endothelin-1 and pranidipine

We examined the effects of lomerizine, a new diphenylmethylpiperazine Ca2+ channel blocker, on the normal circulation in the optic nerve head and long posterior ciliary artery, and on endothelin-1-induced hypoperfusion in the optic nerve head in anesthetized rabbits using a hydrogen gas clearance method and laser Doppler flowmetry. These effects were compared with those of nilvadipine and pranidipine. Lomerizine (0.1 and 0.3 mg/kg, i.v.) significantly increased tissue blood flow in the optic nerve head and the putative blood flow in the long posterior ciliary artery with smaller reduction of blood pressure (0.3 mg/kg, i.v.) and without change in heart rate. On the other hand, nilvadipine (0.003 and 0.01 mg/kg, i.v.) and pranidipine (0.003 and 0.01 mg/kg, iv.) each significantly increased blood flow and lowered blood pressure. Moreover, lomerizine (0.1 and 0.3 mg/kg, i.v.) and nilvadipine (0.01 mg/kg, i.v.), when administered 5 min before an endothelin-1 injection (10(-6) M, 100 microl), inhibited the hypoperfusion in the optic nerve head. These results suggest that lomerizine improves the ocular circulation with minimal cardiovascular side effects. Therefore, lomerizine may have clinical potential for the treatment of eye diseases associated with local circulatory disturbances, such as normal-tension glaucoma.

Topics: Animals; Blood Circulation; Blood Flow Velocity; Blood Pressure; Calcium Channel Blockers; Ciliary Arteries; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Intraocular Pressure; Laser-Doppler Flowmetry; Male; Nifedipine; Optic Disk; Piperazines; Rabbits; Regional Blood Flow

Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. Calcium antagonists have been shown to improve endothelial function in hypertensive patients. Here we report that pranidipine, one of the latest long-acting calcium antagonists in the dihydropyridine group, enhances the actions of NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP accumulation in vascular smooth muscle cells cocultured with ECs, whereas amlodipine and nifedipine had no significant effects. In addition, pranidipine also suppressed basal and thrombin-stimulated endothelin-1 production from ECs. Pranidipine also enhanced cGMP accumulation in rat aortic segments with endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had no effect in the presence of N(G)-monomethyl-L-arginine, an inhibitor of NO synthesis. Pranidipine did not affect the basal expression of endothelial NO synthase in ECs. However, pranidipine upregulated the activity of superoxide dismutase in ECs. These findings suggest that pranidipine enhances NO action through inhibition of superoxide-induced NO decomposition in the vessel wall. Thus, pranidipine may be useful in the treatment of impaired endothelial function in patients with hypertension.

Topics: Amlodipine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Cells, Cultured; Coculture Techniques; Cyclic GMP; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Male; Muscle, Smooth, Vascular; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Superoxide Dismutase