CARDIOVASCULAR EFFECTS OF THE NEW NITRIC-OXIDE DONOR, PIRSIDOMINE - HEMODYNAMIC PROFILE AND TOLERANCE STUDIES IN ANESTHETIZED AND CONSCIOUS DOGS

被引:20
作者
BOHN, H [1 ]
MARTORANA, PA [1 ]
SCHONAFINGER, K [1 ]
机构
[1] CASSELLA AG,DEPT MED CHEM,W-6000 FRANKFURT 61,GERMANY
关键词
PIRSIDOMINE; IS-5-MN (ISOSORBIDE-5-MONONITRATE); HEMODYNAMICS; TOLERANCE; (DOG);
D O I
10.1016/0014-2999(92)90013-T
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 pirisidomine, 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. Furthermore, the results of the tolerance studies are consistent with the hypothesis of a different mechanism for the release of NO with the sydnonimines and the organic nitrates.
引用
收藏
页码:71 / 78
页数:8
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