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Studies on the Effects of the N-Terminal Domain Antibodies of CalcitoninReceptor-Like Receptor and Receptor Activity–Modifying Protein 1 on CalcitoninGene-Related Peptide-Induced Vasorelaxation in Rat Uterine Artery¹

Department of Obstetrics and Gynecology,³ University of Texas Medical Branch, Galveston, Texas 77555-1062 Department of Endocrinology,⁴ Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903-0019

The vascular relaxation sensitivity to calcitonin gene-related peptide (CGRP) is enhanced during pregnancy, compared with nonpregnant human and rat uterine arteries. In the rat uterine artery, two types of CGRP receptors have been shown to coexist, CGRP-A receptor, which is a complex of calcitonin receptor-like receptor (CRLR), and receptor activity–modifying protein (RAMP₁) and CGRP-B receptor, which is different from CRLR. In the present study, we hypothesized that: 1) CGRP-induced vasorelaxation in rat uterine artery is mediated through CGRP-A receptor and 2) N-terminal (Nt) domain of CRLR (Nt-CRLR) has a major contribution in ligand binding and mediating CGRP- induced relaxation effects in rat uterine artery. Polyclonal antibodies against Nt-domain of CRLR and RAMP₁ (Nt-RAMP₁) were raised in rabbits and characterized for their specificity and were used to inhibit CGRP-induced vasorelaxation in rat uterine artery. For vascular relaxation studies, uterine arteries from Day 18 pregnant rats were isolated, and responsiveness of the vessels to CGRP was examined with a small vessel myograph. CGRP (10^–10 to 10^–7 M) produced a concentration-dependent relaxation of norepinephrine-induced contractions in Day 18 pregnant rat uterine arteries. These effects were significantly (P < 0.05) inhibited when uterine arteries were incubated with the antibody raised against Nt-CRLR (PD₂ = 6.75 ± 0.20) and were totally abolished in presence of antibodies for both Nt-CRLR and Nt-RAMP₁ (PD₂ = 6.14 ± 0.35). In contrast, a monoclonal antibody for CGRP-B receptor had no effect on CGRP-induced rat uterine artery relaxation. These studies suggest that CGRP effects in rat uterine artery are mediated through CGRP-A receptor and that Nt-domain of CRLR may play a predominant role in CGRP binding and thus in causing CGRP-induced uterine artery relaxation.

¹ Grant support received from National Institutes of Health Grants HL58144, HL72650, and HD40828.

² Correspondence: Chandrasekhar Yallampalli, D.V.M., Ph.D., Department of Obstetrics and Gynecology, 301 University Blvd., Medical Research Building, Room 11.138, Galveston, TX 77555-1062. FAX: 409 747 0475; chyallam{at}utmb.edu

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