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

Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555

Address all correspondence and requests for reprints to: Chandra Yallampalli, DVM, Ph.D., Distinguished Professor, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Boulevard, Medical Research Building, Room 11.138, Route 1062, Galveston, Texas 77555-1062. E-mail: chyallam{at}utmb.edu.

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 µM)-induced concentration-dependent relaxation was significantly (P < 0.05) higher in females [pD₂(–log EC₅₀ of the molar concentration), 7.05 ± 0.10; maximal relaxation response (E_max), 69.2 ± 3.46%] than males (pD₂, 6.53 ± 0.08; E_max, 53.28 ± 4.86%). The increased relaxation was lost when the females were ovariectomized (OVX) (pD₂, 6.14 ± 0.24; E_max, 39.68 ± 5.68%). The reduced relaxation response in OVX rats was reversed by administration of either progesterone (P₄; pD₂, 7.18 ± 0.07; E_max, 72.4 ± 2.76%) or 17ß-estradiol (E₂; pD₂, 7.00 ± 0.14; E_max, 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 µM) was more potent in antagonizing the AM effects (E_max, P₄: 25.92 ± 5.32%; E₂: 29.11 ± 7.41%) than AM_22–52 (100 µM). 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.