Pirsidomine, a novel nitric oxide donor, suppresses ischemic arrhythmias in anesthetized pigs.
The hemodynamic profile and antiarrhythmic properties of pirsidomine, a nitric oxide donor, were examined in pigs. Intravenous administration of pirsidomine (1 mg/kg) to chloralose-anesthetized open-chest pigs resulted in a decreased afterload, and a reduced myocardial contractility and myocardial oxygen consumption (assessed by rate-pressure product), with no alterations in heart rate. After induction of regional myocardial ischemia by occlusion of the left anterior descending coronary artery, pigs given pirsidomine experienced fewer ventricular ectopic beats (119 +/- 29) than control animals did (217 +/- 53; p < 0.05), seen primarily as a reduction in the number of couplets and triplets. Although the incidence of ventricular fibrillation was unaffected by pirsidomine, the time to onset of this arrhythmia was significantly prolonged by this intervention (21.3 +/- 0.9 min versus 16.1 +/- 2.5 min in controls; p < 0.05). Furthermore, the ST-segment depression seen throughout the 30-min occlusion period in controls was not sustained beyond 5 min postocclusion in pirsidomine-treated pigs. Taken together, and in the absence of an ex vivo antiplatelet effect with this dose of pirsidomine, these results suggest that the antiarrhythmic effect of pirsidomine lies in its hemodynamic effects, resulting in a reduction of ischemia. The ex vivo effect of pirsidomine on free radical generation from isolated leukocytes was also investigated. Luminol-enhanced chemiluminescence produced by leukocytes in response to phorbol myristate acetate was markedly depressed in cells isolated from blood withdrawn after administration of pirsidomine, compared with cells tested before drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Wainwright
C L
CL
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland.
Martorana
P A
PA
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D004562:Electrocardiography / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D010974:Platelet Aggregation / Q000187:drug effects; D013552:Swine; D013558:Sydnones / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D005609:Free Radicals; D013558:Sydnones; D014665:Vasodilator Agents; C073303:pirsidomine