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.