The role of Gi proteins in reduced vasorelaxation response to beta-adrenoceptor agonists in rat aorta during maturation.
Beta-adrenoceptor mediated vasorelaxation and cAMP production decline during maturation and aging in rat aorta. beta-adrenoceptor-stimulated vasorelaxation is mainly triggered by Gsalpha-mediated activation of adenylyl cyclase. beta(2)-adrenoceptors can also activate Gi protein which inhibits adenylyl cyclase activity. In this study, we examined the role of Gi proteins in the decreased beta-adrenoceptor mediated responses during maturation. Pertussis toxin treatment of aortic rings to inhibit Gialpha activation completely restored age related decline in isoproterenol-stimulated maximal vasorelaxation in 3-month old rats. This treatment increased the potency, but not the maximal response of isoproteronol to produce vasorelaxation in 6 month old rats. The maximal isoproteronol stimulated cAMP responses were also partially restored in pertussis toxin-treated rings from 3 or 6-month old rats. We also examined beta-adrenoceptor stimulated binding of (35)[S]GTPgammaS to Gsalpha and Gialpha1/2 in aortic membranes from 1, 3 and 6-month old rats. In 1-month old rats, isoproterenol-stimulated (35)[S]GTPgammaS binding to Gsalpha was significantly higher than that of 3 or 6-month old rats. Isoproterenol-stimulated (35)[S]GTPgammaS binding to Gialpha1/2 was found to be significantly increased in 3 or 6-month old rats compared to 1-month old rats. The results of this study showed that beta-adrenoceptor-mediated activation of Gs and Gi proteins was declined and increased, respectively, and inhibition of the Gi mediated activity by pertussis toxin treatment partially restored impaired vasorelaxation and cAMP response to beta-adrenoceptor stimulation during maturation in rat aorta. The decrease in beta-adrenoceptor mediated activation of Gs gradually increased during maturation. All together these results indicated that beta-adrenoceptor mainly activates Gs protein in aorta from 1-month old rats, while it activates Gi and with a certain degree of decline it also activates Gs in aorta from 3 and 6-months old rats and not only the increase in beta-adrenoceptor coupling to Gi but also the decrease in its coupling to Gs play a role in the impaired beta-adrenoceptor responses in rat aorta during maturation.
Baloğlu
Emel
E
Department of Pharmacology and Clinical Pharmacology, Medical Faculty of Ankara University, Sihhiye, Ankara 06100, Turkey.
Kiziltepe
Ozlem
O
Gürdal
Hakan
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000375:Aging; D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects* / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D000526:Alprenolol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol