endothelin-1 and beraprost

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

This study aimed to evaluate the effect of oral beraprost sodium, a prostaglandin I2 analogue, on symptoms of intermittent claudication in patients with arteriosclerosis obliterans. The research design consisted of a before and after treatment study without comparison groups. The subjects comprised arteriosclerosis obliterans patients who experienced intermittent claudication. Furthermore, this study aimed to assess the mechanism of action of beraprost sodium via blood sampling and measurements of flow-mediated vasodilatation before and after treatment.. The study was performed prospectively in 7 patients with arteriosclerosis obliterans. Beraprost sodium (40 microg) was orally administered to 7 patients at study entry, followed by administration of 120 microg/day for 12 weeks. Blood sampling and measurements of flow-mediated vasodilatation were performed before and after treatment at study entry, 4 weeks, and 12 weeks after treatment. Treadmill exercise tests were performed three times at study entry, 4 weeks, and 12 weeks after treatment. The ankle-brachial index (ABI) was measured at rest and after exercise.. Pain-free walking distances increased by 138% at 12 weeks after treatment. Maximum walking distances increased by 133%. The ABI was significantly increased at 4 weeks and 12 weeks after treatment at rest. Endothelin-1 levels tended to be decreased at 1 h after administration of 40 microg beraprost sodium. N(G),N(G)-dimethyl-L-arginine, nitrate ions, and flow-mediated vasodilatation.. Beraprost sodium tended to decrease endothelin-1 levels and improved symptoms of intermittent claudication in patients with arteriosclerosis obliterans.

Topics: Administration, Oral; Aged; Ankle Brachial Index; Arginine; Arteriosclerosis Obliterans; Biomarkers; Endothelin-1; Epoprostenol; Exercise Test; Exercise Tolerance; Humans; Intermittent Claudication; Platelet Aggregation Inhibitors; Prospective Studies; Time Factors; Treatment Outcome; Vasodilation; Vasodilator Agents; Walking

This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension.. Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment.. All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041).. Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.

Topics: Adolescent; Adrenomedullin; Antihypertensive Agents; Atrial Natriuretic Factor; Child; Child, Preschool; Endothelin-1; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Natriuretic Peptide, Brain; Peptides

The agents which increase intracellular cyclic AMP (cAMP) or cyclic GMP (cGMP) have been found to counteract the effects of the vasoconstrictive agents such as endothelin-1 (ET-1). To clarify the mechanism of this interaction, we evaluated the activities of mitogen-activated protein kinase (MAPK) cascade, one of the important signal transduction system of ET-1. Beraprost sodium, an analogue of PGI2, and adrenomedullin, a cAMP-raising agent, inhibited ET-1-induced activation of MAPK. Dibutyryl cAMP (Bt2-cAMP) and 8-bromo-cGMP (8-Br-cGMP), cell permeable analogues of cAMP and cGMP, were also able to inhibit the activation of MAPK and MAPK kinase (MAPKK) by ET-1 without interfering basal activities. In contrast, phorbol 12, 13-dibutylate (PDBu)-induced activation of MAPK and MAPKK was inhibited by Bt2-cAMP but not by 8-Br-cGMP. Interestingly, atrial natriuretic peptide (ANP) partially inhibited PDBu-induced activation of MAPK and MAPKK. These results indicate that cAMP and cGMP inhibit ET-1-induced activation of MAPK in cultured mesangial cells at different steps; the former might inhibit at a step downstream of PKC and the latter prior to PKC. The data also suggest that ANP might have cGMP-independent effect on MAPK.

Topics: Adrenomedullin; Animals; Bucladesine; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Cyclic AMP; Cyclic GMP; Endothelin-1; Enzyme Activation; Enzyme Inhibitors; Epoprostenol; Glomerular Mesangium; Mitogen-Activated Protein Kinase Kinases; Nucleotides, Cyclic; Peptides; Phorbol 12,13-Dibutyrate; Protein Kinases; Rats; Signal Transduction