beraprost and diphloretin-phosphate

To elucidate the effect of Beraprost, a stable prostaglandin (PG) I2 analogue, on airway smooth muscle functions and its mechanism of action, we studied canine bronchial segments under isometric conditions in vitro. Addition of PGI2 and its analogues dose-dependently relaxed bronchial smooth muscle precontracted with acetylcholine, with the rank order of potency being Beraprost (1) > or = Hoprost (0.65) > PGI2 (0.04), accompanied by the corresponding increase in intracellular cyclic AMP levels. The Beraprost- and PGI2-induced muscle relaxations were significantly inhibited by each of the PG antagonist diphloretin phosphate, the adenylate cyclase inhibitor SQ 22,536, and the Na(+)-K(+)-ATPase inhibitor ouabain. Beraprost and PGI2 at concentrations insufficient to cause muscle relaxation reduced the contractile responses to electrical field stimulation, whereas they were without effect on those to exogenous acetylcholine. These results suggest that Beraprost not only potently relaxes airway smooth muscle through cyclic AMP production and the subsequent stimulation of Na(+)-K(+)-ATPase but also reduces neurally mediated contraction by inhibiting the release of acetylcholine from the cholinergic nerve terminals.

Topics: Acetylcholine; Adenine; Adenylyl Cyclase Inhibitors; Animals; Bronchi; Dogs; Electric Stimulation; Epoprostenol; Female; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Ouabain; Polyphloretin Phosphate; Potassium Chloride; Prostaglandin Antagonists; Sodium-Potassium-Exchanging ATPase

TRK-100, a stable analogue of prostaglandin I2 (PGI2), relaxed isolated arteries of the dog precontracted with PGF2 alpha or K+; the relaxation was in the order of mesenteric and renal greater than coronary and femoral greater than basilar and middle cerebral arteries. The relaxation by TRK-100 was not affected by treatment with atropine, propranolol, cimetidine, aminophylline, and indomethacin, but was suppressed by diphloretin phosphate, a prostaglandin antagonist. Treatment with TRK-100 attenuated the contraction induced by PGF2 alpha and Ca2+ in mesenteric and basilar arteries previously exposed to Ca2+-free medium, but did not significantly alter the contractile response to Ca2+ in the arteries exposed to Ca2+-free medium and depolarized by excess K+. TRK-100 and nitroglycerin relaxed isolated mesenteric arteries to a similar extent; however, when continuously infused into mesenteric arteries in anaesthetized dogs, TRK-100 produced greater vasodilatation than nitroglycerin. It is concluded that TRK-100 relaxes dog mesenteric and renal arteries more than cerebral arteries; the relaxation appears to derive from interference with the release of Ca2+ from intracellular stores and with the transmembrane Ca2+ influx through a receptor-operated channel. TRK-100 may vasodilate large and small mesenteric arteries and resistance vessels to a similar extent, whereas nitroglycerin preferentially dilates the large artery.

Topics: Animals; Basilar Artery; Calcium; Dinoprost; Dogs; Epoprostenol; Female; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitroglycerin; Polyphloretin Phosphate; Prostaglandins F; Splanchnic Circulation; Vasodilator Agents