Effect of ethacrynic acid, a glutathione-S-transferase inhibitor, on nitroglycerin-mediated cGMP elevation and vasorelaxation of rabbit aortic strips.
The effects of ethacrynic acid (ECA), an inhibitor of glutathione-S-transferase, on both the pharmacologic and biochemical responses of aortic tissue to nitroglycerin (GTN) were evaluated. Using the rabbit aortic strip model, relaxation responses to 0.6 microM GTN were measured with and without ECA (0.2 mM) pretreatment. These same strips were frozen, and the concentrations of cGMP in the strips were measured using a 3H-labeled radioimmunoassay. Both the relaxation response and the increase in cGMP upon GTN treatment were reduced significantly by pretreatment of the strips with ECA. A correlation was observed between the decreases in the pharmacodynamic and biochemical responses upon ECA pretreatment. cGMP levels in strips treated with sodium nitroprusside, which generates nitric oxide by mechanisms distinct from that for organic nitrates, were not decreased by ECA pretreatment. These observations suggest that the mechanism of GTN action involves a glutathione-S-transferase-mediated metabolic step for GTN and that the isozyme(s) involved in this activation process may be inhibited by ECA.
Kenkare
S R
SR
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143-0446.
Benet
L Z
LZ
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004976:Ethacrynic Acid / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D011817:Rabbits; D014316:Tritium; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D014316:Tritium; D009599:Nitroprusside; D005982:Glutathione Transferase; D005996:Nitroglycerin; D006152:Cyclic GMP; D004976:Ethacrynic Acid