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

Acute and chronic administration of nitric oxide (NO) synthase (NOS) inhibitors increase mean arterial blood pressure (MAP) in rats but their hemodynamic effects in other species remain unknown. Moreover, the role of NO in the control of exercise-induced vasodilation is still debated. To answer these questions, six dogs were instrumented for the continuous measurement of cardiac output (GO, electromagnetic flow probe on the aorta), MAP (aortic catheter) and left ventricular pressure (Konigsberg 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 resulted in NOS inhibition evidenced (a) in vivo by a reduction of the hypotensive responses to graded doses of acetylcholine and bradykinin, (b) ex vivo by a decrease in the relaxation of the femoral artery to acetylcholine (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 conscious, MAP measured at rest remained unchanged following one week L-NNA treatment (from 90 +/- 2 at D0 to 91 +/- 5 mmHg at D7). However, TPR 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 (from 100 +/- 7 at DO to 60 +/- 7 beats/min at D7). L-NNA induced-increase in TPR was completely reversed by a bolus injection of nitroglycerin (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 dyn. s. cm(-5) at D7) after L-NNA than in the control state. Thus, NOS inhibition in resting conscious dogs by L-NNA markedly increases peripheral resistance but does not increase arterial pressure. In addition, L-NNA blunts both exercise-induced peripheral vasodilation and increase in cardiac output, despite metabolic vasodilation.