Effects of chronic receptor blockade on excitation-contraction coupling in rat aortic rings.
The effects of an intracellular Ca2+ depletor (ryanodine), a Ca2+ channel antagonist (felodipine), a protein kinase C inhibitor (staurosporine) as well as caffeine, cholera and pertussis toxin have been examined on noradrenaline-induced contractions in aortic rings from rats pretreated i.v. with either saline or phenoxybenzamine for 7 days. Ryanodine (3 and 10 microM) was able to both potentiate and inhibit noradrenaline-evoked contractions in aortic rings from phenoxybenzamine-treated rats. However, ryanodine did not affect the concentration-response curves to noradrenaline in tissues from saline-treated rats. Further, felodipine (1 and 10 nM) and staurosporine (10 nM) inhibited noradrenaline-induced contractions in aortic rings from phenoxybenzamine- but not saline-treated rats. Pertussis toxin (100 ng/ml) also inhibited contractions produced by noradrenaline in rings from phenoxybenzamine- but not saline-treated rats. In contrast to these observations, both caffeine (1 mM) and cholera toxin (3 micrograms/ml) inhibited noradrenaline-evoked contractions in aortic rings from phenoxybenzamine- and saline-treated rats. The results suggest that chronic receptor blockade by phenoxybenzamine leads to alteration in alpha-adrenoceptor-mediated signal transduction in the aorta. The changes include alteration in Ca2+ handling at the plasmalemmal and intracellular levels, as well as an altered action of pertussis toxin-sensitive G-protein, but not of cholera toxin-sensitive G-protein.
Tabrizchi
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Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D002772:Cholera Toxin / Q000494:pharmacology; D015736:Felodipine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D037342:Pertussis Toxin; D010643:Phenoxybenzamine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000470:Alkaloids; D011956:Receptors, Cell Surface; D010566:Virulence Factors, Bordetella; D010643:Phenoxybenzamine; D012433:Ryanodine; D002110:Caffeine; D002772:Cholera Toxin; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D019311:Staurosporine; D015736:Felodipine; D002118:Calcium; D009638:Norepinephrine