HEMODYNAMIC-EFFECTS OF SUBCHRONIC NO SYNT HASE INHIBITION IN CONSCIOUS DOGS - ROLE OF EDRF NO IN EXERCISE-INDUCED VASODILATION/

Acute and chronic administration of nitric oxide (NO) synthase (NOS) i nhibitors increase mean arterial blood pressure (MAP) in rats but thei r hemodynamic effects in other species remain unknown. Moreover, the r ole of NO in the control of exercise-induced vasodilation is still deb ated. To answer these questions, six dogs were instrumented for the co ntinuous measurement of cardiac output (GO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (K onigsberg gauge). Total peripheral resistance (TPR) was calculated as MAP/CO ratio and dP/dt was used as an index of cardiac inotropism. The dogs were treated from day 0 (D0) to 7 (D7) by the NOS inhibitor, No- nitro-L-arginine (L-NNA), 20 mg/kg/day (IV). Such a dose resimen resul ted in NOS inhibition evidenced (a) in vivo by a reduction of the hypo tensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acet ylcholine (EC 50 = 2.2 +/- 0.6 10(-7) M after L-NNA vs 2.2 +/- 0.8 10( -8) M in controls). One month after instrumentation, the dogs being co nscious, MAP measured at rest remained unchanged following one week L- NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, T PR increased (from 3 600 +/- 290 at DO to 6 300 +/- 510 dyn. s. cm(-5) at D7) and CO decreased (from 2.1 +/- 0.2 at DO to 1.2 +/- 0.1 1/min at D7) (all p < 0.01), partly as the result of a marked bradycardia (f rom 100 +/- 7 at DO to 60 +/- 7 beats/min at D7). L-NNA induced-increa se in TPR was completely reversed by a bolus injection of nitroglyceri n (10 mu g/kg). During treadmill exercise (12 km/h), heart rate (251 /- 9 at DO vs 226 +/- 11 beats/min at D7), CO (6.3 +/- 0.9 at D0 vs 4. 3 +/- 0.7 1/min at D7) and stroke volume remained significantly lower, and TPR significantly higher (1 662 +/- 278 at DO vs 2 621 +/- 489 dy n. s. cm(-5) at D7) after L-NNA than in the control state. Thus, NOS i nhibition in resting conscious dogs by L-NNA markedly increases periph eral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increas e in cardiac output, despite metabolic vasodilation.