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  • Title: Lack of tolerance to a 24-hour infusion of S-nitroso N-acetylpenicillamine (SNAP) in conscious rabbits.
    Author: Shaffer JE, Han BJ, Chern WH, Lee FW.
    Journal: J Pharmacol Exp Ther; 1992 Jan; 260(1):286-93. PubMed ID: 1731043.
    Abstract:
    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)
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