Cardiovascular effects of the new nitric oxide donor, pirsidomine. Hemodynamic profile and tolerance studies in anesthetized and conscious dogs.
The hemodynamic profile of pirsidomine, a new donor of NO (nitric oxide), was evaluated in dogs. In anesthetized dogs, the intravenous or intraduodenal administration of pirsidomine (0.3-10 mg/kg) decreased dose relatedly the preload and afterload of the heart, total peripheral resistance, cardiac output, left ventricular work and myocardial oxygen consumption. In conscious renal-hypertensive dogs, oral administration of pirsidomine (1.0-10 mg/kg) caused a marked and sustained decrease in systolic blood pressure and left ventricular end-diastolic pressure, which was accompanied by a slight and transient increase in heart rate and contractility. The diastolic blood pressure was affected less than in anesthetized dogs. Similar hemodynamic effects were obtained with M1 (3-(1-(2,6-dimethylpiperidino))-sydnonimine; 0.3-1 mg/kg), the main metabolite of pirsidomine, and with the known NO donor, isosorbide-5-mononitrate (IS-5-MN; 2-10 mg/kg). Tolerance development after repeated administration of pirsidomine and IS-5-MN was also investigated. In anesthetized dogs, repeated intraduodenal administrations of pirsidomine did not attenuate the response whereas tolerance occurred with hemodynamically equieffective doses of IS-5-MN. In conscious dogs, long term oral treatment, three times daily every 8th h for 5 days, revealed tolerance to IS-5-MN, slight or no tolerance to pirsidomine, and no cross-tolerance between the two agents. The results indicate that pirsidomine possesses an antianginal hemodynamic profile similar to that of its main metabolite, M1, and of IS-5-MN. This suggests a common mode of action via the release of NO.(ABSTRACT TRUNCATED AT 250 WORDS)
Bohn
H
H
Department of Pharmacology, Cassella AG, Frankfurt/Main, Germany.
Martorana
P A
PA
Schönafinger
K
K
D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004361:Drug Tolerance; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006977:Hypertension, Renal / Q000503:physiopathology; D007275:Injections, Intravenous; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D013558:Sydnones / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D013558:Sydnones; D014665:Vasodilator Agents; D009569:Nitric Oxide; C073303:pirsidomine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate