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Based on the favorable effects of female sex steroids in vascular functions and the potent hypotensive effects of adrenomedullin (AM), we hypothesized that AM-induced vasodilation is gender dependent, and female sex steroids enhance this effect. In endothelium-intact rat mesenteric artery, AM (1 nm-0.3 microM)-induced concentration-dependent relaxation was significantly (P &lt; 0.05) higher in females [pD2(-log EC50 of the molar concentration), 7.05 +/- 0.10; maximal relaxation response (Emax), 69.2 +/- 3.46%] than males (pD2, 6.53 +/- 0.08; Emax, 53.28 +/- 4.86%). The increased relaxation was lost when the females were ovariectomized (OVX) (pD2, 6.14 +/- 0.24; Emax, 39.68 +/- 5.68%). The reduced relaxation response in OVX rats was reversed by administration of either progesterone (P4; pD2, 7.18 +/- 0.07; Emax, 72.4 +/- 2.76%) or 17beta-estradiol (E2; pD2, 7.00 +/- 0.14; Emax, 70.4 +/- 4.79%). AM mediates its effects through either AM(22-52)-sensitive AM1 receptors [composed of calcitonin receptor-like receptors (CLs) and receptor activity-modifying protein (RAMP)2] or AM2 receptors (CL/RAMP3), which can be antagonized more potently by calcitonin gene-related peptide(8-37) than AM(22-52). Pharmacological characterization suggested the involvement of AM2 receptors in the increased vasodilatory effect of AM in both P4- and E2-treated animals as calcitonin gene-related peptide(8-37) (10 microM) was more potent in antagonizing the AM effects (Emax, P(4): 25.92 +/- 5.32%; E2: 29.11 +/- 7.41%) than AM(22-52) (100 microM). RT-PCR studies also supported the involvement of AM2 receptors because expression of mRNA levels encoding CL (previously reported) and RAMP3 were increased in P4- or E2-treated OVX rats. In conclusion, AM-induced vasodilation is gender-dependent and increased by female sex steroids by increased expression of AM2 receptor components.

endocrinology

Female Sex Steroids Increase Adrenomedullin-Induced Vasodilation by Increasing the Expression of Adrenomedullin2 Receptor Components in Rat Mesenteric Artery