To address the autonomic mechanisms underlying the bradycardia of physical training in human subjects, we performed a cross-sectional study comparing the heart-rate responses to graded doses of isoproterenol in 7 elite marathon runners and 7 age-matched controls, and a longitudinal study in 12 normal volunteers of the effects of 6 wk of intense physical training on lymphocyte beta-adrenergic receptors identified by l-[3H]dihydroalprenolol. We observed no significant differences between marathoners and controls in the dose of isoproterenol that produced a 25-beat/min increment in heart rate, either in the absence (1.9 +/- 0.6 vs. 2.5 +/- 0.6 microgram; P, 0.509) or in the presence of cholinergic blockade (4.4 +/- 1.3 vs. 3.1 +/- 0.4 microgram: P, 0.320). Likewise, we observed no effects of physical training on lymphocyte beta-adrenergic receptors in terms of receptors number (53 +/- 11 vs. 56 +/- 10 fmol/mg protein) or receptor affinity (Kd 4.0 +/- 0.7 vs. 3.6 +/- 0.7 nM) (P, 0.9178). Although our data cannot exclude reduced chronotropic sensitivity to catecholamines as contributing to lowered heart rate in some highly conditioned individuals, these results are consistent with the hypothesis that altered neuronal input to the sinus node is usually a more important mechanism of training bradycardia.