Akademik Veri Yönetim Sistemi
Journal of Pharmacology and Experimental Therapeutics, cilt.283, sa.2, ss.925-931, 1997 (SCI-Expanded)
Desensitization of alpha-1 adrenoceptor (α1AR)-mediated responses in aortic smooth muscle after exposure to catecholaminas or α1AR agonists has been widely demonstrated. To determine whether exposure to an α1AR agonist results in desensitization of α1AR-mediated responses in a resistance artery, rat tail artery rings were exposed to 7.5 or 75 μM phenylephrine (PE) for 22 hr in vitro. Norepinephrine-stimulated contraction was significantly reduced in PE-exposed tail artery rings. Contractions mediated by the α2AR agonists, clonidine and UK 14,304, and by serotonin were also reduced in PE-treated tail artery rings. However, the contractile responses to KCl and ionomycin remained unchanged. Norepinephrine-, PE-, endothelin- and serotonin-stimulated inositol phosphate accumulations were reduced in PE- exposed tail artery rings, whereas KCl- and ionomycin-stimulated inositol phosphate accumulation remained unchanged. The density of membrane α1ARs, measured by specific [125l]12-{[β-(4-hydroxyphenyl)ethyl]aminomethyl}- 1-etralone binding was not changed in PE-desensitized tail arteries. Further studies were performed to examine if alterations in receptor/G protein interaction accompanies arterial desensitization. In these studies receptor- stimulated increases in [35S]GTPγS binding to G proteins was assessed in membranes obtained from vehicle (control) and PE-treated tail arteries. In control membranes α1AR stimulation increased [35S]GTPγS binding to G(αq) and G(αi) proteins, whereas the α2AR agonist UK14,304 activated [35S]GTPγS binding to G(αi) exclusively. Both PE- and UK14,304-induced responses were reduced in membranes from tail arteries that were exposed to either 7.5 or 75 μM PE for 22 hr. Western blot analyses of G protein alpha and beta subunits demonstrated that G(αq) and G(αi) protein levels were decreased in PE-exposed taft artery membranes. These data show that the reduced transmembrane signaling for the α1AR in tail artery after in vitro PE exposure is associated with decreases in G(αq) and G(αi) protein levels. The reduction in these G(α) proteins also appears to mediate the loss of function of α2AR and perhaps of other G protein-coupled receptors.