Influence of endothelium in dose-dependent inhibition and potentiation by isoniazid of isosorbide dinitrate relaxation of rat aorta.
The influence of in vivo administration of isoniazid on the relaxant effect of isosorbide dinitrate was determined by pretreating rats with various doses of isoniazid and obtaining concentration-response curves to isosorbide dinitrate in aortic rings from these animals. In rings with endothelium, isoniazid potentiated responses to isosorbide dinitrate at doses of 10, 30, and 100 mg/kg; 3 and 300 mg/kg were without effect. In endothelium-denuded preparations, potentiation was present only at 10 mg/kg; 3 and 300 mg/kg inhibited relaxation. Other experiments indicated that isoniazid potentiation was prevented by pyridoxine, was reproduced with theophylline, and did not occur with 3-morpholinosydnonimine or papaverine. These results were deemed compatible with the hypothesis that isoniazid inhibits transsulfuration of homocysteine and causes its accumulation in vascular smooth muscle and endothelial cells, where it functions as a thiol intermediate and leads to enhanced bioactivation of isosorbide dinitrate. Potentiation appeared to occur only with moderate increases of homocysteine.
Vidrio
H
H
Department of Pharmacology, School of Medicine, National Autonomous University of Mexico, Mexico City. vidrio@servidor.unam.mx
Fernández
G
G
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D007538:Isoniazid / Q000494:pharmacology*; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*
D000995:Antitubercular Agents; D014665:Vasodilator Agents; C002385:linsidomine; D008981:Molsidomine; D010208:Papaverine; D007548:Isosorbide Dinitrate; D007538:Isoniazid