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We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129 +/- 25/78 +/- 12 (mean +/- S.D.) to a maximum of 141 +/- 30/84 +/- 16 mm Hg at 45 minutes (P less than 0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133 +/- 32/80 +/- 15 to a minimum of 105 +/- 21/62 +/- 12 mm Hg at 60 minutes (P less than 0.01). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140 +/- 33/79 +/- 7 to 129 +/- 31/69 +/- 13 mm Hg at 60 minutes (P less than 0.05 vs. values after the control per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P less than 0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin-angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state.