Angiotensin II–Nitric Oxide Interaction on Sympathetic Outflow in Conscious Rabbits

From the Department of Physiology and Biophysics, University of Nebraska College of Medicine, Omaha, Neb.

Correspondence to Irving H. Zucker, PhD, Department of Physiology and Biophysics, University of Nebraska College of Medicine, 600 S 42nd St, Omaha, NE 68198-4575. E-mail IZUCKER{at}MAIL.UNMC.EDU

Abstract—Increasing evidence suggests that endogenous NO inhibits sympathetic outflow in anesthetized animals. However, in a recent study from this laboratory, we were unable to find any evidence of increased renal sympathetic nerve activity (RSNA) in response to blockade of NO synthesis in conscious rabbits. Because angiotensin II (Ang II) increases sympathetic outflow, one factor for this discrepancy may be the difference in the resting level of Ang II, which may be lower in well-trained conscious animals. In the present study, the effects of blockade of NO synthesis with N-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg IV) on resting RSNA with and without a background intravenous infusion of Ang II (10 ng · kg^-1 · min^-1) was investigated in conscious rabbits. Intravenous administration of L-NAME (30 mg/kg) caused an increase in mean arterial blood pressure (MAP, from 80.4±2.9 to 92.8±2.5; P=.0001) and a decrease in RSNA (from 100±0% to 53.4±8.6%, P=.0016). When the elevated blood pressure was returned to control by infusion of hydralazine (0.01 to 0.06 mg · kg^-1 · min^-1), RSNA returned to the level before L-NAME administration. During a sustained infusion of Ang II (10 ng · kg^-1 · min^-1), L-NAME increased MAP from 89.2±2.9 to 109.0±4.3 mm Hg (P=.0101) and decreased RSNA from 100.0±0% to 53.7±7.5% (P=.0013). Under this circumstance, however, when the MAP was returned to the level that existed before the administration of L-NAME, RSNA increased significantly above the level that existed before the administration of L-NAME (164.5±17.7% versus 100±0%, P=.0151). The enhancement of the sympathetic response by Ang II was completely blocked by the AT₁ receptor antagonist, losartan. In contrast, during a background infusion of phenylephrine, which increased MAP to the same level as produced by Ang II, L-NAME had no effect on RSNA when MAP was returned to the control level. N-Nitro-D-arginine methyl ester had no effect on MAP and RSNA. Intravenous infusion of Ang II alone for 75 minutes had no effect on RSNA when MAP was returned to control levels. These data suggest that an elevated level of Ang II is critical for the inhibitory effect of NO on sympathetic outflow in conscious rabbits and imply that these two substances have a major impact on the regulation of sympathetic outflow.

Key Words: renal nerve activity • arterial pressure • N-nitro-L-arginine methyl ester

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