dinoprost and pranidipine

Pranidipine, a new calcium channel blocker, prolonged endothelium-dependent relaxation induced by acetylcholine in an aortic ring preparation, contracted with prostaglandin F2alpha. This action was not shared by amlodipine. The effect was not modified by indomethacin, suggesting that the action of pranidipine does not involve prostanoid metabolism. N(G)-nitro-L-arginine completely prevented the action of Pranidipine. The drug affected neither nitric oxide (NO) synthase activity nor the level of cyclic GMP in the vessel. Pranidipine did not affect the sensitivity of the contractile proteins to calcium. Pranidipine also did not alter cyclic GMP-induced relaxation in alpha-toxin-skinned vascular preparations. Pranidipine also prolonged glyceryl trinitrate-induced relaxation in the endothelium denuded rat aorta. Furthermore, pranidipine 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 inhibitors of the calcium-activated potassium channel. The results strongly suggest that pranidipine enhances cyclic GMP-independent NO-induced relaxation of smooth muscle by a mechanism other than through NO-induced hyperpolarization. These effects were in direct contrast to amlodipine, another new 1,4-dihydropyridine calcium antagonist.

Topics: Amlodipine; Animals; Aorta; Calcium Channel Blockers; Cyclic GMP; Dihydropyridines; Dimethyl Sulfoxide; Dinoprost; Endothelium, Vascular; Indomethacin; Male; Methylene Blue; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

The action of methyl 3-phenyl-2 (E)-propenyl 1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (pranidipine, OPC-13340, CAS 99522-79-9) on the endothelium-dependent relaxation in the isolated aorta in vitro was examined in comparison with other calcium antagonists (nifedipine, nitrendipine, nicardipine, diltiazem and verapamil). In the isolated aortic preparation of Wistar rats, acetylcholine (10(-5) mol/l), ATP (10(-5) mol/l or histamine (10(-5)-10(-4) mol/l) caused endothelium-dependent relaxation when the strips were previously contracted with prostaglandin F2 alpha. This endothelium-dependent relaxation recovered within a few minutes, although the mechanisms of this contraction after relaxation were not clear. The pretreatment with pranidipine for 20 min extended the duration of the endothelium-dependent relaxation, however, there was no potentiation in magnitude of the relaxation. This effect on the duration of endothelium-dependent relaxation was prominent in pranidipine, namely, other calcium antagonists tested had not this action at clinical concentrations. This phenomenon was also observed when the strips were pre-contracted with norepinephrine. This action of pranidipine might be some beneficial feature for therapeutic use of the compound.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Dihydropyridines; Dinoprost; Endothelium, Vascular; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Rats; Rats, Wistar