Experiments were performed to evaluate the mechanism underlying our recent observation that reserpine but not surgical denervation up-regulates rat renal cortical beta adrenergic receptors. The specific binding of [125I]iodocyanopindolol was used to quantitate the beta adrenoceptors. Chronic high-dose guanethidine, which decreased renal tissue and circulating catecholamines to the same extent as reserpine, failed to up-regulate renal beta adrenoceptors, which indicates that the effect of reserpine was not due to changes in the ambient catecholamine concentration. Isoproterenol-stimulated renin secretion, a measure of postsynaptic receptor function, was increased by reserpine but not denervation, which indicates that the failure to observe beta adrenoceptor up-regulation by radioligand binding studies after denervation was not an anomaly caused by loss of presynaptic receptors masking postsynaptic supersensitivity. Reserpine was effective even in denervated kidneys. Up-regulation of renal beta adrenoceptors with reserpine occurred even after destruction of peripheral sympathetic nervous system by a combination of adrenal demedullation and high-dose guanethidine administration. A lower daily dose of reserpine (0.3 mg/kg instead of 0.5 mg/kg), which caused no weight loss, was effective in producing beta adrenoceptor up-regulation. Antagonism of reserpine depletion of nerve terminal norepinephrine by tranylcypromine, a monoamine oxidase inhibitor, did not nullify renal beta adrenoceptor up-regulation. Overall, our results indicate that reserpine up-regulation of renal beta adrenergic receptors is independent of the sympathetic nervous system and possibly is a direct effect.