oxadiazoles and Arrhythmias--Cardiac

Sphingosine-1-phosphate (S1P) has been considered to play an important role in ischemia/reperfusion (I/R) injury. We used SEW2871 (SEW), a novel receptor-selective agonist for S1P1, to elucidate the role of S1P1 in myocardial I/R. Isolated perfused rat hearts exposed to S1P (1 and 10 mM) or SEW (1 and 0.1 mM) were subjected to 30 minutes of global no-flow ischemia and 2 hours of reperfusion. S1P at 1 and 10 mM significantly reduced infarct size and CK release compared with vehicle-control. The effect of 0.1 microM SEW on infarct size was modest. After I/R, S1P at both doses and SEW at 0.1 microM improved developed pressure (LVDP). SEW at 1 mM significantly prolonged the duration of ventricular tachycardia and ventricular fibrillation, leading to irreversible reperfusion tachyarrhythmias in 60% of the hearts. This is the first demonstration of the critical role of the S1P1 receptor in I/R injury.

Topics: Aniline Compounds; Animals; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Heart; In Vitro Techniques; Male; Models, Biological; Molecular Structure; Myocardial Infarction; Myocardial Reperfusion Injury; Oxadiazoles; Perfusion; Phenyl Ethers; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sodium-Calcium Exchanger; Thiophenes; Time Factors; Ventricular Function, Left

: In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes.. Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C.. Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f).. Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Amphotericin B; Analysis of Variance; Animals; Arrhythmias, Cardiac; Cardiomegaly; Colforsin; Enzyme Inhibitors; Guanylate Cyclase; Hydrazines; Isoproterenol; Male; Membrane Potentials; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrogen Oxides; omega-N-Methylarginine; Oxadiazoles; Patch-Clamp Techniques; Penicillamine; Pyridines; Rats; Rats, Inbred SHR; Sinoatrial Node

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 micrograms kg-1 as an i.v. bolus - 15 min prior to coronary occlusion - followed by an infusion of 0.05 micrograms kg-1 min-1. Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and delta R% changes and to document both the number of ventricular premature beats and the onset of ventricular fibrillation; aortic pressure and cardiac output were measured; thromboxane B2 plasma levels, platelet aggregation produced by ADP, and molsidomine plasma levels were determined before and at 10, 30 and 75 min after the start of the drug protocol. Molsidomine protected the treated animals from early (10 min) post-ischaemic ventricular fibrillation (0 of 20 vs 6 of 20, P = 0.0202), reduced the incidence of overall post-occlusion ventricular fibrillation (3 of 20 vs 10 of 20, P = 0.0407) and improved the total survival rate (P = 0.0067). In molsidomine treated dogs: mean aortic pressure and the rate-pressure product were lowered 10 min after the start of the drug; immediate post-occlusion (3 min) ST segment changes (0.82 +/- 0.52 vs 1.52 +/- 0.78 mV, P less than 0.025) and delta R% changes (37 +/- 50 vs 90 +/- 84%, P less than 0.025) were less marked; the number of ventricular premature beats was lowered and finally, a progressive decline of platelet aggregation produced by ADP was achieved after 75 min of drug infusion. These results were obtained in the presence of mean plasma levels of molsidomine ranging from 20 to 28 ng ml-1. The time-action curve of the antifibrillatory effect of molsidomine parallels those at the level of post-ischaemic electrocardiographic changes.

Topics: Adenosine Diphosphate; Animals; Arrhythmias, Cardiac; Cardiac Output; Coronary Disease; Dogs; Electrocardiography; Heart Rate; Heart Ventricles; Molsidomine; Oxadiazoles; Platelet Aggregation; Sydnones; Thromboxane B2; Vascular Resistance

Topics: Angina Pectoris; Arrhythmias, Cardiac; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Molsidomine; Oxadiazoles; Sydnones; Vasodilator Agents

Topics: Aconitum; Amides; Aminobutyrates; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Azoles; Cyclization; Dogs; Heart Rate; In Vitro Techniques; Ligation; Methods; Ouabain; Oxadiazoles; Rabbits; Tetrazoles