Lack of tolerance to a 24-hour infusion of S-nitroso N-acetylpenicillamine (SNAP) in conscious rabbits.
In order to design a means to preclude the development of nitrate tolerance, an in vivo model of nitroglycerin (GTN) tolerance was developed in the rabbit to examine the tolerance potential of S-nitroso vasodilators. Three separate studies were performed with 54 male New Zealand white rabbits which were instrumented for chronic infusion of vehicle or of either S-nitroso N-acetylpenicillamine (SNAP) or GTN (n = 6/group). Each vasodilator was infused for 24 hr at a dose rate of 60 nmol/kg/min. Three and 24 hr after the end of the infusion, each rabbit was anesthetized with pentobarbital and instrumented to monitor blood pressure, and dose-response curves were performed using SNAP or GTN. The dose-response curves were analyzed to determine the degree of displacement of the treated rabbit's dose-response curves compared to that of the vehicle-treated rabbit. Relative to the vehicle group, the GTN dose-response curve for systolic blood pressure in the GTN-infused rabbits was dextrally shifted 25.0-fold (P less than .05); 24 hr later the dextral shift was 0.9. The corresponding shifts in the SNAP dose-response curves were 2.7- and 0.5-fold, respectively. When SNAP was infused for 24 hr, the corresponding 3- and 24-hr dextral shifts for GTN were: 7.8- (P less than .05) and 0.7-fold; for SNAP they were: 1.9- and 0.6-fold. In a third study, N-acetylcysteine was coinfused (0.14 mg/kg/min, 200 mg/kg cumulative dose) with GTN over 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Shaffer
J E
JE
Glaxo Inc. Research Institute, Research Triangle Park, North Carolina.
Han
B J
BJ
Chern
W H
WH
Lee
F W
FW
D000109:Acetylcholine / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004903:Erythrocyte Aggregation / Q000187:drug effects; D006400:Hematocrit; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D009599:Nitroprusside; D026423:S-Nitroso-N-Acetylpenicillamine; D005996:Nitroglycerin; D010396:Penicillamine; D000109:Acetylcholine; D000111:Acetylcysteine