PRANIDIPINE, A NEW 1,4-DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKER, ENHANCES CYCLIC GMP-INDEPENDENT NITRIC OXIDE-INDUCED RELAXATION OF THE RAT AORTA

Pranidipine, a new calcium channel blocker, prolonged endothelium-depe ndent relaxation induced by acetylcholine in an aortic ring preparatio n, contracted with prostaglandin F-2 alpha. This action was not shared by amlodipine. The effect was not modified by indomethacin, suggestin g that the action of pranidipine does not involve prostanoid metabolis m. N-G-nitro-L-arginine completely prevented the action of Pranidipine . The drug affected neither nitric oxide (NO) synthase activity nor th e level of cyclic GMP in the vessel. Pranidipine did not affect the se nsitivity of the contractile proteins to calcium. Pranidipine also did not alter cyclic GMP-induced relaxation in a-toxin-skinned vascular p reparations. Pranidipine also prolonged glyceryl trinitrate-induced re laxation in the endothelium denuded rat aorta. Furthermore, pranidipin e enhanced relaxation of the aorta induced by glyceryl trinitrate even in the presence of methylene blue, a guanylyl cyclase inhibitor. This action was not modified by iberiotoxin or by charybdotoxin, two inhib itors of the calcium-activated potassium channel. The results strongly suggest that pranidipine enhances cyclic GMP-independent NO-induced r elaxation of smooth muscle by a mechanism other than through NO-induce d hyperpolarization. These effects were in direct contrast to amlodipi ne, another new 1,4-dihydropyridine calcium antagonist.