A blunting of the chronotropic and inotropic responses of the heart to beta-adrenergic stimulation occurs following chronic exposure to hypobaric hypoxia. To pursue the mechanism(s) involved, observations were made in six intact, conscious goats at sea level and in another six goats maintained in a decompression chamber at 445 Torr (approximately 4,300m) for 10 days (Pao2 = 43 Torr). No significant group differences in cardiac frequency and various indices of myocardial performance (peak dP/dt, time-to-peak dP/dt, Vmax) were demonstrable either before or after cholinergic blockade with intravenous atropine methyl bromide, 1 mg/kg. Following hemodynamic studies, thoracotomies were performed and full-thickness biopsies were obtained from the free wall of each of the cardiac chambers. Neither monoamine oxidase activity nor norepinephrine level of any region of the heart was altered by chronic hypoxia. However, a twofold increase (P less than 0.001) in catechol O-methyltransferase activity above sea-level values was found in both the atria and ventricles of the hypoxic animals. Thus, the attenuation in cardiac responsiveness to beta-adrenoceptor stimulation in chronic hypoxia appears unrelated to the level of vagal activity, but may be attributable to enhanced enzymatic inactivation of catecholamines.