beraprost and Hypoxia

Some patients with chronic obstructive pulmonary disease (COPD) have pulmonary hypertension (PH) that adversely affects survival. We performed a systematic review and meta-analysis to assess whether PH-specific therapies have an effect for stable COPD. Data sources were Medline, EMBASE, Cochrane Central Register of Controlled Trials, Korea med and references from relevant publications. Randomized prospective trials that compared PH specific therapy in COPD for more than 6 weeks with placebo were included. The outcomes were the exercise capacity and adverse events. Four randomized controlled trials involving 109 subjects were included in the analysis. Two trials involved bosentan, one sildenafil and one beraprost. The studies varied in duration of treatment from 3 to 18 months. In a pooled analysis of four trials, exercise-capacity was not significantly improved with PH-specific treatment for COPD (risk ratio, -5.1; 95% CI, -13.0 to 2.8). COPD with overt PH significantly improved the exercise capacity (mean difference, 111.6; 95% CI, 63.3 to 159.9) but COPD with PH unknown did not (mean difference, 26.6; 95% CI, -24.3 to 77.5). There was no significant difference in hypoxemia (mean difference, 2.6; 95% CI, -3.7 to 8.8). PH specific treatments have a significant effect in improving exercise capacity in COPD with overt PH.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Databases, Factual; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Surveys and Questionnaires

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Cells, Cultured; Disease Models, Animal; Epoprostenol; Hypoxia; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxygen; Potassium Channels, Voltage-Gated; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Up-Regulation; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Topics: Administration, Inhalation; Animals; Chronic Disease; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Receptors, Prostaglandin; RNA, Messenger

To determine whether beraprost sodium (beraprost) can cause pulmonary vasodilation in chronic hypoxic pulmonary hypertension, we measured the hemodynamic effects of intravenous beraprost, a stable and orally active agent with a PGI2-like structure, in chronic hypoxic (H) and normoxic (N) rats. During anesthesia baseline pulmonary artery pressure (PAP) was 32.0 +/- 1.0 in H rats and 18.0 +/- 0.4 mmHg in N rats. Intravenous beraprost (20 micrograms/kg) elicited acute pulmonary vasodilation by 17.7 +/- 4.6% (5.6 +/- 1.4 mmHg) in H rats and by 16.8 +/- 2.1% (3.0 +/- 0.6 mmHg) in N rats, which indicates that the relative degree of acute pulmonary vasodilation caused by beraprost was similar in H and N rats. Thirty minutes after the drug was injected, PAP had not returned to baseline levels in either H or N rats, and it was lower in H rats (90 +/- 2%) than in N rats (95 +/- 2%). Lungs were isolated and perfused with saline, and those from H rats and N rats showed similar pulmonary vasodilator responses to 2 and 20 micrograms/kg beraprost. These results indicate that although beraprost caused a similar degree of acute pulmonary vasodilation in H and N rats, in H rats the response lasted longer. Thus PGI2 derivatives may be useful as vasodilators in some patients with primary and secondary pulmonary hypertension.

Topics: Animals; Blood Pressure; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilation

1. The present study was performed to determine whether beraprost, a new stable analogue of prostacyclin, may exert beneficial effects on the transmembrane action potentials during normoxia and hypoxia-reoxygenation in isolated right ventricular muscles of the guinea-pig. 2. Under normal oxygenation, beraprost (0.01-100 mumol-1) had no effects on the electrophysiological parameters. 3. Hypoxic conditions induced a decrease in action potential duration (APD) without affecting other action potential parameters. Beraprost inhibited this hypoxia-induced decrease in APD. However, beraprost had no effect on the decrease in contractile force induced by hypoxia, whereas it significantly improved the recovery of contractile force after reoxygenation. 4. Pinacidil-induced shortening of APD was not antagonized by beraprost. 5. Hypoxia significantly decreased the myocardial adenosine triphosphate (ATP) level, which was also prevented by beraprost. 6. These results suggested that beraprost may inhibit the hypoxia-induced shortening of APD by some mechanisms which contribute to the maintenance of muscle ATP level.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Epoprostenol; Guanidines; Guinea Pigs; Heart; Heart Ventricles; Hypoxia; In Vitro Techniques; Male; Membrane Potentials; Myocardial Contraction; Myocardium; Oxygen; Papillary Muscles; Pinacidil; Vasodilator Agents

1. The present study was undertaken to determine whether beraprost, a stable prostacyclin-mimetic agent, may exert a beneficial effect on post-hypoxic recovery of cardiac function and metabolism. Isolated rabbit hearts were perfused by the Langendorff method for 20 min under glucose-free hypoxic conditions, followed by 45 min reoxygenation in the presence of glucose, and their functional and metabolic changes with or without beraprost-treatment were examined. 2. Hypoxic insult induced cessation of cardiac contractile force, depletion of myocardial high-energy phosphates, accumulation of tissue calcium, and release of creatine kinase and ATP metabolites. Subsequent reoxygenation resulted in a poor recovery of cardiac contractile force (less than 10% of the pre-hypoxic value), a poor restoration of high-energy phosphates, and increase in calcium content. A further release of creatine kinase and ATP metabolites from the heart was observed during reoxygenation. 3. Treatment with 0.45 microM beraprost during the whole hypoxic period resulted in a significant suppression of the increase in tissue calcium, and the release of creatine kinase and ATP metabolites during hypoxic perfusion. This treatment also elicited a significant post-hypoxic recovery of the cardiac contractile force and the tissue high-energy phosphates. Reoxygenation-induced release of creatine kinase and ATP metabolites was also prevented by treatment with beraprost. 4. When hearts were treated with prostacyclin sodium (0.50 microM) in the same manner for the purpose of comparison, similar improvement of post-hypoxic contractile and metabolic recovery were observed. 5. These results demonstrate that treatment with either beraprost or prostacyclin is beneficial for post-hypoxic recovery of cardiac function and metabolism. Since the observed effects on post-hypoxic contractile recovery were exerted at a concentration of approximately 0.50 microM of these agents (a concentration far from the physiological range) the underlying mechanism appears to be different from the physiological action of prostacyclin.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Body Water; Calcium; Creatine Kinase; Epoprostenol; Heart; Hypoxia; In Vitro Techniques; Myocardial Contraction; Myocardium; Perfusion; Platelet Aggregation Inhibitors; Rabbits