HEMODYNAMIC-EFFECTS OF NG-MONOMETHYL-L-ARGININE AND NG-NITRO-L-ARGININE METHYL-ESTER IN CONSCIOUS, UNRESTRAINED RATS

Male, Long Evans and homozygous Brattleboro rats were chronically instrumented with pulsed Doppler probes (to monitor regional blood flows) or electromagnetic flow probes (to monitor cardiac output) and intravascular catheters. In conscious, unrestrained, Long Evans rats, hemodynamic responses to intravenous (i.v.) bolus doses of N(G)-monomethyl-L-arginine (L-NMMA, 0.3-300 mg/kg) and N(G)-nitro-L-arginine methyl ester (L-NAME, 0.1-10 mg/kg) were assessed. Both compounds (ed dose-dependent hypertension, but the increase in mean arterial blood pressure was more rapid and the bradycardia more marked with L-NMMA than with L-NAME (although the latter did not affect cardiac baroreflex sensitivity). L-NMMA and L-NAME caused marked renal, mesenteric, and hindquarters vasoconstriction, particularly at the higher doses, but the profiles of change in vascular conductances following L-NMMA and L-NAME were different, possibly due to pharmacokinetic factors (L-NAME has to be converted to its active form by an esterase). L-arginine opposed the effects of L-NMMA and L-NAME. The hypertension induced by L-NAME was associated with marked reductions in cardiac index, stroke index, peak aortic flow (F), + dF/dt(max), and total peripheral conductance. These changes must have buffered the pressor effects of L-NAME, and could have been secondary to the increase in afterload. Brattleboro rats responded to i.V. L-NMMA and L-NAME in a similar way to Long Evans rats. Brattleboro rats provided with drinking water containing L-NMMA (I mg/ml) or L-NAME (0.1 mg/ml) developed hypertension but no bradycardia; the hypertension was associated with a particularly marked hindquarters vasoconstriction. In Long Evans rats treated with L-NAME, the hypotensive responses to glyceryl trinitrate, acetylcholine, and endothelin-1 were enhanced, and in some animals the hypotensive effect of bradykinin was also increased. In the presence of L-NAME, increases in regional blood flow still occurred in response to acetylcholine, bradykinin, and endothelin-1. Collectively, these results are consistent with a substantial, nitric oxide (NO)-mediated vasodilator tone in regional vascular beds in vivo. However, inhibition of this tone does not give a quantitative estimate of its importance because the pressor effect due to the fall in total peripheral conductance is opposed by a marked reduction in cardiac function. Under conditions in which NO-mediated vascular tone is substantially reduced, agonists such as acetylcholine, bradykinin, and endothelin-1 can still cause pronounced vasodilatations.