Abstract :
Hypertension is present in the majority of patients with chronic renal failure and is a major risk factor for the excessive mortality from heart attack and stroke. Although this hypertension has been thought to be largely volume dependent, recent evidence suggests that vasoconstrictor mechanisms also are involved. For example, we have provided microneurographic evidence for sympathetic overactivity in patients with chronic renal failure (Converse et al., N Engl J Med, 1992). There also is evidence for chronic inhibition of nitric oxide (NO) synthase due to accumulation of an endogenous NO synthase inhibitor (asymmetric dimethyl arginine) which is not cleared by the failing kidney. NO is not only the endogenous endothelium-derived relaxing factor but it also appears to be an important inhibitory neurotransmitter in the sympathetic nervous system, involved, at least in anesthetized animals, in the tonic inhibition of sympathetic outflow from the brainstem. We therefore are performing experiments in conscious rats and humans to test the hypothesis that inhibition of NO synthesis causes sustained sympathetic overactivity, which contributes to hypertension in chronic renal failure. Based on the data to be presented, the conclusions to date are as follows: First, in rats with normal renal function, there is an important sympathetic neural component to the sustained hypertension produced by chronic pharmacologic inhibition of NO synthase. Second, in normal humans, we have not found microneurographic evidence for a sympathetic neural component to the rapid elevation in blood pressure during acute pharmacologic inhibition of NO synthase (Hansen et al., Hypertension, 1994). Third, in patients with chronic renal failure, however, preliminary data indeed support the hypothesis that endogenous tonic inhibition of NO synthesis contributes to sympathetic overactivity.
