Sympathectomy attenuates chronic, but not acute, hypertension caused by nitric oxide inhibition.

Pharmacologic inhibitors of nitric oxide (NO) such as nitro-L-arginine-methyl-ester (L-NAME) have been firmly established to cause acute and chronic hypertension in many animal species, but the underlying mechanisms are incompletely understood. Previous studies from several laboratories, including ours, have led to seemingly contradictory conclusions as to whether sympathetic activation resulting from inhibition of neuronally-produced NO contributes to L-NAME-induced hypertension This neurogenic hypothesis was not supported during acute (<1 hr) pharmacologic inhibition of NO in humans (Hansen et al, Hypertension, 1994) but was strongly supported during chronic (1 week) inhibition of NO in rats (Sander et al, Hypertension, 1995). To determine if the different conclusions are due to acute vs. chronic inhibition of NO, we compared effects of guanethidine-induced sympathectomy on acute vs. chronic L-NAME induced hypertension in conscious unrestrained rats. Acute L-NAME (5 mg/kg i.v. bolus) caused MAP to increase similarly in control rats (n=10) vs. rats with sympathectomy (n=8): +43 ± 3 vs. +51 ± 4 mmHg (p=ns). In contrast, in the same rats chronic L-NAME (50 mg/kg/day i.v. for 7 days with osmotic pumps) caused MAP to increase twice as much in control rats (n=6) vs. rats with sympathectomy (n=7): +57 ± 6 vs. +28 ± 4 mmHg (p<0.01). To further clarify the time-course of the sympathectomy-sensitive component of L-NAME-induced hypertension, we then measured MAP continuously during 8 hrs of L-NAME (2.1 mg/kg/hr i.v.). During the first 30 min of L-NAME, MAP increased similarly in control rats (n=8) vs. rats with sympathectomy (n=7): +30 ± 4 vs. +25 ± 6 mmHg (p=ns). Between the 1st-8th hr of L-NAME, however, MAP increased further only in control rats: control rats vs. rats with sympathectomy (8 hrs): +47 ±5 vs. +26 ± 8 mmHg (p<0.01). We conclude that, in the rat, the full expression of chronic, but not acute, L-NAME-induced hypertension is dependent upon an intact sympathetic nervous system. This delayed onset of the sympathetic component may account for much of the conflicting data in the literature. We now plan to determine whether these results can be extrapolated to humans.