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 <0.05). On the other hand, pretreatment with 10 −8 mol/L E-4021 augmented AM-induced vasorelaxation in the intact aorta (−49.0±7.9%, P <0.05) but not in the denuded one. E-4021 also enhanced acetylcholine (ACh)-induced vasorelaxation in the rat intact aorta (10 −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 <0.05). In perfused kidneys, AM-induced vasorelaxation was also augmented by preincubation with E-4021 (10 −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 <0.01). AM significantly increased NO release from rat kidneys (ΔNO: +11.3±0.8 fmol · min –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 <0.01) but did not affect ACh-induced NO release from the kidneys. In the aorta and the kidney, 10 −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.