cyclic-gmp and Pulmonary-Embolism

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.

Topics: Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Embolism; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome; Walk Test

We talk about a hypersensitive bronchial system, when under certain endogen prepositions or exogen influences, upon which a healthy persons reacts hardly or not at all, it comes to a significant raise of the airway resistances. Probably this is the prestadium of a chronic obstructive airway disease, which often occurs with patients suffering from an existant bronchial disease. Therefore it is important for actual clinical practice to discuss those problems, which interfere with the raise of sensitivity of the bronchial airways. The discussion should be based on the actual state of science, because several therapeutic problems and consequences ensue.

Topics: Adenosine Triphosphate; Adenylyl Cyclases; Airway Obstruction; Allergens; Asthma; Bacterial Infections; Bronchi; Bronchial Provocation Tests; Cyclic AMP; Cyclic GMP; Parasympatholytics; Pulmonary Embolism; Receptors, Adrenergic, alpha; Receptors, Adrenergic, beta; Virus Diseases

The pulmonary vasodilation induced by adrenomedullin may be beneficial in the acute pulmonary embolism (APE) setting. This study examined effects of adrenomedullin in sheep with microsphere-induced APE.. Twenty four anesthetized, mechanically ventilated sheep were randomly assigned into 3 groups (n=8 per group): animals not subjected to any intervention (Sham), animals with APE induced by microspheres (500 mg, intravenously) treated 30 min later by intravenous physiological saline (Emb group) or intravenous adrenomedullin (50 ng/kg/min) during 30 min (Emb+Adm group). Plasma concentrations of cyclic adenosine (cAMP) and guanosine monophosphate (cGMP) were determined by enzyme immunoassay.. Variables did not change over time in sham animals. In both embolized groups, microsphere injection significantly (P<0.05) increased pulmonary vascular resistance index (PVRI) and mean pulmonary artery pressure (MPAP) from baseline by 181% and 111-142%, respectively (% change in mean values). Adrenomedullin significantly decreased PVRI (18%-25%) and significantly increased cardiac index (22%-25%) from values recorded 30 min after APE (E30), without modifying MPAP. Adrenomedullin decreased mean arterial pressure (18%-24%) and systemic vascular resistance index (32%-40%). Embolization significantly increased arterial-to-end tidal CO2 gradient, alveolar-to-arterial O2 gradient, and pulmonary shunt fraction from baseline, but these variables were unaffected by adrenomedullin. While adrenomedullin significantly increased plasma cAMP, cGMP levels were unaltered.. Adrenomedullin induces systemic and pulmonary vasodilation, possibly via a cAMP mediated mechanism, without modifying the gas exchange impairment associated with APE. The pulmonary anti-hypertensive effect of adrenomedullin may be offset by increases in cardiac index.

Topics: Acute Disease; Adrenomedullin; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Hypertension, Pulmonary; Lung; Male; Pulmonary Embolism; Sheep; Vasodilation; Vasodilator Agents

Andrographolide is a novel NF-κB inhibitor from the leaves of Andrographis paniculata. Platelet activation is relevant to a variety of thrombotic diseases. However, no data are available concerning the effects of andrographolide in platelet activation. The aim of this study was to examine the mechanisms of andrographolide in preventing platelet activation. Andrographolide (25-75 μΜ) exhibited a more potent activity of inhibiting platelet aggregation stimulated by collagen. Andrographolide inhibited collagen-stimulated platelet activation accompanied by relative Ca(2+) mobilization; thromboxane A(2) formation; and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Andrographolide markedly increased cyclic GMP, but not cyclic AMP levels. Andrographolide also stimulated endothelial nitric oxide synthase (eNOS) expression, NO release, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. ODQ, an inhibitor of guanylate cyclase, markedly reversed the andrographolide-mediated inhibitory effects on platelet aggregation, p38 MAPK and Akt phosphorylation, and the andrographolide-mediated stimulatory effect on VASP phosphorylation. Furthermore, a PI3 kinase inhibitor (LY294002) but not a PKC inhibitor (Ro318220) significantly diminished p38 MAPK phosphorylation; nevertheless, a p38 MAPK inhibitor (SB203580) and LY294002 diminished PKC activity stimulated by collagen. Andrographolide also reduced collagen-triggered hydroxyl radical (OH([Symbol: see text])) formation. In vivo studies revealed that andrographolide (22 and 55 μg/kg) is effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism and significantly prolonged platelet plug formation in mice. This study demonstrates for the first time that andrographolide possesses a novel role of antiplatelet activity, which may involve the activation of the eNOS-NO/cyclic GMP pathway, resulting in the inhibition of the PI3 kinase/Akt-p38 MAPK and PLCγ2-PKC cascades, thereby leading to inhibition of platelet aggregation.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Calcium; Collagen; Cyclic GMP; Diterpenes; Humans; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type III; Platelet Activation; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Pulmonary Embolism; Thromboxane A2

The current therapy of acute pulmonary embolism is focused on removing the mechanical obstruction of the pulmonary vessels. However, accumulating evidence suggests that pulmonary vasoconstriction drives many of the hemodynamic changes found in this condition. We examined the effects of stimulation of soluble guanylate cyclase with BAY 41-2272 (5-Cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrim idin-4-ylamine) in an anesthetized dog model of acute pulmonary embolism. Hemodynamic and arterial blood gas evaluations were performed in non-embolized dogs treated with vehicle (N=5), and in embolized dogs (intravenous injections of microspheres) that received BAY 41-2272 intravenously in doses of 0.03, 0.1, 0.3, and 1 mg/kg/h or vehicle (1 ml/kg/h of 1.13% ethanol in saline, volume/volume). Plasma cGMP and thiobarbituric acid reactive substances concentrations were determined using a commercial enzyme immunoassay and a fluorometric method, respectively. The infusion of BAY 41-2272 resulted in a decrease in pulmonary artery pressure by approximately 29%, and in pulmonary vascular resistance by approximately 46% of the respective increases induced by lung embolization (both P<0.05). While the higher doses of BAY 41-2272 produced no additional effects on the pulmonary circulation, they caused significant arterial hypotension and reduction in systemic vascular resistance (both P<0.05). Although BAY 41-2272 increased cGMP concentrations (P<0.05), it did not affect the hypoxemia and the increased oxidative stress caused by lung embolization. These results suggest that stimulation of soluble guanylate cyclase with low (but not high) doses of BAY 41-2272 produces selective pulmonary vasodilation during acute pulmonary embolism. The dose-dependent systemic effects produced by BAY 41-2272, however, may limit its usefulness in larger doses.

Topics: Acute Disease; Animals; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Female; Guanylate Cyclase; Hemodynamics; Lipid Peroxides; Male; Pulmonary Embolism; Pyrazoles; Pyridines; Respiration

We compared the lipid-lowering, vasodilating, anti-thrombotic and anti-inflammatory properties of NCX 6560, a novel NO-releasing derivative of atorvastatin, with those of atorvastatin. NCX 6560 and atorvastatin induced similar inhibition of cholesterol biosynthesis in rat smooth muscle cells (IC(50)=1.9+/-0.4 and 3.9+/-1.0 microM, respectively). However, in hyperlipidemic mice, a 5-week oral treatment with NCX 6560 (46.8 mg/kg/day, p.o.) was more effective than equivalent atorvastatin (40 mg/kg/day, p.o.) at lowering serum cholesterol (NCX 6560: -21% vs controls, P<0.05; atorvastatin: -14% vs control, P=NS). In norepinephrine-precontracted rabbit aortic rings, NCX 6560-induced vasodilation (EC(50)=53.5+/-8.3 microM) and in PC12 cells it stimulated cGMP formation (EC(50)=1.8+/-0.7 microM), while atorvastatin was inactive. In lipopolysaccharide from Escherichia coli (LPS)-treated RAW 264.7 macrophages, NCX 6560 reduced iNOS expression and dimer assembly more efficiently than atorvastatin and inhibited nitrite accumulation (IC(50)=6.7+/-1.6 microM) and TNFalpha release. U46619- or collagen plus epinephrine-induced platelet pulmonary thromboembolism in mice was reduced by NCX 6560 at 46.8 mg/kg p.o. (mortality: -44% and -56% vs vehicle, respectively; P<0.05), but not by atorvastatin 40 mg/kg, p.o. In the U46619-induced mortality model, isosorbide mononitrate (ISMN) (20 mg/kg, p.o.), a pure NO-donor, was also active (mortality: -40%, P<0.05). NCX 6560 significantly reduced ex vivo platelet adhesion to collagen at high shear (-31+/-1.3% vs vehicle), and so did ISMN (-33.3+/-1.7% vs vehicle). Atorvastatin was ineffective. NCX 6560, but not atorvastatin, reduced blood pressure in eNOS knockout mice (-16%, P<0.001 vs vehicle), an effect not observed in wild type mice. On the contrary, ISMN provoked a significant drop of blood pressure both in wild type (-20%, P<0.05 vs vehicle) and in eNOS-/- mice (-21%, P<0.05 vs vehicle). In conclusion, NCX 6560 exerts greater lipid-lowering, anti-thrombotic and anti-inflammatory effects than atorvastatin, due to a large extent to NO release.

Topics: Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Aorta, Thoracic; Atorvastatin; Blood Pressure; Cell Line; Cholesterol; Cyclic GMP; Fibrinolytic Agents; Heptanoic Acids; Hyperlipidemias; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Myocytes, Smooth Muscle; Nitric Oxide Donors; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; PC12 Cells; Pulmonary Embolism; Pyrroles; Rabbits; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vasodilator Agents

Activating the nitric oxide (NO)-cyclic guanosine 3',5'-monophosphate (cGMP) pathway improves haemodynamics following acute pulmonary thromboembolism (APT). However, the role of NO synthase (NOS) isoforms in the responses to APT has not been determined. We examined the effects of selective and non-selective inducible NOS (iNOS) inhibition.. Haemodynamic evaluations were performed in non-embolized dogs treated with saline (control group; n = 4), L-NAME (NAME group; n = 3), or aminoguanidine (AG group; n = 3), and in dogs that received the same drugs and were embolized with 5 mL kg(-1) of clots made with autologous blood (Emb group, n = 9; NAME + Emb group, n = 4 and AG + Emb group, n = 7). The lung concentrations of nitrite/nitrate (NOx) and cGMP were determined by chemiluminescence and ELISA respectively.. Acute pulmonary thromboembolism increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 21.4 +/- 1.7 mmHg and by 843 +/- 34 dyn s cm(-5) m(-2), respectively, in Emb group. MPAP and PVRI increased to higher levels in the NAME + Emb group 15 min after APT and all dogs in this group died 15-30 min after APT. Conversely, lower MPAP and PVRI levels were found in the AG + Emb group 2 h after APT compared with the Emb group (both P < 0.05). Higher NOx concentrations were found in the Emb group compared with the other groups (all P < 0.05). Higher cGMP concentrations were found in the Emb and AG + Emb groups compared with the other groups (all P < 0.05).. These results indicate that endogenous NO protects against APT-induced cardiovascular responses. Moreover, iNOS-derived NO possibly produces unfavourable effects, which are counteracted by aminoguanidine. However, non-NO-related mechanisms may also be involved.

Topics: Acute Disease; Animals; Blood Pressure; Cyclic GMP; Dogs; Female; Guanidines; Lung; Male; Models, Animal; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase Type II; Pulmonary Embolism; Vascular Resistance

Sildenafil attenuates acute pulmonary embolism (APE)-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during APE have not been examined yet. In the present study, we examined the hemodynamic effects of combined diethylenetriamine/nonoate (DETA-NO, 1microMol kg(-1), i.v.) and sildenafil (0.25mg/kg, i.v.) in an anesthetized dog model of APE. Plasma nitrite/nitrate (NO(x)) and cyclic GMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that this dose of DETA-NO did not attenuate APE-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 15, 30 and 45min after the administration of sildenafil alone or after the combined administration of DETA-NO and sildenafil (all P<0.05). No significant differences among groups were observed in the respiratory parameters. While DETA-NO significantly increased NO(x) concentrations by approximately 4microM, cyclic GMP concentrations increased only when sildenafil was administered (all P<0.05). These results show that the combined administration of 1microMol kg(-1) of DETA-NO and sildenafil is not advantageous compared with sildenafil alone, thus suggesting that sildenafil alone produced maximum attenuation of APE-induced pulmonary hypertension, as far as the NO-cGMP pathway is concerned.

Topics: Animals; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dogs; Drug Interactions; Female; Heart Rate; Hemodynamics; Male; Nitrates; Nitric Oxide Donors; Nitrites; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sulfones; Time Factors; Vascular Resistance

Sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension. However, the hemodynamic effects of sildenafil in combination with other vasodilators during acute pulmonary embolism have not been examined yet. In the present study, we examined the hemodynamic effects of combined sildenafil (0.25 mg/kg, i.v.) and L-arginine (100, 200, 500, and 1000 mg/kg/h, i.v.) in an anesthetized dog model of acute pulmonary embolism. Plasma nitrite/nitrate (NO(x)) and cGMP concentrations were determined using an ozone-based chemiluminescence assay and a commercial enzyme immunoassay, respectively. We found that L-arginine alone did not attenuate acute pulmonary embolism-induced pulmonary hypertension. However, significant decreases in mean pulmonary artery pressure were observed 30, 45, 60, and 75 min after the administration of sildenafil alone or after the combined administration of sildenafil and L-arginine (all P < 0.05). No significant differences among groups were observed in the respiratory parameters. While L-arginine significantly increased NO(x) concentrations, cGMP concentrations increased only when sildenafil was administered (all P < 0.05). These results suggest that while sildenafil attenuates acute pulmonary embolism-induced pulmonary hypertension, L-arginine does not enhance the beneficial hemodynamic effects of sildenafil. In addition, these findings suggest that stimulation of NO synthesis with L-arginine during acute pulmonary embolism does not produce beneficial effects.

Topics: Acute Disease; Analysis of Variance; Animals; Arginine; Blood Pressure; Cyclic GMP; Dogs; Female; Heart Rate; Hypertension, Pulmonary; Infusions, Intravenous; Male; Nitrates; Nitrites; Piperazines; Pulmonary Artery; Pulmonary Embolism; Purines; Respiration; Sildenafil Citrate; Sulfones; Time Factors; Vasodilator Agents