Interactions of nitroglycerin and sulfhydryl-donating compounds in coronary microvessels.
Previous studies have shown the effect of nitroglycerin on coronary microvessels < 100 microns in diameter is markedly enhanced by L-cysteine. These studies were performed to examine the mechanisms responsible for this effect. Under control conditions, nitroglycerin caused potent dilations of large (> 200 microns diam) coronary microvessels while having minimal effects on small (< 100 microns diam) coronary microvessels [peak relaxations 85 +/- 4 vs. 23 +/- 3% (mean +/- SE) of endothelin-1-constricted vessels, respectively]. L-Cysteine (100 microM) and N-acetylcysteine (100 microM) markedly enhanced nitroglycerin-induced relaxations of small coronary microvessels (peak relaxation 84 +/- 6 and 87 +/- 12%, respectively) while having no effect on relaxations of vessels > 100 microns. In contrast, neither L-methionine (100 microM) nor glutathione (100 microM) enhanced nitroglycerin's vasodilation of small coronary microvessels. The effects of L-cysteine and N-acetylcysteine on the augmentation of nitroglycerin vasodilatation in smaller coronary microvessels was abolished in the presence of buthionine sulfoximine (100 microM), a potent inhibitor of intracellular glutathione synthesis. Buthionine sulfoximine had no effect on the vasodilatation produced by nitroprusside. These data demonstrate that, in smaller coronary microvessels, L-cysteine and N-acetylcysteine enhance nitroglycerin-induced vasodilatation by increasing intracellular glutathione concentrations. Intracellular glutathione, formed from either L-cysteine or N-acetylcysteine, may participate in the formation of an intermediate of nitroglycerin biotransformation or may maintain a redox potential within coronary microvessels that favors enzymatic bioconversion of nitroglycerin.
Wheatley
R M
RM
Department of Medicine, Emory University, Atlanta, Georgia 30322.
Dockery
S P
SP
Kurz
M A
MA
Sayegh
H S
HS
Harrison
D G
DG
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D002021:Buffers; D019328:Buthionine Sulfoximine; D003326:Coronary Circulation / Q000187:drug effects*; D003545:Cysteine / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D002021:Buffers; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D009569:Nitric Oxide; D019328:Buthionine Sulfoximine; D005996:Nitroglycerin; D005978:Glutathione; D003545:Cysteine; D010100:Oxygen