Vasodilator mechanism of intermedin/adrenomedullin-2 in anesthetized rats.

Abstract

We examined whether the vasodepressor effect of intermedin/adrenomedullin-2, a new member of the calcitonin gene-related peptide family, acted via activation of the nitric oxide/L-arginine pathway, the prostanoid pathway, or the opening of K+ channels. Intermedin/adrenomedullin-2 (0.3-30 nmol/kg) dose-dependently decreased mean arterial pressure (ED50 of 2.3 +/- 0.69 nmol/kg) and increased heart rate in anesthetized rats. The depressor effect of intermedin/adrenomedullin-2 (3 nmol/kg, ED70 dose) was unaffected by pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthase, 50 mg/kg i.v.), indomethacin (cyclooxygenase inhibitor, 10 mg/kg i.v.), tetraethylammonium (TEA, nonspecific K(+)-channel blocker; 60 mg/kg i.v.) or the respective vehicle. Pretreatment with mecamylamine (ganglionic blocker, 10 mg/kg i.v.) augmented the depressor response and abolished the tachycardic effect of intermedin/adrenomedullin-2 (3 nmol/kg). Therefore, the depressor effect of intermedin/adrenomedullin-2 is not mediated via the nitric oxide/L-arginine pathway, production of prostanoids or opening of TEA-sensitive K+ channels, but is opposed by activity of the sympathetic nervous system. Its tachycardic effect is mediated via the baroreflex mechanism.