Vasodilator mechanism of intermedin/adrenomedullin-2 in anesthetized rats

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, non-specific 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.