Brain neurons that express the pro-opiomelanocortin gene secrete multiple forms of beta-endorphin (beta E) which subserve diverse bioregulatory processes. beta E-1-31, for example, is a potent analgetic but beta E-1-27 acts as an opioid antagonist and beta E-1-26, as well as the N-acetyl derivatives of all 3 peptides, lack opioid receptor activity. The present study examines the effects of beta-endorphin processing on its central cardioregulatory potency. Consistent with previous reports, intracisternal beta E-1-31 (1.5 nmol) injection lowered mean arterial pressure (MAP); MAP was reduced by 29.7 +/- 3.9 mm Hg at 60 min and returned toward baseline by 120 min. Unexpectedly, beta E-1-27 displayed a 10-fold greater hypotensive potency than beta E-1-31. At 0.15 nmol, it produced a response equivalent to 1.5 nmol beta E-1-31 while 1.5 nmol beta E-1-27 sustained a maximal reduction in MAP (49.2 +/- 3.9 mm Hg) throughout the 120-min test period. In contrast, beta E-1-26 and N-acetyl-beta E-1-26, -1-27 and -1-31 were inactive at 1.5 nmol. Bradycardia accompanied the depressor response to the higher beta E-1-27 dose but not to beta E-1-31. Naloxone pretreatment completely blocked the depressor effects of both beta E-1-31 and beta E-1-27, and reversed the bradycardia produced by beta E-1-27, suggesting that both peptides act through opioid receptors. beta E-1-27 also stimulated catecholamine release from the perfused adrenal gland but beta E-1-31 was inactive. These findings emphasize the importance of regionally selected post-translational processing in defining the functional specificity of beta E peptides.