Adrenomedullin-2, a novel calcitonin/calcitonin-gene-related peptide family peptide, relaxes rat mesenteric artery: influence of pregnancy

Abstract

Adrenomedullin-2 (ADM2), a novel calcitonin/calcitonin-gene-related peptide family peptide, is reported to reduce blood pressure in both normal and hypertensive rats. This study demonstrates gestational regulation of circulatory ADM2 in rat plasma. ADM2 dose-dependently reduces the mean arterial pressure in rats, whereas the hypotensive effect of ADM2 is significantly higher during pregnancy. In addition, immunoreactive ADM2 protein is distributed in perivascular fibers of rat mesenteric artery, and levels of pre-pro-ADM2 are significantly (P<0.05) elevated in pregnant compared with nonpregnant rat mesenteric artery. Furthermore, incubation of endothelium intact arterial tissue from pregnant rats with ADM217-47, an ADM2 antagonist, shifted the dose-dependent relaxation curve to the right in wire myography. Inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) or endothelial nitric oxide synthase with N-nitro-L-arginine methyl ester (100 microM) reduced the relaxation of mesenteric artery induced by ADM2. Inhibition of adenylate cyclase with SQ22536 (10 microM) or protein kinase A with the Rp diastereomer of cyclic adenosine 3',5'-phosphorothioate (10 microM) also reduced the maximal relaxation responses induced by ADM2. Blockade of calcium-activated potassium channels with tetraethylammonium chloride (1 mM) inhibited the ADM2-induced relaxation, whereas blockade of ATP-sensitive potassium channels with glybenclamide (10 microM) did not affect the relaxation response. Hence the mechanism of ADM2-induced vasorelaxation is nitric oxide and receptor mediated and cGMP and cAMP dependent and occurs through activation of calcium-activated potassium channels. In conclusion, rat pregnancy is associated with increased levels of circulatory and vascular tissue ADM2 with concomitant increase in the in vivo hypotensive effect of ADM2 and vascular reactivity of mesenteric artery to ADM2, thus suggesting involvement of ADM2 in vascular adaptations during pregnancy.