NO CROSS-TOLERANCE BETWEEN S-NITROSOCAPTOPRIL AND NITROGLYCERIN IN DOG CORONARY-ARTERIES IN-VIVO

S-Nitrosocaptopril (S-NO-Cap), a nitrate and an angiotensin-converting enzyme (ACE) inhibitor, may be produced after coadministration of nit roglycerin (NTG) and captopril (CAP). We synthesized S-NO-Cap and inve stigated its in vivo tolerance. In open-chest dogs, S-NO-Cap [300 mu g ; intracoronary (i.c.)] and NTG (50 mu g, i.c.) increased coronary blo od flow (CBF) similarly (8.0 vs. 9.0 ml/min; p = NS; n = 5). After a 2 -h i.c. NTG infusion at high dose (1.32 mu mol/min), NTG (50 mu g, i.c .) had no significant effect on CBF, whereas S-NO-Cap (300 mu g, i.c.) still produced an attenuated increase in CBF (4.9 ml/min; p < 0.05 vs . control). On the other hand, after a 2-h i.c. infusion of S-NO-Cap ( 1.32 mu mol/min), the CBF response to S-NO-Cap (300 mu g) showed no at tenuation, whereas that to NTG (50 mu g) was potentiated (8.8 vs. 12.6 ml/min; p < 0.05; n = 6). Under basal conditions, S-NO-Cap (30-300 mu g, i.c.) increased CBF dose dependently, whereas CAP (30-300 mu g, i. c.) had no effect on CBF, suggesting that S-NO-Cap dilates coronary ve ssels by a nitrate action but not by an ACE-inhibitory action. In nons urgical dogs, 2-h intravenous (i.v.) infusion of S-NO-Cap (1.32 mu mol /min) had a stable hypotensive effect, whereas that of NTG (1.32 mu mo l/min) gradually attenuated the effect. Plasma NO3-, an oxidative prod uct of nitric oxide (NO), increased after both infusions, suggesting t hat S-NO-Cap may act partially as an NO donor, similarly to NTG. Plasm a ACE activity was reduced after an S-NO-Cap infusion (5.84 vs. 4.10 I U/L; p < 0.01; n = 5), and plasma aldosterone was markedly increased a fter NTG infusion relative to that after S-NO-Cap infusion (243.0 vs. 38.6 pg/ml; p < 0.05). Plasma norepinephrine increased after both infu sions (393.6 vs. 289.0 pg/ml; p = NS). As judged by the increase in CB F, whereas S-NO-Cap showed partial tolerance with NTG, no tolerance wa s found with S-NO-Cap itself. The in vivo coronary vascular response t o S-NO-Cap may, therefore, be partially reduced by activation of the a drenergic or renin-angiotensin-aldosterone systems or both induced by NTG, because S-NO-Cap showed no cross-tolerance with NTG in our earlie r in vitro study.