Erschienen in:
The Journal of Physiology, 568 (2005) 2, Seite 483-495
Sprache:
Englisch
DOI:
10.1113/jphysiol.2005.085019
ISSN:
0022-3751;
1469-7793
Entstehung:
Anmerkungen:
Beschreibung:
<jats:p>Chloride (Cl<jats:sup>−</jats:sup>) channels expressed in vascular smooth muscle cells (VSMC) are important to control membrane potential equilibrium, intracellular pH, cell volume maintenance, contraction, relaxation and proliferation. The present study was designed to compare the expression, regulation and function of CFTR Cl<jats:sup>−</jats:sup> channels in aortic VSMC from <jats:italic>Cftr<jats:sup>+/+</jats:sup></jats:italic> and <jats:italic>Cftr<jats:sup>−</jats:sup><jats:sup>/</jats:sup><jats:sup>−</jats:sup></jats:italic> mice. Using an iodide efflux assay we demonstrated stimulation of CFTR by VIP, isoproterenol, cAMP agonists and other pharmacological activators in cultured VSMC from <jats:italic>Cftr<jats:sup>+/+</jats:sup></jats:italic>. On the contrary, in cultured VSMC from <jats:italic>Cftr<jats:sup>−</jats:sup><jats:sup>/</jats:sup><jats:sup>−</jats:sup></jats:italic> mice these agonists have no effect, showing that CFTR is the dominant Cl<jats:sup>−</jats:sup> channel involved in the response to cAMP mediators. Angiotensin II and the calcium ionophore A23187 stimulated Ca<jats:sup>2</jats:sup><jats:sup>+</jats:sup>‐dependent Cl<jats:sup>−</jats:sup> channels in VSMCs from both genotypes. CFTR was activated in myocytes maintained in medium containing either high potassium or 5‐hydroxytryptamine (5‐HT) and was inhibited by CFTR<jats:sub>inh</jats:sub>‐172, glibenclamide and diphenylamine‐2,2′‐dicarboxylic acid (DPC). We also examined the mechanical properties of aortas. Arteries with or without endothelium from <jats:italic>Cftr<jats:sup>−/−</jats:sup></jats:italic> mice became significantly more constricted (∼2‐fold) than that of <jats:italic>Cftr<jats:sup>+/+</jats:sup></jats:italic> mice in response to vasoactive agents. Moreover, in precontracted arteries of <jats:italic>Cftr<jats:sup>+/+</jats:sup></jats:italic> mice, VIP and CFTR activators induced vasorelaxation that was altered in <jats:italic>Cftr<jats:sup>−/−</jats:sup></jats:italic> mice. Our findings suggest a novel mechanism for regulation of the vascular tone by cAMP‐dependent CFTR chloride channels in VSMC. To our knowledge this study is the first to report the phenotypic consequences of the loss of a Cl<jats:sup>−</jats:sup> channel on vascular reactivity.</jats:p>