PROADRENOMEDULLIN NH2-TERMINAL 20-PEPTIDE, A NEW PRODUCT OF THE ADRENOMEDULLIN GENE, INHIBITS NOREPINEPHRINE OVERFLOW FROM NERVE-ENDINGS

Proadrenomedullin NH2-terminal 20 peptide (PAMP) and adrenomedullin, which are derived from proadrenomedullin, exhibit remarkable hypotensive action, We investigated the effect of PAMP and adrenomedullin on peripheral sympathetic neural transmission, Using perfused rat mesenteric arteries, PAMP (0, 1, 5, and 10 pmol/ml) decreased norepinephrine overflow by periarterial electrical nerve stimulation in a dose-dependent fashion (0.244+/-0.043, 0.231+/-0.048, 0.195+/-0.061, and 0.168+/-0.051 ng/gram tissue weight: NS, P < 0.05, and P < 0.02, respectively), In contrast to PAMP, adrenomedullin (1, 5,and 10 pmol/ml) did not change it, In contrast, vasoconstrictive response of mesenteric arteries to exogenous norepinephrine was significantly attenuated by 10 pmol/ml of adrenomedullin but not by the same dose of PAMP, Calcitonin gene-related peptide (8-37) [CGRP(8-37)], a CGRP receptor antagonist, inhibited the vasodilatory effect of adrenomedullin but could not suppress the sympathoinhibitory effect of PAMP. Neither a nicotinic antagonist, hexamethonium, nor a presynaptic alpha(2) antagonist, yohimbine, blocked the sympathoinhibitory effect of PAMP. Thus, it suggests that PAMP and adrenomedullin, which are derived from the same gene, exhibit different hypotensive mechanisms: PAMP inhibits neural transmission at peripheral sympathetic nerve ending, although adrenomedullin directly dilates vascular smooth muscle, possibly through CGRP-like receptor.