Lack of cross-tolerance between nitroglycerin and endothelium-derived relaxing factor-mediated vasoactive agents in spontaneously hypertensive rats.
The purpose of this study was to determine whether cross-tolerance develops between nitroglycerin and endothelium-derived relaxing factor (EDRF)-mediated vasoactive agents in vivo. Spontaneously hypertensive rats (SHR) were made tolerant by pretreatment with high doses of nitroglycerin (100 mg/kg s.c., 3 times/day, for 3 consecutive days). The hypotensive effect of challenge doses of nitroglycerin (1, 10, 300, 100 micrograms/kg i.v.) was completely abolished in nitroglycerin-pretreated SHR. To evaluate cross-tolerance, the effects of the following EDRF-dependent vasoactive agents on blood pressure were determined in groups of nitroglycerin-pretreated and vehicle-pretreated SHR: acetylcholine, bradykinin and L-arginine. In addition, the hypotensive effects of zaprinast (M & B 22,928), a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, and the hypertensive effects of the nitric oxide-synthase inhibitor N omega-nitro-L-arginine were also evaluated. In all cases, there was no difference in the effects of these agents on blood pressure when compared in nitroglycerin-pretreated (tolerant) and vehicle-pretreated (non-tolerant) SHR. The use of a variety of agents which modulate EDRF release or its effects by several different mechanisms suggests that cross-tolerance does not occur between nitroglycerin and EDRF in vivo.
Department of Cardiovascular Pharmacology, Sterling Winthrop Pharmaceuticals Research Division, Rensselaer, NY 12144.
L
L
De Garavilla
M L
ML
Volberg
P F
PF
Pratt
P J
PJ
Silver
R A
RA
Buchholz
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000494:pharmacology; D004361:Drug Tolerance; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine; D005996:Nitroglycerin / Q000494:pharmacology*; D011688:Purinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D014665:Vasodilator Agents / Q000494:pharmacology*
D011688:Purinones; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D005996:Nitroglycerin; C011145:zaprinast; D000109:Acetylcholine; D001920:Bradykinin