Sympathetic mechanisms play an important role in the acute regulation of renin release in humans. On the other hand, the effect of chronic sympathetic deprivation on the renin-aldosterone system has not been fully evaluated. We, therefore, studied 24 patients with severe autonomic failure due to pure autonomic failure (n = 14) or to multiple system atrophy (n = 10). Supine plasma renin activity (PRA) was low (0.09 +/- 0.01 ng/(L*s)) and remained virtually unchanged in the upright posture (0.10 +/- 0.01 ng/(L*s)) despite profound orthostatic hypotension to levels that should activate renal baroreceptors. Isoproterenol, at doses that produced significant tachycardia and hypotension, also failed to stimulate PRA. Furthermore, renin-producing cells were absent in the kidneys of two autopsy cases. Norepinephrine depletion alone could not explain these findings because no correlation was found between plasma norepinephrine and PRA, and because PRA was normal in patients with intact sympathetic innervation but congenital absence of norepinephrine. In contrast, supine and upright plasma aldosterone were normal in autonomic failure patients (220 +/- 20 and 440 +/- 70 pmol/L). We speculate that direct sympathetic innervation is essential for the maintenance of renin, perhaps by providing trophic stimuli.