Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat

Abstract

Abstract —We previously reported that adrenomedullin (AM), a potent vasodilator peptide discovered in pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat kidney. To further investigate whether the NO-cGMP pathway is involved in the mechanisms of AM-induced vasodilation, we examined the effects of E-4021, a cGMP-specific phosphodiesterase inhibitor, on AM-induced vasorelaxation in aortic rings and perfused kidneys isolated from Wistar rats. We also measured NO release from the kidneys using a chemiluminescence assay. AM (10 ⁻¹⁰ to 10 ⁻⁷ mol/L) relaxed the aorta precontracted with phenylephrine in a dose-dependent manner. Denudation of endothelium (E) attenuated the vasodilatory action of AM (10 ⁻⁷ mol/L AM: intact (E+) −25.7±5.2% versus denuded (E−) −7.8±0.6%, P −8 mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (−49.0±7.9%, P −7 mol/L ACh −36.6±8.4% versus 10 ⁻⁸ mol/L E-4021+10 ⁻⁷ mol/L ACh −62.7±3.1%, P −9 mol/L AM −15.4±0.6% versus 10 ⁻⁸ mol/L E-4021+10 ⁻⁹ mol/L AM −23.6±1.2%, P –1 · g ^–1 kidney at 10 ⁻⁹ mol/L AM), which was not affected by E-4021. E-4021 enhanced ACh-induced vasorelaxation (10 ⁻⁹ mol/L ACh −9.7±1.7% versus 10 ⁻⁸ mol/L E-4021+10 ⁻⁹ mol/L ACh −18.8±2.9%, P −4 mol/L of N ^G -nitro- l -arginine methyl ester, an NO synthase inhibitor, and 10 ⁻⁵ mol/L of methylene blue, a guanylate cyclase inhibitor, reduced the vasodilatory effect of AM. These results suggest that the NO-cGMP pathway is involved in the mechanism of AM-induced vasorelaxation, at least in the rat aorta and kidney.