Calcium utilization in the vasoconstriction to enantiomers of SK&F 89748-A

WD Matthews, RA Macia, JJ Beckeringh, RM DeMarinis, A de Jonge, MJ Thoolen, B Wilffert, PB Timmermans and PA van Zwieten

The effects of calcium entry blockade on the vasoconstriction to the selective alpha-1 adrenoceptor agonists d- and I-SK&F 89748-A (1,2,3,4- tetrahydro-8-methoxy-[5-methylthiol] -2-naphthalenamine HCl) in pithed rats and in rat and guinea-pig isolated aortas were studied. The log- dose response curves for the increase in diastolic pressure in pithed rats to i.v. injections of both enantiomers of SK&F 89748-A were maximally shifted only 5-fold to the right after pretreatment of the animals with nifedipine (1 or 3 mg/kg i.a.) or l-verapamil (0.3 or 1 mg/kg i.a.), showing the relative insensitivity of the vasopressor responses to SK&F 89748-A to these calcium entry blockers. In the rat isolated aorta, the contractile responses to the l-enantiomer of SK&F 89748-A were significantly more susceptible to calcium entry blockade with l-verapamil, nifedipine and D600 than the d-isomer. The contractions of the guinea-pig isolated aorta to both isomers proved highly insensitive to calcium slow channel blockade by D600. These results indicate that the contractions of vascular smooth muscle in pithed rats in vivo and of guinea-pig isolated aortas in vitro initiated by the d-and l-isomers of SK&F 89748-A are largely dependent upon processes not requiring an influx of extracellular calcium. The differential sensitivity to calcium entry blockade of the contractile responses of rat isolated aortas to the d- and l-isomers of SK&F 89748- A may reflect different ways of interaction of both enantiomers with the alpha-l adrenoceptor on rat aorta.

Volume 232, Issue 2, pp. 330-336, 02/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics