Calcitonin gene-related peptide dilates the pregnant rat uterine vascular bed via guanylate cyclase, ATP- and Ca-sensitive potassium channels and gap junctions.
We studied the mechanism of calcitonin gene-related peptide (CGRP)-induced vasorelaxation in isolated uterine vascular beds of pregnant rats. The vascular beds were perfused in situ with Krebs buffer containing dextran and indomethacin, an inhibitor of cyclooxygenase. Baseline perfusion pressure was maintained with norepinephrine. When applied as a bolus, CGRP caused a decreased perfusion pressure in uterine vascular beds that was dose-dependent and equal in both mid-pregnant and late-pregnant rats. The non-selective inhibitor of nitric oxide synthase (NOS), Nomega-nitro-L-arginine methyl ester (L-NAME), did not significantly affect CGRP-induced vasodilatation in vascular beds of either group. CGRP-induced vasodilatation was not influenced by preincubation with the inhibitors of adenylate cyclase (SQ 22536 or MDL 12330A), but was significantly attenuated by the selective inhibitor of soluble guanylate cyclase (ODQ). The vasorelaxant effect of CGRP was not significantly influenced by the inhibitor of voltage-gated potassium (KV) channels (4-aminopyridin), but was significantly attenuated by an inhibitor of calcium-regulated potassium (KCa) channels (tetraethylammonium) and by an inhibitor of adenosine triphosphate-sensitive potassium (KATP) channels (glibenclamide). The gap junction uncoupling agent (carbenoxolone) also significantly attenuated the CGRP-induced decrease in perfusion pressure. We conclude that vasorelaxation induced by CGRP in the pregnant rat uterine vascular bed is not dependent on endothelial nitric oxide. In the uterine circulation of late-pregnant rats, the CGRP effect involves activation of soluble guanylate cyclase, but not adenylate cyclase, and does involve KCa and KATP channels and gap junctions.
Vedernikov
Y P
YP
Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas 77555, USA. yvederni@utmb.edu
Fulep
E E
EE
Saade
G R
GR
Garfield
R E
RE
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D005260:Female; D017629:Gap Junctions / Q000502:physiology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014481:United States; D014599:Uterus / Q000098:blood supply* / Q000201:enzymology / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D015221:Potassium Channels; D000255:Adenosine Triphosphate; D006162:Guanylate Cyclase; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium