This study examined the dose-response effects of caffeine on plasma K+ balance during prolonged exercise. Two series of experiments were performed. In series A, 1 h after ingestion of 9 mg/kg dextrose (placebo) or 9 mg/kg caffeine, eight subjects cycled at 78% of peak O2 consumption until exhaustion; in series B, in four trials, 1 h after ingestion of 0, 3, 6, or 9 mg/kg caffeine, eight subjects ran on a treadmill at 85% of peak O2 consumption until exhaustion. Blood was sampled from an antecubital vein for analysis of hematocrit, plasma concentrations of epinephrine ([Epi]) and norepinephrine, and [K+]. The change in plasma volume was calculated from hematocrit. During exercise, there was a net addition of K+ to and a net loss of fluid from the plasma compartment. Caffeine had no effect on plasma volume and norepinephrine concentration during exercise. In series A and B 9 mg/kg caffeine and in series B 6 mg/kg caffeine resulted in a significant attenuation of the increase in plasma [K+] with exercise. In series A increases in plasma [Epi] were 1.4- to 2-fold greater during exercise with caffeine than with placebo. At exhaustion, plasma [Epi] was twofold higher with caffeine (10.1 +/- 2.3 nM) than with placebo (5.3 +/- 0.8 nM), whereas plasma [K+] was only 4.88 +/- 0.18 meq/l with caffeine compared with 5.37 +/- 0.14 meq/l with placebo. It is concluded that caffeine attenuates the increase in plasma [K+] during exercise by stimulation (via one of its metabolites or by increased [Epi]) of tissue Na-K pump activity.(ABSTRACT TRUNCATED AT 250 WORDS)