Reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril: a role of calcitonin gene-related peptide.
Previous studies have shown that the development of tolerance to nitroglycerin is related to a decrease in the release of endogenous calcitonin gene-related peptide (CGRP). In the present study, we explored whether endogenous CGRP is involved in reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril in rats in vivo and vitro. Tolerance was induced by exposure to nitroglycerin (4.4 x 10(-6) M) for 10 min in vitro or by pretreatment with nitroglycerin (10 mg/kg, s.c.) three times a day for 8 days in vivo. Nitroglycerin (3 x 10(-9)-10(-6) M) caused a concentration-dependent relaxation in the isolated rat thoracic aorta, an effect that was reduced by CGRP-(8-37) (3 x 10(-7) M) or capsaicin (3 x 10(-7) M). Preincubation with nitroglycerin for 10 min significantly decreased its vasodilation, which was restored in the presence of N-acetylcysteine (10(-5) M) or captopril (10(-5) M). Nitroglycerin (150 microg/kg, i.v.) produced a depressor effect and an increase in concentrations of nitric oxide and CGRP, and the effects of nitroglycerin disappeared after pretreatment with nitroglycerin for 8 days. However, tolerance to nitroglycerin in vivo also was partially restored in the presence of N-acetylcysteine or captopril. The present results suggest that reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril is related to the increased release of CGRP in the rat.
Zhou
Zhi-Hong
ZH
Department of Pharmacology, Xiang-Ya Medical College, Central South University, Changsha, Hunan 410078, PR China.
Jiang
Jun-lin
JL
Peng
Jun
J
Deng
Han-Wu
HW
Li
Yuan-Jian
YJ
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
D009569:Nitric Oxide; D002216:Captopril; D005996:Nitroglycerin; D015740:Calcitonin Gene-Related Peptide; D000111:Acetylcysteine