A NEWLY IDENTIFIED PEPTIDE, PROADRENOMEDULLIN N-TERMINAL-20 PEPTIDE, INDUCES HYPOTENSIVE ACTION VIA PERTUSSIS-TOXIN-SENSITIVE MECHANISMS

Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) are novel hypotensive peptides. Although they are derived from the sa me gene product, proadrenomedullin, their hypotensive mechanisms are d ifferent; PAMP inhibits the release of norepinephrine from the periphe ral sympathetic nerve endings, whereas AM fosters vasodilation by elev ating intracellular cAMP, possibly via activation of cholera toxin-sen sitive G proteins. In PC12 cells, PAMP inhibited N-type calcium channe l via activation of pertussis toxin-sensitive mechanisms. To clarify t he relationship between the hypotensive effect of PAMP and pertussis t oxin-sensitive mechanisms, we administered pertussis vaccine intraperi toneally into rats for 3 consecutive days. By using mesenteric artery preparation, we showed that PAMP's ability to decrease norepinephrine overflow was significantly attenuated in pertussis toxin-treated rat ( -18.5+/-6.9%; P<.05 versus control rats). In electrically stimulated p ithed rat, PAMP (20 and 40 nmol/kg) showed a hypotensive effect (-13+/ -5 and -18+/-7 mm Hg, respectively; P<.05, P<.01), whereas in per tuss is vaccine-treated rat it did not (-2+/-3 and -8+/-9 mm Hg, respective ly; P=NS). Also, in pithed rat, plasma norepinephrine level was signif icantly elevated by electrical stimulation in both control (0.323+/-0. 035 ng/mL) and pertussis vaccine-treated groups (0.355+/-0.079 ng/mL). After injection of PAMP (40 nmol/kg), plasma norepinephrine level sig nificantly decreased in the control group (0.225+/-0.044 ng/mL; P<.01) but not in the pertussis vaccine-treated group (0.392+/-0.021 ng/mL; P=NS). Moreover, in conscious rats, intravenous administration of PAMP (40 nmol/kg) did not evoke hypotension after pertussis vaccine treatm ent, although untreated controls had significantly decreased arterial pressure (-5+/-2 versus -20+/-3 mm Hg; P<.01). In contrast to PAMP, th e administration of AM (1 nmol/kg) significantly reduced the blood pre ssure of pertussis vaccine-treated as well as control rats (-20+/-5 ve rsus -18+/-7 mm Hg; P=NS). These results demonstrate that the ability of PAMP to inhibit norepinephrine release from peripheral sympathetic nerve endings and to decrease blood pressure is pertussis toxin sensit ive. Our findings thus suggest that despite being derived from the sam e gene, PAMP and AM apparently produce hypotension by activating diffe rent signaling pathways.