cyclic-gmp and beraprost

The purpose of the present study was to determine whether a stimulator of soluble guanylyl cyclase, BAY 41-2272, inhibits platelet aggregation and to clarify its interaction with nitric oxide (NO).. Blood was collected from anaesthetized Wistar Kyoto rats. The aggregation of washed platelets was measured and the production of cAMP and cGMP was determined.. In adenosine 5'-diphosphate (ADP)-induced platelet aggregation, the anti-aggregating effects of BAY 41-2272, nitroglycerin, sodium nitroprusside and DEA-NONOate were associated with increased levels of cGMP while that of beraprost, a prostacyclin analogue, was correlated with an increase in cAMP. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) prevented the effects of BAY 41-2272 and that of nitroglycerin and sodium nitroprusside, but only inhibited the increase in cGMP produced by of DEA-NONOate. Hydroxocobalamin, an NO scavenger, inhibited the effects of the three NO donors and BAY 41-2272 but did not affect those of beraprost. ADP-induced aggregation and the effects of BAY 41-2272 were not affected by L-nitroarginine. A positive interaction was observed between BAY 41-2272 and the three NO donors. BAY 41-2272 potentiated also the anti-aggregating effects of beraprost, and again this potentiation was inhibited by hydroxocobalamin.. Inhibition of platelet aggregation by BAY 41-2272 requires the reduced form of soluble guanylyl cyclase and the presence of NO. The positive interaction observed between BAY 41-2272 and various NO donors is qualitatively similar whatever the mechanism involved in NO release. Furthermore, a potent synergism is observed between BAY 41-2272 and a prostacyclin analogue, but only in the presence of NO.

Topics: Animals; Cyclic AMP; Cyclic GMP; Drug Interactions; Drug Synergism; Epoprostenol; Guanylate Cyclase; Male; Nitric Oxide; Nitric Oxide Donors; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Rats; Rats, Inbred WKY; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.

Topics: Administration, Oral; Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Male; Piperazines; Probability; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Survival Rate; Vascular Patency; Vasodilator Agents

We investigated the relation between cyclic AMP (cAMP) and nitric oxide (NO) production, as well as the effect of NO on Na , K+-ATPase activity in the human neuroblastoma cell line SH-SY5Y. Two cAMP agonists, dibutyryl cAMP (DBC) and beraprost sodium (BPS), increased cAMP accumulation and NO production in a time and dose dependent manner at 50 mmol/l glucose. On the other hand, cellular sorbitol and myo-inositol contents and protein kinase C activity were not altered by DBC or BPS. A specific protein kinase A inhibitor, H-89, suppressed increases in nitrite/nitrate and cyclic GMP (cGMP) and protein kinase A activity stimulated by DBC or BPS. This finding suggests that cAMP stimulates NO production by activating protein kinase A via a pathway different from the sorbitol-myo-inositol-protein kinase C pathway. We observed that an NO donor, sodium nitroprusside, and an NO agonist, L-arginine, enhanced ouabain sensitive Na+, K+-ATPase activity at 50 mmol/l glucose. We also found that a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited Na+, K+-ATPase activity at 5 mmol/l glucose, and partially suppressed the enzyme activity stimulated by DBC or BPS. The results of this study suggest that cAMP regulates protein kinase A activity, NO production and ouabain sensitive Na+, K+-ATPase activity in a cascade fashion. The results also suggest that protein kinase A at least partially regulates Na+, K+-ATPase activity without mediation by NO in SH-SY5Y cells. We speculate that cAMP and NO are two important regulatory factors in the pathogenesis of diabetic neuropathy.

Topics: Bucladesine; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Enzyme Inhibitors; Epoprostenol; Humans; Isoquinolines; Kinetics; Neuroblastoma; Nitrates; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Ouabain; Sodium-Potassium-Exchanging ATPase; Sulfonamides; Tumor Cells, Cultured

Combined administration of inhaled nitric oxide and beraprost sodium resulted in a more intense decrease in pulmonary vascular resistance than nitric oxide given alone (mean -33% vs -45%, p <0.05), without serious systemic hypotension. Combined therapy with nitric oxide and beraprost sodium is highly desirable in treating primary and secondary pulmonary hypertension in children.

Topics: Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Drug Synergism; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Lung; Nitric Oxide; Vascular Resistance; Vasodilation; Vasodilator Agents

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

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