists for CB(1)- and CB(2)- receptors, respectively, reduced infarct size at a concentration of 50 nM. 5 PEA enhanced the phosphorylation level of p38 MAP kinase during ischaemia. PEA perfusion doubled the baseline phosphorylation level of ERK1/2, and enhanced its increase upon reperfusion. The cardioprotective effect of PEA was completely blocked by the p38 MAP kinase inhibitor, SB203580, and significantly reduced by the ERK1/2 inhibitor, PD98059, and the PKC inhibitor, chelerythrine. 6 In conclusion, endocannabinoids exert a strong cardioprotective effect in a rat model of ischaemia-reperfusion that is mediated mainly through CB(2)-receptors, and involves p38, ERK1/2, as well as PKC activation.

Topics: Amides; Animals; Arachidonic Acids; Biomarkers; Blotting, Western; Camphanes; Cannabinoid Receptor Modulators; Endocannabinoids; Ethanolamines; Glycerides; Heart; Imidazoles; L-Lactate Dehydrogenase; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; p38 Mitogen-Activated Protein Kinases; Palmitic Acids; Piperidines; Protein Kinase C; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Rimonabant; Signal Transduction

A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.

Topics: Animals; Aza Compounds; Brain Ischemia; Dogs; Enzyme Inhibitors; Haplorhini; Humans; In Vitro Techniques; Injections, Intravenous; Male; Microsomes, Liver; Myocardial Ischemia; Naphthyridines; Phenanthridines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Rats, Wistar; Solubility; Structure-Activity Relationship; Tissue Distribution; Water

The contrasting pattern of cardiac inotropy induced by human peptide endothelin-1 (ET-1) has not been satisfactorily explained. It is not clear whether ET-1 is primarily responsible for increased myocardial ET-1 expression and release with resultant inotropic effects, or for the induction of myocardial hypertrophy and heart failure. There are at least two subtypes of endothelin receptors (ET(A) and ET(B)) and the inotropic effects of ET-1 differ depending on the receptor involved. Along with some other groups, we reported significant subtype-ET(B) endothelin receptor down-regulation in human cardiac cells preincubated with endothelin agonists (Drímal et al. 1999, 2000). The present study was therefore designed to clarify the subtype-selective mechanisms underlying the inotropic response to ET-1 and to its ET(B)-selective fragment (8-21)ET-1 in the isolated rat heart. The hearts were subjected to (1-21)ET-1 and to (8-21)ET-1, or to 30 min of stop-flow ischemia followed by 40 min of reperfusion, both before and after selective blockade of endothelin receptors. The present study revealed that both peptides, ET-1 and its (8-21)ET-1 fragment, significantly reduced coronary blood flow in nmolar and higher concentrations. The concomitant negative inotropy and chronotropy were marked after ET-1, while the infusion of the ET-1(8-21) fragment produced a slight but significant positive inotropic effect. Among the four endothelin antagonists tested in continuous infusion only the non-selective PD145065 and ET(B1/B2) selective BQ788 (in molar concentrations) slightly reduced the early contractile dysfunction of the heart induced by ischemia, whereas ET(A)-selective PD155080 partially protected the rat heart on reperfusion.

Topics: Amino Acid Sequence; Animals; Coronary Circulation; Dioxoles; Endothelin-1; Endothelins; Heart; Heart Failure; Heart Rate; Humans; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oligopeptides; Peptide Fragments; Perfusion; Piperidines; Rats; Rats, Wistar; Ventricular Function, Left; Ventricular Pressure

We have examined the involvement of the endocannabinoid system in the cardioprotection triggered by lipopolysaccharide (LPS). Rats were treated with saline or LPS (10 microg x Kg(-1)). 24 h later, hearts were excised, retrogradely perfused, submitted to a low-flow ischaemia (0.6 ml x min(-1)) for 90 min and reperfused for 60 min. Some hearts were perfused with either SR 141716A (a cannabinoid CB(1), receptor antagonist 1 microM), SR 144528 (a CB2 receptor anagonist microM), NNLA (3 microM) or sodium nitroprusside (1 microM) 5 min before ischaemia and during the ischaemic period. The cardioprotective effects of LPS treatment, in terms of infarction and functional recovery, were not altered by the perfusion of SR 141716A but abolished by both SR 144528 and NNLA. Finally, SR 144528 abolished the beneficial effects of SNP perfusion. Our results suggest an involvement of endocannabinoids, acting through the CB2 receptors, in the cardioprotection triggered by LPS against myocardial ischaemia. This could be attributed to a relationship between cannabinoids and NO.

Topics: Animals; Camphanes; Cannabinoid Receptor Modulators; Heart; Lipopolysaccharides; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Piperidines; Protective Agents; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The effect of endothelin (ET)-1 on cardiac energetics is not fully understood.. In isolated, coronary-perfused rat hearts, we measured left ventricular contractility index (E(max)), pressure-volume area (PVA), and myocardial oxygen consumption (MVO(2)) before and after administration of ET-1 (1x10(-)(9) mol/L). ET-1 increased E(max) by 48+/-16% (P<0.01) and the total MVO(2) by 24+/-11% (P<0.01). The MVO(2)-PVA relations were linear both before and after ET-1 (r>0.99). ET-1 shifted MVO(2)-PVA upward, increasing the MVO(2) intercept by 24+/-13%. At the same time, ET-1 decreased the slope (S), with 1/S (contractile efficiency) being 46+/-5% before and 56+/-5% after ET-1 (P<0.01). ET-1-induced increases in E(max) and in contractile efficiency were abolished by an ET(A) receptor blocker (S-0139) but not by an ET(B) blocker (BQ-788). Although high [Ca(2+)] perfusion increased E(max) and the intercept to the same extent as ET-1, it did not change S. N(G)-Nitro-L-arginine (an inhibitor of nitric oxide synthase) increased the coronary perfusion pressure as much as ET-1, but S again remained unchanged. Dimethylamyloride (Na(+)/H(+) exchanger inhibitor) partially blocked the positive inotropic effect of ET-1 but not the ET-1-induced increase in the contractile efficiency.. Agonistic effects of ET-1 on the ET(A) receptor economized the chemomechanical conversion efficiency of the left ventricular unit myocardium by a mechanism independent of the Na(+)/H(+) exchanger. This unique oxygen-saving effect of ET-1 may play an adaptive role in the failing myocardium, in which local accumulation of ET-1 is present.

Topics: Amiloride; Animals; Antihypertensive Agents; Caffeic Acids; Cardiotonic Agents; Drug Interactions; Endothelin-1; Heart; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oleanolic Acid; Oligopeptides; Oxygen; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley

Topics: Aged; Cholinesterase Inhibitors; Donepezil; Female; Humans; Indans; Myocardial Ischemia; Piperidines

1. The NHE1 isoform of the Na(+)/H(+) exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na(+)/H(+) antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. 2. Recovery of pH(i) following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na(+)/H(+) exchanger. pH(i) recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC(50) 3.3+/-1.3 nM) versus NHE2-expressing cells (2.3+/-1.0 microM). The respective IC(50) values for cariporide were 103+/-28 nM (NHE1) and 73+/-46 microM (NHE2). 3. In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10 - 100 microg kg(-1) min(-1) i.v.) inhibited ischaemia-mediated ventricular tachycardia (71 - 100%) and reperfusion-induced ventricular fibrillation (75 - 87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg(-1)) produced anti-arrhythmic effects when administered either before or during ischaemia. 4. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2+/-3.4% (control group) versus 15.3+/-3.9% (SL 59.1227 0.6 mg kg(-1) i.v.). 5. SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na(+)/H(+) exchanger inhibitor. It possesses marked cardioprotective properties.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Coronary Disease; Guanidines; Heart Rate; Heart Ventricles; Hydrogen-Ion Concentration; Imidazoles; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Piperidines; Rabbits; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Sulfones

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cardiovascular Diseases; Humans; Multicenter Studies as Topic; Myocardial Ischemia; Oximes; Piperidines; Platelet Aggregation Inhibitors; Ramipril; Randomized Controlled Trials as Topic

1,2-Diacylglycerol (1,2-DAG) and phosphatidic acid (PA) are produced by phospholipase C and D activity and play a key role as second messengers in receptor-mediated signal transduction. So far, little is known about alterations of endogenous 1,2-DAG and PA production during myocardial ischemia.. Rat isolated perfused hearts were subjected to global ischemia, total lipids were extracted, and separated by thin-layer chromatography. The mass of PA and 1,2-DAG were quantified using laserdensitometric analysis of visualized lipids.. Compared to normoxic control values (1,2-DAG 713 +/- 45 ng/mg protein, PA 171 +/- 11 ng/mg protein), the myocardial content of 1,2-DAG and PA was unaltered after 10 min of ischemia. Prolonged myocardial ischemia (20 min), however, which was accompanied by marked overflow of endogenous norepinephrine, significantly increased the mass of both second messengers (1,2-DAG 1062 +/- 100 ng/mg protein, PA 340 +/- 29 ng/mg protein). The increase in PA and 1,2-DAG in response to ischemia was abolished by inhibition of ischemia-induced norepinephrine release as well as by alpha1-adrenergic blockade but unaffected by beta-adrenergic blockade. While inhibition of diacylglycerol kinase did not affect ischemia-induced increase in PA and 1,2-DAG, inhibition of phosphatidylinositol-specific phospholipase C activity significantly suppressed ischemia-induced increase in 1,2-DAG but did not affect endogenous production of PA indicating phospholipase C-independent formation of PA and activation of both, phospholipase C and D, in the ischemic heart.. Ischemia elicits an alpha1-adrenergic receptor-mediated increase in the mass of myocardial PA and 1,2-DAG. The increase in endogenous PA is suggested to be due to the activation of myocardial phospholipase D, whereas 1,2-DAG is formed predominantly by activation of phospholipase C in the ischemic heart.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Adrenergic Uptake Inhibitors; Analysis of Variance; Animals; Chromatography, Thin Layer; Desipramine; Diacylglycerol Kinase; Diglycerides; Estrenes; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Norepinephrine; Perfusion; Phosphatidic Acids; Piperidines; Prazosin; Propranolol; Pyrrolidinones; Quinazolines; Quinazolinones; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; Time Factors; Type C Phospholipases

1. CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against ischaemia- and reperfusion-induced arrhythmia was evaluated in anesthetized rats. 2. Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion. 3. In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30-300 microg kg(-1)) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 microg kg(-1) in VF (incidence: 42%) and mortality (8%), and at 300 microg kg(-1) in VT (50%), VF (33%) and mortality (8%). This protective effect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30-1000 microg kg(-1)) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be sufficient to explain its potency. 4. In the same model, co-administration of ineffective doses of diltiazem (300 microg kg(-1)) and a sodium and calcium overload inhibitor, R56865 (100 microg kg(-1)), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of R56865 at the same dose with CP-060S (300 microg kg(-1)) did not add to the effect of a single treatment of CP-060S. 5. In the ischaemia-induced arrhythmia model, CP-060S (300 microg kg(-1)) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg(-1)) was ineffective. 6. These results suggest that CP-060S inhibits both ischaemia- and reperfusion-induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzothiazoles; Calcium Channel Blockers; Diltiazem; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion; Piperidines; Rats; Rats, Sprague-Dawley; Thiazoles; Thiazolidines

The aim of the present study was to develop a coronary thrombolysis model using the copper coil technique in closed-chest pigs. The first goal (protocol I) was to obtain a reproducible size of myocardial infarction by controlling the coronary occlusion period, a prerequisite for evaluation of myocardioprotective interventions. The second goal (protocol II) was to study if thrombin and platelet aggregation inhibitors influence the rate of thrombolysis, the degree of reocclusion, and the time of coronary patency when added to a thrombolytic regimen (recombinant tissue-type plasminogen activator, rt-PA). Coronary thrombosis was produced by insertion of a thrombogenic copper coil into the LAD of 40 anesthetized pigs. The animals were divided into six groups as follows: Protocol I, group 1: Open-chest, lysis initiated with intracoronary rt-PA (50 mg) concomitant with intravenous heparin and acetylsalicylic acid (ASA) (n=6). Group 2: Closed-chest, lysis initiated with intracoronary rt-PA concomitant with intravenous heparin and ASA (n=10). Protocol II, group 3: Closed-chest, lysis initiated with intravenous rt-PA (n=6). Group 4: Closed-chest, lysis initiated with intravenous rt-PA concomitant with heparin (n=6). Group 5: Closed-chest, lysis initiated with intravenous rt-PA concomitant with inogatran, a low molecular weight thrombin inhibitor (n=6). Group 6: Closed-chest, lysis initiated with intravenous rt-PA immediately after intravenous administration of ASA (n=6). Protocol 1; Reperfusion was achieved in all closed- and open-chest pigs. The time to thrombolysis was 5+/-1.6 and 6+/-3.0 min (mean+/-SD) for closed- and open-chest pigs, respectively. Reocclusions were rare (one in group 1). The size of the ischemic myocardial area was 21+/-11% of the left ventricular area in group 1 and 22+/-6% in group 2. The corresponding values for infarct size as a proportion of the ischemic area were 58+/-10% and 68+/-14%, respectively. The closed-chest model was subsequently used to study the effect of the thrombin and platelet aggregation inhibitors (inogatran, heparin, and ASA) as conjunctive agents to rt-PA-induced thrombolysis (groups 3-6). To mimic its clinical use, rt-PA was administered intravenously. Time to lysis after rt-PA only (group 3) was 33+/-24 min. Concomitant treatment with heparin (group 4), inogatran (group 5), and ASA (group 6) did not significantly influence time to lysis. All adjunctive compounds did, however, prolong the time to reocclusion, which oc. The described closed-chest pig model was feasible as regards the induction and lysis of a thrombus in the left coronary artery, giving reproducible areas of myocardial ischemia and infarction. This model was useful for the evaluation of pharmacological interventions in the thrombolysis process.

Topics: Animals; Antithrombins; Aspirin; Blood Flow Velocity; Coronary Thrombosis; Glycine; Hemodynamics; Heparin; Myocardial Ischemia; Piperidines; Reperfusion Injury; Swine; Thrombolytic Therapy

The aim of the present study was to compare the influence of terikalant, a blocker of inwardly rectifying K+ channels, galanin, a neuropeptide of 29 aminoacids with a complex mechanism of action including an activation of inwardly rectifying K+ channels and glibenclamide, a blocker of ATP-sensitive K+ channels, on simulated ischaemia-induced changes in contractility and response to phenylephrine of rat-isolated heart muscle. Experiments were performed on isolated rat heart papillary muscles. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (-dF/dt), time to peak contraction (ttp) and relaxation time at 10% of total amplitude of contraction (tt10). In the presence of 1 microM of galanin, as well as terikalant, simulated ischaemia caused a decrease in Fc, +dF/dt and -dF/dt, however, it significantly increased a drop in Fc and -dF/dt. After 60 min of reperfusion, all the measured parameters recovered completely except Fc in the galanin group. Terikalant, but not galanin, prevents the negative inotropic action of phenylephrine observed in the control group. On the other hand, addition of 1 microm of glibenclamide to the no-substrate solution prevented the simulated ischaemia-induced decrease in Fc, +dF/dt and -dF/dt. In this group phenylephrine did not cause the negative inotropic action. The above mentioned data reveal that pretreatment with the inhibitors of ATP-sensitive and inwardly rectifying K+ channels protect rat-isolated papillary muscle against ischaemia-induced disturbances in contractility.

Topics: Animals; Chromans; Female; Galanin; Glyburide; Male; Myocardial Contraction; Myocardial Ischemia; Papillary Muscles; Phenylephrine; Piperidines; Potassium Channels; Rats; Rats, Wistar

We investigated the effect of NIP-121, a novel ATP-sensitive K+ channel opener, on myocardial damage during ischemia/reperfusion. The action potential and contractile force of coronary-perfused guinea pig right ventricular walls were recorded. The preparations were subjected to 30-min no-flow ischemia with or without NIP-121 or glibenclamide, followed by 60-min reperfusion. In untreated tissues, decreases in action potential duration (APD) and contractile force and an increase in resting tension were observed during the no-flow period. On reperfusion, transient arrhythmias were observed and resting or contractile force returned to <50% of preischemic values. NIP-121, at 0.3 microM, a concentration showing only a slight negative inotropic effect, caused a faster decrease in APD and contractile force but abolished the increase in resting tension (RT) during the no-flow period. On reperfusion, no arrhythmia was observed in NIP-121-treated preparations, and contractile force recovered to approximately 80% of the preischemic value. Glibenclamide 1 microM attenuated the decrease in APD but affected neither the decrease in contractile force nor the increase in RT during the no-flow period. On reperfusion, the incidence of arrhythmia was increased in glibenclamide-treated preparations, and the recovery of basal tension and contractile force was inhibited: Contractile force recovered to only approximately 15% of the preischemic value. NIP-121 was also shown to attenuate the decrease in tissue ATP during ischemia and reperfusion. We demonstrated that NIP-121 may have protective effects against myocardial injury during ischemia and reperfusion. Activation of ATP-sensitive K+ current may be an adaptive mechanism for cardioprotection under compromised blood flow.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Glyburide; Guinea Pigs; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Oxadiazoles; Piperidines; Potassium Channels

The effects of two endothelin (ET) receptor antagonists, PD 155080 (ET(A) selective) and BQ-788 (ET(B) selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 microM) reduced coronary resistance, but had no effect on ET-1 release. Low concentrations of BQ-788 (2 and 20 nM) had no effect on coronary resistance; high concentrations (0.2 and 2 microM) increased it approximately 2-fold; all concentrations increased ET-1 release (up to 24-fold). Similar results were obtained in reperfused hearts. Although concentrations of ET-1 were higher in interstitial fluid than coronary effluent, levels never exceeded the low pg/ml range. These results indicate that (1) ET(A) receptors mediate coronary constriction, whereas ET(B) receptors bind and sequester ET-1, and (2) ET-1 displaced by ET(B) antagonist accesses ET(A) receptors resulting in coronary constriction.

Topics: Animals; Coronary Vessels; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Heart Rate; In Vitro Techniques; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Oligopeptides; Piperidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Vascular Resistance; Ventricular Function, Left

Impairment of myocardial contraction ("myocardial stunning") occurs during reperfusion after short ischemic periods. Substance P (SP) is widely distributed in heart and can be released by various stimuli including myocardial hypoxia. Our previous study shows SP has a negative inotropic effect in guinea pig heart. The objective of this study was to investigate whether SP contributes to the myocardial stunning after brief global ischemia. Guinea pig hearts in a Langendorff preparation were subjected to 15 min of global ischemia followed by 60 min reperfusion. Experiments were performed without and with pretreatment with neurokinin-1 (NK1) receptor antagonists, spantide (10(-6)M) or CP-99,994-01 (10(-6)M) in order to study the role of SP. Experiments were also performed in hearts which were perfused with atropine, phentolamine, and nadolol (10(-6)M each) to examine the role of neurotransmitters and autonomic receptors. A group of hearts obtained from capsaicin-pretreated guinea pigs was also investigated. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), heart rate, and perfusion pressure were monitored. At the end of reperfusion, the LVDP of control hearts recovered to only 55 +/- 6% (+/- SEM) of preischemic baseline and the LVEDP increased significantly (P > 0.05). With pretreatment with spantide or CP-99,994-01, LVDP recovered to 88 +/- 2% or 78 +/- 2% of the preischemic baseline, respectively. The LVEDP of these hearts was not different from preischemic baseline and much smaller than in control hearts. There were no differences in heart rate and perfusion pressure compared to baseline among all groups. Similar results were obtained in hearts perfused with autonomic blockers. However, recoveries of LVDP and LVEDP were faster in hearts perfused with autonomic blockers during the first 10 min of reperfusion. Pretreatment with capsaicin also significantly improved recovery of LVDP and LVEDP. In conclusion, substance P is involved in postischemic myocardial dysfunction and neurokinin-1 receptors mediate this action. The NK1 receptor antagonists may be useful in prevention of "myocardial stunning".

Topics: Analgesics; Animals; Capsaicin; Guinea Pigs; Heart Rate; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Stunning; Piperidines; Substance P; Ventricular Dysfunction, Left

SQ 32,926 and SQ 32,547, two dihydropyrimidine calcium channel blockers, were characterized as potent inhibitors of depolarization-induced contractions of isolated smooth muscle preparations. In rat aorta, the IC50 values were 5.5 nM for SQ 32,547 and 8.1 nM for SQ 32,926, values which compare favorably with that of 2.9 nM for nifedipine. The dihydropyrimidines were also tested in a model of stable angina: pacing-induced ischemia in dogs. Both SQ 32,547 and SQ 32,926 reduced the ST-segment elevation observed in vehicle-treated animals. No significant changes in hemodynamic status were detected, suggesting that a reduction in cardiac work secondary to afterload reduction was probably not a major contributor to the protective effects. Neither was increased coronary blood flow important for the antiischemic outcome because no significant effects of the dihydropyrimidines were observed on ischemic regional blood flow. SQ 32,547 was also studied in globally ischemic, isolated rat hearts. In this model, SQ 32,547 was protective because it significantly reduced contracture formation and lactate dehydrogenase (LDH) release. Washing out the effect of SQ 32,547 in isolated hearts and smooth muscles was difficult, presumably due to its lipophilicity. In the smooth muscle preparations, the effects of both nifedipine and SQ 32,926 were much more easily washed out. As with other calcium channel blockers, increasing the antiischemic effects of SQ 32,547 was associated with a higher cost in terms of cardiac function. In summary, the two novel dihydropyrimidines, SQ 32,547 and SQ 32,926 showed antiischemic properties in animal models.

Topics: Animals; Calcium Channel Blockers; Dogs; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Male; Muscle Contraction; Myocardial Ischemia; Piperidines; Pyrimidines; Rabbits; Rats; Rats, Sprague-Dawley; Swine

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Action Potentials; Animals; Benzothiazoles; Biomechanical Phenomena; Electric Conductivity; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Papillary Muscles; Piperidines; Reference Values; Sodium; Tetrodotoxin; Thiazoles

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart; Hemodynamics; Injections, Intravenous; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperidines; Rabbits; Random Allocation; Thiazoles

Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H3-receptors inhibits norepinephrine release, we searched for the presence of H3-receptors directly in sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human atria. Norepinephrine was released by depolarization with K+. The presence of H3-receptors was ascertained because the selective H3-receptor agonists (R) alpha-methylhistamine and imetit reduced norepinephrine release, and the specific H3-receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca(2+)-channel blocker omega-conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H3-receptors was obtained by showing that transmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranolol and attenuated in a concentration-dependent manner by (R) alpha-methylhistamine. Also, thioperamide antagonized the effect of (R) alpha-methylhistamine. Our findings are the first demonstration that H3-receptors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine release. Since myocardial ischemia causes intracardiac histamine release, H3-receptor-induced attenuation of sympathetic neurotransmission may be clinically relevant.

Topics: Cell Separation; Electric Stimulation; Exocytosis; Heart; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; In Vitro Techniques; Indoles; Methylhistamines; Myocardial Ischemia; Myocardium; Norepinephrine; Piperidines; Protein Kinase C; Receptors, Histamine H3; Synaptosomes; Thiourea

Previous studies have shown that in heart there are two kinetically distinct components of delayed rectifier current: a rapidly activating component (IKr) and a more slowly activating component (IKs). The presence of IKr and/or IKs appears to be species dependent. We studied the nature of the delayed rectifier current in human ventricle in whole-cell and single-channel experiments.. Ventricular myocytes were obtained from hearts of patients with ischemic or dilated cardiomyopathy. Single-channel currents and whole-cell tail currents were recorded at negative potentials directly after return from a depolarizing step. Single-channel currents were measured in the cell-attached patch configuration with 140 mmol/L K+ in the pipette. In the present study, we identified a voltage-dependent channel with a single-channel conductance of 12.9 +/- 0.8 pS (mean +/- SEM, n = 5) and a reversal potential near to the K+ equilibrium potential, suggesting that the channel is selective to K+ ions. Channel activity was observed only after a depolarizing step and increased with the duration and amplitude of the depolarization, indicating time- and voltage-dependent activation. Activation at +30 mV was complete within 300 milliseconds, and the time constant of activation, determined in the whole-cell configuration, was 101 +/- 25 milliseconds (mean +/- SEM, n = 4). The voltage dependence of activation could be described by a Boltzmann equation with a half-activation potential of -29.9 mV and a slope factor of 9.5 mV. The addition of the class III antiarrhythmic drug E-4031 completely blocked channel activity in one patch. No indications for the presence of IKs were found in these experiments.. The conformity between the properties of IKr and those of the K+ channel in the present study strongly suggests that IKr is present in human ventricle.

Topics: Action Potentials; Anti-Arrhythmia Agents; Cardiomyopathy, Dilated; Cells, Cultured; Heart Ventricles; Humans; Myocardial Ischemia; Myocardium; Piperidines; Potassium Channels; Pyridines

R56865 was previously characterized as an inhibitor of Na and Ca overload that has beneficial effects during ischemia and reperfusion. An isolated guinea-pig heart preparation was subjected to 60 minutes of ischemia and 60 minutes of reperfusion. R56865 was given before ischemia and with the onset of reperfusion, applying different dosing schedules, including an initial loading dose. R56865 below 0.1 mumol/l had no cardiodepressant effects in normoxic hearts and at 0.1 mumol/l reduced left ventricular pressure marginally. The onset of ischemic contracture was delayed only at this concentration. R56865 given before ischemia potently inhibits delayed sustained fibrillation occurring during reperfusion in the concentration range between 0.01 mumol/l and 0.1 mumol/l. Analysis of cellular Na+, K+, and Ca2+ concentrations revealed that R56865 substantially improves the ionic homeostasis of myocardial cells. Most importantly, the compound also reduced the incidence of delayed sustained fibrillation when given at the onset of reperfusion. R56865 was most effective when fast equilibration of drug with tissue was achieved by giving an initial loading dose. In particular, the cellular Na+ and Ca2+ contents were improved using this dosing scheme. The results are compatible with the classification of R56865 as an inhibitor of Na+ and Ca2+ overload.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Benzothiazoles; Calcium; Calcium Channel Blockers; Extracellular Space; Guinea Pigs; Heart; In Vitro Techniques; Lidocaine; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperidines; Potassium; Sodium; Thiazoles; Verapamil

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Coronary Circulation; Male; Myocardial Ischemia; Perfusion; Piperidines; Potassium; Potassium Channels; Rats; Rats, Wistar; Ventricular Fibrillation

The electrophysiologic effects of a new anti-arrhythmic agent NE-10064 were compared with known class III drugs, E-4031 and sotalol, in sheep Purkinje fibres paced at 1 Hz under normal and simulated ischaemic conditions. NE-10064 0.3-3 microM and sotalol 0.3-300 microM prolonged action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) concentration dependently without affecting APD50 under normal conditions. E-4031 0.3-300 microM prolonged APD50, APD90, and ERP concentration dependently. Percentage increases in APD90 of 20 +/- 6, 27 +/- 6, and 33 +/- 9 were calculated for NE-10064 3 microM, sotalol 300 microM, and E-4031 1 microM under normal conditions, respectively. The concentration-response curves for all three drugs were shifted to the right under simulated ischaemic conditions. The shift was more marked for NE-10064 and sotalol. Percentage increases in APD90 of 8 +/- 5, 13 +/- 2, and 23 +/- 4 were observed with NE-10064 3 microM, sotalol 300 microM, and E-4031 1 microM during simulated ischaemia. NE-10064 exhibits electrophysiologic characteristics similar to those of known class III agents. Its ability to prolong APD90 under normal conditions may explain its antiarrhythmic action in vivo.

Topics: Animals; Anti-Arrhythmia Agents; Hydantoins; Imidazoles; Imidazolidines; In Vitro Techniques; Myocardial Ischemia; Piperazines; Piperidines; Purkinje Fibers; Pyridines; Sheep; Sotalol

The cardiac electrophysiologic and antiarrhythmic actions of two Class III ketone- and alcohol-containing spirobenzopyran piperidine analogs, L-702,958 and L-706,000 [MK-499], respectively, were assessed in vitro and in vivo. L-702,958 and L-706,000 [MK-499] selectively blocked the rapidly activating component of the delayed rectifier K+ current in guinea pig isolated ventricular myocytes (IC50 values, 14.6 and 43.9 nM, respectively), and prolonged effective refractory period in ferret isolated papillary muscles (EC25 values, 10.5 and 53.8 nM, respectively). In anesthetized dogs, L-702,958 and L-706,000 [MK-499] increased ventricular refractory periods (ED20 values, 3.3 and 9.2 micrograms/kg i.v., respectively) and concomitantly increased ECG QT interval and left ventricular+dP/dt. Cumulative i.v. administrations of up to 100 micrograms/kg of L-702,958 and 300 micrograms/kg L-706,000 [MK-499] in anesthetized dogs increased atrial and ventricular refractoriness and prolonged the ECG QT interval, but did not alter atrial, atrioventricular nodal, His-Purkinje or ventricular conduction indices. In anesthetized dogs studied chronically (9.2 +/- 1.1 days) after anterior myocardial infarction, the cumulative i.v. administrations of 100 micrograms/kg of L-702,958 and 300 of micrograms/kg L-706,000 [MK-499] suppressed the induction of ventricular tachyarrhythmia by programmed ventricular stimulation (suppression rates: 8 of 10, 80% and 9 of 11, 82%, respectively) and reduced the incidence of lethal ventricular arrhythmias (incidence of lethal ischemic arrhythmias: 4 of 10, 40% and 1 of 11 9%, respectively, compared to 34 of 40, 85%, in vehicle controls. L-702,958 and L-706,000 [MK-499] (cumulative 100 and 300 micrograms/kg i.v., respectively) did not facilitate the induction of arrhythmias by programmed ventricular stimulation in postinfarction dogs. After equivalently effective p.o. doses in conscious dogs, L-702,958 (10 micrograms/kg) and L-706,000 [MK-499] (30 micrograms/kg) increased ECG QT interval with long durations of action of approximately 9 and 14 hr, respectively. L-706,000 [MK-499] elicited a more consistent and sustained prolongation of the QT interval than L-702,958. These findings show that both L-702,958 and L-706,000 [MK-499] are potentially useful agents for the prevention of malignant ventricular arrhythmias in the setting of myocardial ischemic injury.

Topics: Animals; Anti-Arrhythmia Agents; Benzopyrans; Dogs; Electrocardiography; Female; Ferrets; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Male; Molecular Structure; Myocardial Ischemia; Piperidines

The anti-ischemic effects of a new, selective and potent cyclic 3',5'-guanosine monophosphate-specific phosphodiesterase (phosphodiesterase type V) inhibitor, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ]piperidine-4- carboxylate (E4021), in a vasopressin-induced guinea pig anginal model were examined and compared with those of coronary vasodilators with a guanylate cyclase-activating action. An intravenous injection of vasopressin (0.2 IU/kg) into anesthetized guinea pigs produced ST segment elevation on the electrocardiogram (an index of myocardial ischemia) of 0.28 +/- 0.02 mV (n = 10) from the baseline within 30 s. E4021 administered intravenously at doses of 0.03 and 0.1 mg/kg, 5 min before the injection of vasopressin, significantly inhibited the ST segment elevation to 0.15 +/- 0.03 mV (n = 6, P < 0.01) and 0.17 +/- 0.02 mV (n = 6, P < 0.01), respectively. Three guanylate cyclase activators, isosorbide dinitrate (0.1 mg/kg), nicorandil (0.1 mg/kg), and FK409 (0.3 mg/kg), also significantly reduced the ST segment elevation to 0.18 +/- 0.03, 0.11 +/- 0.02 and 0.17 +/- 0.02 mV, respectively. In a second experiment, E4021 was administered intraduodenally 30 min before the injection of vasopressin to examine its oral effectiveness. Intraduodenal E4021, at doses of 1.0 and 3.0 mg/kg, also significantly inhibited the ST segment elevation to 0.16 +/- 0.02 mV (n = 6, P < 0.01) and 0.13 +/- 0.02 mV (n = 6, P < 0.01), respectively. It is concluded that the potent phosphodiesterase type V inhibitor, E4021, administered intravenously or intraduodenally, ameliorated myocardial ischemia similarly to guanylate cyclase activators. Thus, E4021 may be an orally effective drug in the treatment of angina pectoris.

Topics: Animals; Drug Interactions; Electrocardiography; Guinea Pigs; Injections, Intravenous; Isosorbide Dinitrate; Male; Myocardial Ischemia; Niacinamide; Nicorandil; Nitro Compounds; Phosphodiesterase Inhibitors; Piperidines; Quinazolines; Vasodilator Agents; Vasopressins

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

1. Microelectrode recording techniques were used to study the effects of several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)-sotalol, UK-66,914, UK-68,798 and E-4031 on action potential duration (APD) were determined in guinea-pig isolated papillary muscles. The compounds were evaluated under normoxic or hypoxic/ischaemic conditions at 36.5 degrees C and compared to glibenclamide, which is considered to be a blocker of ATP-dependent potassium channels. Prolongation of action potential duration at 90% repolarization (APD90) was taken as an indirect measure of potassium channel blockade. 2. Under normoxic conditions, the Class III compounds prolonged APD in a concentration-dependent manner. According to EC15 values, the order of potency of the Class III compounds was found to be UK-68,798 > E-4031 > UK-66,914 > (+)-sotalol. Glibenclamide did not significantly prolong APD90 under normoxic conditions. 3. Perfusion with an experimental hypoxic or ischaemic bathing solution produced qualitatively similar effects on action potentials. Over a period of 20-25 min in either of the experimental solutions, there was a small decrease in action potential amplitude (APA) and a prominent shortening of APD. The ischaemic solution also depolarized the resting membrane potential by about 15 mV. 4. (+)-Sotalol and UK-66,914 did not reverse the shortening of APD induced by perfusion with hypoxic Krebs solution. High concentrations of glibenclamide (10 microM) and UK-68,798 (30 and 60 microM) partially reversed the hypoxia-shortened APD. Glibenclamide was more potent and exhibited a greater time-dependent action than UK-68,798. 5. During experimental ischaemia, the Class III compound E-4031 (10 microM, n = 7) produced small, but significant, increases in the APD90 (11 +/-3 ms after 20 min) which were not clearly time-dependent(14 +/- 4 ms after 30 min). UK-68,798 (10 microM) also produced a small, but insignificant, increase in APD90(12 =/-6 ms at 20 min, n = 4). Higher concentrations of UK-68,798 (30 and 60 microM, n = 4) did not produce a consistently significant increase in APD90 during ischaemia: significance was only attained after 20 min in the presence of 60 microM UK-68,798 (24 +/- 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 microM) produced large time-dependent increases in ischaemic APD90 (34 +/- 11 ms at 7 min, n = 9) which were significant 15 min or

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Electrophysiology; Glyburide; Guinea Pigs; Heart; Hypoxia; In Vitro Techniques; Microelectrodes; Myocardial Ischemia; Papillary Muscles; Piperidines; Potassium Channels; Pyrazines; Pyridines; Sotalol

The compound R56865 protects the heart from irreversible ischemic damage. The proposed mechanism of its action is a reduction of Ca2+ overload secondary to a reduction of intracellular Na+, caused by blockade of the Na(+)-channel. In addition, cardioprotection is ascribed to blockade of the Na(+)-sensitive K(+)-channel (IK-Na). We tested whether R 56865 delays cellular electrical uncoupling, one aspect of irreversible ischemic damage that is due to Ca2+ overload. Also, we studied whether the Na(+)-channel and IK-Na are involved in cardioprotection by relating delay of the onset of cellular electrical uncoupling to changes of conduction velocity and action potential duration (APD80), respectively. Experiments were performed with isolated perfused rabbit papillary muscles that were treated with 1 microM R 56865 for 45 min prior to ischemia. Uncoupling started at 15.0 +/- 0.8 min (mean +/- S.E.M., n = 12) of ischemia in the control group and at 23.4 +/- 1.7 min in the R 56865 group (n = 9, P < 0.005 vs control). R 56865 tended to decrease conduction velocity and to increase APD80 during pre-treatment, but these changes were not statistically significant. During ischemia, conduction velocity was statistically not different between the R 56865 group and the control group. APD80 was significantly longer in the R 56865 than in the control group during the first 7 min of ischemia and similar after that. We conclude that R 56865 delays the onset of cellular uncoupling during ischemia and that this effect is not related to changes of conduction velocity and at most in part to changes of APD80.

Topics: Action Potentials; Animals; Benzothiazoles; Calcium; Heart Conduction System; In Vitro Techniques; Myocardial Contraction; Myocardial Ischemia; Piperidines; Rabbits; Thiazoles

In a perfused guinea-pig heart model of myocardial ischaemia, reducing coronary flow by 95% for four successive 6 min periods caused a reproducible net loss of K+ into the coronary perfusate. This was reduced in a concentration-dependent manner by ATP dependent K+ channel blockers (glibenclamide and glipizide) and calcium channel blockers (verapamil and nifedipine). Other K+ channel blockers (UK-66,914, 4-aminopyridine, R56865 and phentolamine) and beta 1-adrenoceptor and beta 2-adrenoceptor antagonists (betaxolol and ICI118551) did not reduce this loss significantly. A single 30 min low-flow period reliably induced K+ release and ventricular fibrillation in control hearts. Glibenclamide, glipizide and phentolamine suppressed ventricular fibrillation but not ischaemic K+ loss in this model. R56865 and 4-aminopyridine and coadministration of betaxolol and ICI118551 yielded similar results while UK-66,914 suppressed neither. In our model, modulation of ischemic K+ loss and suppression of ventricular fibrillation were not closely associated and appeared to occur via separate mechanisms.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Benzothiazoles; Calcium Channel Blockers; Disease Models, Animal; Glipizide; Glyburide; Guinea Pigs; In Vitro Techniques; Male; Myocardial Ischemia; Piperidines; Potassium; Potassium Channels; Pyrazines; Pyridines; Sympatholytics; Thiazoles; Ventricular Fibrillation