title: Cirrhosis decreases vasoconstrictor response to electrical field stimulation in rat mesenteric artery: role of calcitonin gene-related peptide.
abstract: Our study determines alterations in the vasoconstrictor response elicited by electric field stimulation (EFS) in mesenteric arteries from cirrhotic rats treated with CCl(4), and how calcitonin gene-related peptide (CGRP) participates in this response. Vasoconstriction induced by EFS was analysed in the absence and presence of the CGRP receptor antagonist CGRP(8-37) in arterial segments from control and cirrhotic rats. The vasodilator response to exogenous CGRP was tested in both groups of rats, and the interference of the guanylate cyclase inhibitor ODQ or the K(ATP) channel blocker glibenclamide was analysed only in segments from cirrhotic rats. The vasodilator response to the K(ATP) channel opener pinacidil and to 8-bromo-cyclic GMP was tested. The K(ATP) currents were recorded using the patch-clamp technique. Expression of receptor activity-modifying protein 1 (RAMP1), calcitonin receptor-like receptor, Kir 6.1 and sulfonylurea receptor 2B (SUR2B) was also analysed. Release of CGRP and cGMP was measured. The EFS-elicited vasoconstriction was less in segments from cirrhotic rats. The presence of CGRP(8-37) increased the EFS-induced response only in segments from cirrhotic rats. The CGRP-induced vasodilatation was greater in segments from cirrhotic rats, and was inhibited by ODQ or glibenclamide. Both pinacidil and 8-bromo-cyclic GMP induced a stronger vasodilator response in segments from cirrhotic rats. Pinacidil induced greater K(ATP) currents in cirrhotic myocytes. Expression of RAMP1, calcitonin receptor-like receptor, Kir 6.1 and SUR2B was not modified by liver cirrhosis. Liver cirrhosis increased CGRP release, but did not modify cGMP formation. The decreased vasoconstrictor response to EFS in cirrhosis is mediated by increased vasodilator response to CGRP, as well as increased K(ATP) channel gating. This effect of CGRP may play a role in the splanchnic vasodilatation present in liver cirrhosis.
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Blanco-Rivero
authors.forename: Iván
authors.initials: I
authors.lastname: Márquez-Rodas
authors.forename: Esther
authors.initials: E
authors.lastname: Sastre
authors.forename: Angel
authors.initials: A
authors.lastname: Cogolludo
authors.forename: Francisco
authors.initials: F
authors.lastname: Pérez-Vizcaíno
authors.forename: Lara
authors.initials: L
authors.lastname: del Campo
authors.forename: Ma Paz
authors.initials: MP
authors.lastname: Nava
authors.forename: Gloria
authors.initials: G
authors.lastname: Balfagón
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein / Q000097:blood / Q000235:genetics; D002251:Carbon Tetrachloride / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D005905:Glyburide / Q000494:pharmacology; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D020110:Pinacidil / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058262:Receptor Activity-Modifying Protein 1 / Q000096:biosynthesis / Q000235:genetics; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology*; D011955:Receptors, Drug / Q000096:biosynthesis / Q000235:genetics; D064233:Sulfonylurea Receptors; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D018528:ATP-Binding Cassette Transporters; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058286:Calcitonin Receptor-Like Protein; D054086:KATP Channels; D010069:Oxadiazoles; D010446:Peptide Fragments; D024661:Potassium Channels, Inwardly Rectifying; D011810:Quinoxalines; C545508:Ramp1 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D018015:Receptors, Calcitonin Gene-Related Peptide; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; C058636:calcitonin gene-related peptide (8-37); C016276:8-bromocyclic GMP; D020110:Pinacidil; D002251:Carbon Tetrachloride; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D005905:Glyburide