Role of Nitric Oxide in the Development of Vascular α 1 -Adrenoreceptor Desensitization and Pressure Diuresis in Conscious Rats

Abstract

Abstract We evaluated whether a minor impairment of the l -arginine–nitric oxide pathway would affect the desensitization of vascular α-adrenoreceptor and pressure diuresis induced by prolonged intravenous infusion of phenylephrine (an α-adrenoreceptor agonist) in conscious Wistar-Kyoto rats. We examined dose-pressor–response curves to phenylephrine after an intravenous infusion of phenylephrine (2.5 μg·kg −1 ·min −1 ) or saline for 9 hours with and without concomitant infusion of N ω - l -arginine methyl ester (L-NAME) given to partially inhibit the l -arginine–nitric oxide pathway. In addition, to evaluate the effect of plasma volume loss on the pressor response to phenylephrine, we evaluated the dose-pressor–response curves to phenylephrine after intravenous injection of furosemide (5 mg/kg) or infusion of phenylephrine (5 μg·kg −1 ·min −1 ) for 9 hours. The renin-angiotensin, vasopressin and autonomic nervous systems were blocked before the examination of dose-pressor responses. Prolonged infusion of phenylephrine (2.5 μg·kg −1 ·min −1 ) shifted the dose pressor–response curve to this agent rightward, with significantly increased log ED 50 (the dose needed to reach 50% of the maximal response) to a similar extent in both L-NAME–treated (0.51±0.05 versus 0.93±0.07 μg/kg) and –untreated (0.79±0.06 versus 1.08±0.03 μg/kg) rats. The log ED 50 value after phenylephrine infusion (5 μg·kg −1 ·min −1 ) was significantly higher than that after furosemide injection (1.28±0.06 versus 1.02±0.01 μg/kg, respectively, P <.01), although the two treatments induced a similar loss of plasma volume. The slope in the linear relationship between the average change in mean arterial pressure during the 9-hour infusion period and the rate of urine excretion was significantly depressed in L-NAME–treated versus control rats (L-NAME: 0.057 mL·kg −1 ·h −1 ·mm Hg −1 , control: 0.146 mL·kg −1 ·h −1 ·mm Hg −1 , P <.05). In conclusion, a minor impairment of the l -arginine–nitric oxide pathway does not appear to interfere with the desensitization of vascular α-adrenoreceptor but does inhibit the pressure-diuresis response in conscious normotensive rats.