Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent. It is metabolized in humans to pinacidil N-oxide. To determine whether pinacidil's metabolism or effects were influenced by either liver disease or the subject's debrisoquin phenotype, eight patients with chronic stable cirrhosis and 13 healthy subjects were studied. Seven of the healthy volunteers were extensive metabolizers of debrisoquin, whereas six were of the poor metabolizer phenotype. Neither the clearance of pinacidil nor the production of the N-oxide was altered by the subjects' debrisoquin phenotype. Cirrhosis produced a 50% reduction in pinacidil's clearance (20.7 +/- 1.4 vs. 42.1 +/- 5.1 L/hr; P less than 0.0005) and a prolongation in the elimination t1/2 from 3.9 +/- 0.3 to 6.1 +/- 0.6 hours (P less than 0.01). Less pinacidil was metabolized to the N-oxide metabolite in the patients with cirrhosis than in the normal individuals. Thus pinacidil's metabolism and clearance are reduced in patients with cirrhosis but are independent of debrisoquin phenotype.
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PMID:Effect of cirrhosis and debrisoquin phenotype on the disposition and effects of pinacidil. 378 Jan 26

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.
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PMID:Cirrhosis decreases vasoconstrictor response to electrical field stimulation in rat mesenteric artery: role of calcitonin gene-related peptide. 2114 25