Molsidomine prevents post‐ischaemic ventricular fibrillation in dogs

Abstract

Forty anaesthetized dogs were subjected to left circumflex coronary artery ligation followed by reperfusion. Molsidomine was randomly administered to 20 dogs (50 μg kg−1 as an i.v. bolus −15 min prior to coronary occlusion – followed by an infusion of 0.05 μg kg−1 min−1). Standard electrocardiographic leads 2 and 3 were continuously recorded to measure ST segment and ΔR% 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 < 0.025) and ΔR% changes (37 ± 50 vs 90 ± 84%, P < 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.

Failure of nitric oxide donors to alter arrhythmias induced by acute myocardial ischaemia or reperfusion in anaesthetized rats

“…Despite using two different nitric oxide donors and a wide range of doses giving haemodynamic responses varying from very mild to marked hypotension, there were no changes in the incidence or severity of either ischaemia-induced or reperfusioninduced arrhythmias. These results contradict previous reports of antiarrhythmic activity observed with either glyceryl trinitrate (Borer et al, 1974;Kent et al, 1974;Stockman et al, 1975) or molsidomine (Martorana et al, 1983;Cano et al, 1986).…”

“…There does not seem to be any obvious explanation for the bradycardia induced by SIN-1 in our experiments. In other species, SIN-1, or other sydnonimines, either caused tachycardia or had no effect on heart rate (Cano et al, 1986;Groves et al, 1993;Wainwright & Martorana, 1993). However, in the present study, the severity of arrhythmias did not appear to be related to the dose of SIN-1.…”

“…Since the drug-induced changes in ventricular fibrillation thresholds were confined to the area made ischaemic by coronary artery occlusion it was concluded that they were related to the influence of the drug on ischaemia rather than a non-specific cardiac membrane stabilizing effect. In the studies with molsidomine, both Martorana et al (1983) and Cano et al (1986) concluded that the beneficial effects of this drug were due to its ability to improve blood flow to the ischaemic area.…”

The influence of molsidomine on infarct size: An acute post-infarction pilot study with 303 patients

“…Furthermore, this study failed to demonstrate an efficacy of molsidomine on ventricular fribrillation, in contrast with conclusion of Cano based on animal experiments [2]. Since rhythm was not monitored continuously, we did not investigate nonclinical arrhythmias such as premature ventricular beats or nonsustained ventricular tachycardia.…”

“…According to the method of Sobel [2] with the correction of Tansey [7], infarct size is the product of a proportionality constant K, body weight, and en-zyme release measured by the area under the curve of the serial enzyme concentration dosages. Enzyme criteria: A blood sample for dosage of CK with its MB fraction was drawn every 4 hours within the first 24 hours, then every 6 hours on the second day, and twice daily for the last 8 days.…”