dinoprost and beraprost

1. Previous clinical studies with prostaglandin I(2) (PGI(2)) analogue beraprost sodium suggested the potential effects on protection of cardiovascular events in patients with peripheral artery disease. Although the mechanism is not well known, experimental studies have shown protective effects of endothelial cells. This study was designed to examine the effects of beraprost sodium on vascular endothelial function in the forearm of patients with coronary artery disease. 2. Beraprost sodium (120 microg/day) was orally administered to 14 coronary artery disease patients for 4 weeks and then stopped for 4 weeks. Eleven control patients did not receive beraprost sodium treatment. Reactive hyperemia was induced in the forearm, endothelium-dependent vasodilatation was assessed by plethysmography, and urinary 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) was measured at baseline, 4 weeks and 8 weeks. 3. Both groups had similar reactive hyperemic responses at baseline. In the control group, reactive hyperemic response and urinary 8-iso-PGF(2alpha) remained unchanged for 8 weeks. In the beraprost group, maximum forearm blood flow increased significantly (P = 0.01) after 4 weeks of treatment and returned to baseline at 8 weeks. Duration of hyperemia increased significantly (P = 0.003) after 4 weeks, and remained greater than baseline at 8 weeks (P = 0.02). Urinary 8-iso-PGF(2alpha) decreased significantly (P = 0.03) after 4 weeks, and tended to be lower at 8 weeks (P = 0.07). Changes in reactive hyperemia correlated weakly but significantly with changes in 8-iso-PGF(2alpha) (P < 0.001). 4. Beraprost sodium decreased oxidative stress and improved forearm endothelium-dependent vasodilatation in coronary artery disease patients. The favorable effects on vascular endothelium could potentially lead to a decrease in vascular events.

Topics: Aged; Coronary Artery Disease; Dinoprost; Double-Blind Method; Endothelium, Vascular; Epoprostenol; Female; Forearm; Hemodynamics; Humans; Hyperemia; Male; Prospective Studies; Regional Blood Flow; Vasodilation; Vasodilator Agents

We wished to determine the action of prostaglandins (PG) and to analyze pharmacologically the mechanisms of their action in isolated human uterine arteries in special reference to mediators liberated from the endothelium and subendothelial tissues. Helical strips of the human uterine artery with and without the endothelium were suspended in the Ringer-Locke solution for isometric tension recording. The relaxant response to PGF2 alpha was reversed to a contraction by cyclooxygenase inhibitors and suppressed by tranylcypromine, a PGI2 synthase inhibitor, but was not influenced by endothelium denudation. Relaxations induced by PGE2 and beraprost, a PGI2 analogue, were augmented by cyclooxygenase inhibitors and tranylcypromine but were not affected by ONO3708, an antagonist of vasoconstrictor prostanoids, and endothelium denudation. The potentiating effect of indomethacin was observed in the strips both with and without the endothelium and was antagonized by treatment with beraprost. The relaxation caused by PGF2 alpha apparently is mediated by PGI2 released from subendothelial tissues, whereas the PGE2-induced relaxation is due to the direct action on smooth muscle; the action may be eliminated by the basal release of PGI2 from subendothelial tissues.

Topics: Adult; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Female; Humans; In Vitro Techniques; Middle Aged; Phenylephrine; Potassium Chloride; Thromboxane A2; Uterus; Vasodilation

The vascular contractile mechanism of prostacyclin (PGI2) was investigated using beraprost sodium (BPS), a stable PGI2 analog. Ring strips without endothelium isolated from canine femoral veins and arteries were used. BPS induced a dose-dependent contraction without precontraction and after precontraction with norepinephrine (NE) or 60 mM K+ in the veins. In contrast, BPS induced a dose-dependent relaxation after precontraction with U46619, a thromboxane A2 (TXA2) analog, or prostaglandin F2 alpha (PGF2 alpha) in the veins. In the arteries, BPS induced contraction at higher concentrations after precontraction with NE. However, BPS relaxed arteries dose-dependently after precontraction with PGF2 alpha. By pretreatment with 13-azaprostanoic acid (13-APA), a TXA2/endoperoxide receptor antagonist, the dose-response curve of BPS in the veins was shifted to the right. Schild plot analysis resulted in a linear regression with a slope of 0.86 +/- 0.13, which was not significantly different from unity, and the pA2 value for 13-APA against BPS was 7.10 +/- 0.06. By pretreatment with BPS, the dose-response curve of U46619 in the veins was shifted to the right. Kaumann plot analysis resulted in a linear regression with a slope of 0.89 +/- 0.09, which was not significantly different from unity, and the pA2 value for BPS against U46619 was 5.68 +/- 0.04. These findings indicate that BPS is a partial agonist for the TXA2/endoperoxide receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Dinoprost; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Female; Femoral Artery; Femoral Vein; In Vitro Techniques; Male; Norepinephrine; Potassium; Prostaglandin Endoperoxides, Synthetic; Prostanoic Acids; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

In helical strips of dog coronary arteries contracted with prostaglandin F2 alpha, relaxant responses to atrial natriuretic peptide (ANP), nitric oxide (NO), nitroglycerin and 8-bromo cyclic GMP were markedly inhibited or abolished by treatment with a high concentration of sodium nitroprusside, whereas the responses to beraprost and papaverine were not influenced. A similar suppression of the responses to ANP, NO, and sodium nitroprusside was observed after treatment with nitroglycerin. The relaxations induced by NO and nitroglycerin were abolished by methylene blue and oxyhemoglobin, whereas the response to ANP was not influenced. The sodium nitroprusside-induced relaxation was significantly potentiated by methylene blue but was abolished by oxyhemoglobin. The increase in cyclic GMP caused by ANP and nitroglycerin was not influenced by treatment with sodium nitroprusside, despite the fact that the responses to ANP and nitroglycerin were suppressed. It can be concluded that ANP and nitroglycerin or sodium nitroprusside share the same mechanism of action on intracellular processes occurring after the synthesis of cyclic GMP in dog coronary artery smooth muscle cells and that cross-tachyphylaxis between nitroglycerin, sodium nitroprusside, and ANP in the mechanical response is not associated with an impaired production of cyclic GMP.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Atrial Natriuretic Factor; Coronary Vessels; Cyclic GMP; Dinoprost; Dogs; Epoprostenol; Female; In Vitro Techniques; Isometric Contraction; Male; Methylene Blue; Muscle Relaxation; Muscle, Smooth, Vascular; Nitrates; Nitroglycerin; Nitroprusside; Oxyhemoglobins; Papaverine; Platelet Aggregation Inhibitors; Vasodilator Agents

Prostaglandins liberated from the uterus in response to chemical and physical stimuli would be important modulators of uterine arterial tone and blood flow. This study was aimed at analyzing mechanisms of vasodilator action of prostaglandins in uterine arteries.. Canine uterine artery strips were suspended in Ringer-Locke solutions for isometric tension recording.. Prostaglandin F2 alpha-induced relaxation was reversed to contraction by cyclooxygenase inhibitors and suppressed by tranylcypromine (prostaglandin I2 synthesis inhibitor) or diphloretin phosphate (an inhibitor of prostaglandin F2 alpha and prostaglandin I2 actions) but was unaffected by endothelium denudation. Prostaglandin E2-induced relaxation was not attenuated by indomethacin but was partially inhibited by a nitric oxide synthase inhibitor and endothelium denudation. Relaxation induced by beraprost (prostaglandin I2 analog) was suppressed by diphloretin phosphate but was not influenced by indomethacin and endothelium denudation.. It appears that prostaglandin F2 alpha-induced relaxation is mediated by prostaglandin I2 released from subendothelial tissues, whereas prostaglandin E2-induced relaxation is caused by release of endothelium-derived nitric oxide and also by an endothelium-independent mechanism.

Topics: Animals; Arteries; Dinoprost; Dinoprostone; Dogs; Endothelium, Vascular; Epoprostenol; Female; In Vitro Techniques; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandins; Uterus; Vasodilation

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