Differential influence of calcium channel-blockers on prostanoid generation and thromboxane-mediated vasoconstriction in rabbit lungs

W Seeger, M Rohrenbach, C Ernst and H Neuhof

In blood-free perfused and ventilated rabbit lungs, the influence of calcium channel-blockers on pulmonary prostanoid generation and thromboxane-mediated vasoconstriction was investigated. The specific pathways of arachidonic acid (AA) metabolism were stimulated by repetitive pulmonary artery injection of the calcium-ionophore A 23187, which induces the liberation of endogenous AA, or by repetitive application of exogenous AA. In control lungs, both stimuli provoked reproducible phasic vascular pressor responses, accompanied by the release of thromboxane A2 and prostaglandin I2 into the perfusion fluid. Repeated stimulus application in the presence of increasing concentrations of different calcium antagonists showed a dose-dependent inhibition of the pressor responses by all agents. The rank order of potency was nimodipin greater than LU-40883 (verapamil derivative) greater than diltiazem and D-888 (verapamil derivative) greater than verapamil for the ionophore-induced pressure increase, whereas diltiazem was nearly ineffective in the presence of exogenously applied AA. The prostanoid release after application of A 23187 was influenced differentially by the calcium channel-blockers. It was not affected by nimodipin and verapamil, it was slightly depressed by the verapamil derivatives D-888 and LU-40883 and it was dose-dependently and in higher concentrations nearly inhibited completely by diltiazem. We conclude that the thromboxane-mediated pulmonary vasoconstriction is inhibited by different-type calcium channel-blockers with a marked rank order of potency. The prostanoid generation induced by stimulation of the lung vascular AA metabolism is influenced differentially by these agents.

Volume 242, Issue 2, pp. 646-653, 08/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics