Persistence of the Response to SIN1 on Isolated Coronary Arteries Rendered Tolerant to Nitroglycerin In Vitro or In Vivo

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Abstract
Experiments were performed on isolated canine and human coronary arteries to provide more insight into the mechanisms responsible for the vascular tolerance to nitroglycerin that is induced under in vitro or in vivo conditions. It vitro tolerance was produced after an incubation of coronary ring segments with nitroglycerin (10 .mu.M for 30 min at physiological pH). After elevation of tone with KCl (15 mM), dose-response curves were constructed for nitroglyferin or SIN1 (3-morpholino-syndnonimin) on control and tolerant rings. On canine tolerant rings the dose-response curve for nitroglycerin-induced relaxations was significant (p < 0.001) shifted to the right, and 50% of the maximal relaxation (ED50) increased from 55 .+-. 9 nM to 1.2 .+-. 0.2 .mu.M. Pretreatment of tolerant rings with N-acetylcysteine (NAC, 10 .mu.M 10 min before KCl-induced contraction) partially restored the responsiveness to nitroglycerin, with ED50 reducing to 0.56 .+-. 0.03 .mu.M (p < 0.02). On the other hand, the dose-response curves to SIN1 were not significantly altered. Similar results were obtained on human preparations. On isolated canine coronary rings rendered tolerant in vivo by subcutaneous injections of 15 mg/kg nitroglycerin (two times daily for 4 consecutive days), ED50 for nitroglycerin was 0.67 .+-. 0.08 .mu.M (p < 0.001 versus control rings), and NAC again partially restored the responsiveness to nitroglycerin. As for the in vitro tolerance, the relaxations to SIN1 were not significantly altered on these canine rings rendered nitrate tolerant in vivo. The present results show that the responsiveness to SIN1 is not modified on nitrate tolerant rings and that the mechanisms responsible for nitrate tolerance are similar under both in vivo and in vitro conditions.