Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Chloride Channel and Na-k-cl Cotransporter Nkcc1 Isoform Mediate the Vasorelaxant Action of Genistein in Isolated Rat Aorta.
From: Department of Physiology and Pharmacology, School of Medicine, University of Zaragoza, Spain.
European journal of pharmacology
- Publish Date: Aug 2006
- ISSN: 0014-2999
- Volume: 544
- Issue: 1-3
- Pages: 126-31
- Medium: Print
- Language: English
- Citation (JAMA): Valero Marta S, Garay Ricardo P, Gros Pilar, et al. Cystic Fibrosis Transmembrane Conductance Regulator (Cftr) Chloride Channel and Na-k-cl Cotransporter Nkcc1 Isoform Mediate the Vasorelaxant Action of Genistein in Isolated Rat Aorta.. Eur. J. Pharmacol. Aug 2006;544:126-31
Abstract
The soy phytoestrogen genistein is a potent vasorelaxant, but its mechanism of action is poorly understood. Here, we used endothelium-denuded rat aorta to investigate the role of the cyclic AMP(cAMP)-activated, cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, and its associated Na-K-Cl cotransporter NKCC1. Isolated, endothelium-denuded rat aorta was contracted with phenylephrine 1 microM, and the vasorelaxant responses to genistein were investigated under conditions where CFTR was inhibited by DPC (diphenylamine-2-carboxylic acid) or glibenclamide (n=6 for compound). Both compounds fully antagonized the vasorelaxant responses to genistein, with IC50=57+/-18 microM and 42+/-11 microM for DPC and glibenclamide respectively. H-89, a selective protein kinase A (PKA) inhibitor, blocked the vasorelaxant responses to genistein. Finally, the NKCC1 inhibitor, bumetanide fully antagonized the vasorelaxant responses to genistein against phenylephrine- or KCl-induced contractions, with IC50=2.0+/-0.2 microM and 1.6+/-0.5 microM, respectively (n=6 for condition). These results strongly suggest that CFTR opening is involved in the vasorelaxant action of genistein, and that cAMP-dependent CFTR phosphorylation and chloride entry via the NKCC1 cotransporter are required for genistein action.
Mesh Headings (Keywords): Animals, Anthranilic Acids, Aorta, Aspartic Acid, Chlorides, Cyclic AMP, Cystic Fibrosis Transmembrane Conductance Regulator, Dose-Response Relationship, Drug, Genistein, Inhibitory Concentration 50, Male, Nitrates, Rats, Rats, Wistar, Sodium-Potassium-Chloride Symporters
Check for Full Text / PubMed Unique Identifier (PMID): 16859673
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