Although beta blockers' antihypertensive mechanisms have not been clearly delineated, their long-term effects may involve chronic reduction in systemic vascular resistance, which may be the result of sympathetic outflow inhibition. Although a central site of action has been advocated, we sought to identify a peripheral non-cardiac sympatholytic mechanism by studying autonomic function in a small group of nine hypertensive males during treatment with placebo and chronic oral nadolol, a noncardioselective hydrophilic beta blocker with little predicted brain penetration. Nadolol reduced blood pressure and heart rate (both P less than 0.005) while suppressing the blood pressure response to cold stimulus only after parasympathetic inhibition (P less than 0.05); the blunted response to cold stimulus did not correlate with the drug's overall blood pressure lowering effect. Baroreceptor sensitivities to phenylephrine and amyl nitrate stimuli were not enhanced. Several biochemical measures of sympathetic nervous system activity were not influenced by nadolol. Thus, nadolol, while not enhancing baroreflex sensitivity, does seem to have a peripheral non-cardiac sympatholytic effect, but this effect does not account entirely for the long term reduction in blood pressure observed in patients on the drug.