beraprost and Myocardial-Ischemia

Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease.

Topics: Administration, Oral; Cardiovascular Diseases; Epoprostenol; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Myocardial Ischemia; Neovascularization, Physiologic; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Treatment Outcome; Vasodilator Agents

The purpose of this study was to investigate the effects of beraprost sodium, a stable prostacyclin analog, on the parameters of hemostasis, fibrinolysis, and myocardial ischemia in patients with exertional angina. Thirty-one patients with exertional angina who had significant organic coronary artery stenosis in at least one of the three major coronary arteries were selected. All patients underwent quantitative exercise thallium-201 emission computed tomography before and 1 month after 120 micrograms per day of beraprost sodium administration. Before exercise, blood samples were collected from 8:30 a.m. to 9:30 a.m. after the patients had been lying in bed undisturbed for at least 10 minutes. Plasma platelet factor 4 (PF4), fibrinopeptide A (FPA), tissue plasminogen activator antigen (t-PA), and plasminogen activator inhibitor-1 activity (PAI-1) were measured. There were no significant differences in exercise parameters on both exercise tests. However, both the extent and severity scores of ischemia were significantly aggravated (p < 0.05 for both) during beraprost sodium administration. Plasma FPA levels decreased significantly during beraprost sodium administration (p < 0.01). Likewise, plasma PF4 levels decreased significantly during beraprost sodium administration (p < 0.05). As for plasma t-PA antigen levels, there was no significant difference before versus during beraprost sodium administration. Plasma PAI-1 activity levels decreased significantly during beraprost sodium administration (p < 0.05). The results indicate that beraprost sodium has strong antithrombogenic properties. However, its aggravation of myocardial ischemia may limit clinical usage.

Topics: Angina Pectoris; Cardiac Catheterization; Epoprostenol; Female; Fibrinolytic Agents; Hemodynamics; Hemostasis; Humans; Male; Middle Aged; Myocardial Ischemia; Physical Exertion; Platelet Aggregation Inhibitors; Thallium Radioisotopes; Thrombin; Tomography, Emission-Computed

Doxorubicin (DOX) is widely used as an anti-cancer agent although it causes irreversible cardiomyopathy by increasing oxidative stress and deregulating nitric oxide production. Beraprost (BPS), a stable prostacyclin (PGI2) analog, is a potent vasodilator that has beneficial effects on myocardial ischemia. The objectives of the present study were to delineate the uncertain effects of prostcyclin therapy on DOX induced cardiomyopathy and to explore the mechanisms underlying PGI2 and DOX interaction. For this reason, we stimulated endogenous PGI2 production using bicistronic COX-1/PGIS gene transfer and BPS supplementation, and investigated the effects on DOX-induced cardiomyopathy. Caspase-dependent protein content, lactate dehydrogenase (LDH), DNA fragmentation, and TUNEL positive cells were elevated in DOX-treated cardiomyocytes. These indicators were further elevated by adenovirus-COX- 1/PGIS transfection or BPS supplementation. In addition, PGI2 overexpression further increased iNOS expression and superoxide accumulation in cardiomyocytes compared with DOX alone, which may be the reason for aggravated cytotoxicity. Moreover, BPS can induce cAMP response elements (CRE) binding to the iNOS promoter and phospho- cAMP response element binding protein (CREB) expression in a cyclic AMP-dependent manner. Our in vivo studies show that MnTBAP and aminoguanidine treatment of DOX and BPS co-administered in mice can attenuate caspase-3 and PARP-1 protein expression, and improve mouse survival, as observed in the iNOS gene-deleted mice. In conclusion, we demonstrated that BPS or adv-COX-1/PGIS increases PGI2 levels through iNOS expression and peroxynitrite production, via CREB protein phosphorylation; thereby aggravating DOX-mediated cardiotoxicity.

Topics: Animals; Apoptosis; Cardiomyopathies; CREB-Binding Protein; Cyclooxygenase 1; Doxorubicin; Epoprostenol; Male; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Peroxynitrous Acid; Phosphorylation; Prostaglandins; Rats; Rats, Wistar

Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague-Dawley rats, beraprost (200 microg/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administration of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and c-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells.

Topics: Animals; Bone Marrow Cells; Cardiotonic Agents; Cell Movement; Epoprostenol; Male; Myocardial Ischemia; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Treatment Outcome; Vasodilator Agents

We compared the cardioprotective effects during experimental ischemia and reperfusion of beraprost sodium (beraprost), a prostacyclin analog, with those of propranolol and diltiazem. Coronary perfused guinea-pig right ventricular free wall preparations were subjected to 30 min no-flow ischemia with or without drugs, followed by 60 min reperfusion without drugs. In control preparations, decrease in contractile force and increase in resting tension were observed during the no-flow period. On reperfusion, contractile force returned to less than 50% of preischemic values. Beraprost, at 0.1 microM, showed no inotropic effect under normoxic condition and during the no-flow period, but significantly enhanced the recovery of contractile force after reperfusion to about 80% of control values. Propranolol (30 microM) or diltiazem (10 microM) produced similar enhancement of recovery of contractile force after reperfusion, but these two drugs decreased the contractile force under normoxic conditions to less than 20% of control values. Thus, the cardioprotective effect of beraprost was different from those of propranolol and diltiazem in that it was not accompanied by cardiosuppressive effects.

Topics: Animals; Diltiazem; Epoprostenol; Guinea Pigs; Heart; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Platelet Aggregation Inhibitors; Propranolol; Vasodilator Agents