cyclic-gmp and Lung-Diseases--Obstructive

Topics: Arachidonic Acid; Arachidonic Acids; Asthma; Calcium; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Humans; Lung Diseases, Obstructive; Mast Cells; Muscle, Smooth; Respiratory Hypersensitivity

Hemodynamic parameters were measured by ballon tipped catheter in 11 patients with COPD and plasma levels of endothelin1 (ET1), cAMP and cGMP were detected by radioimmunoassay. The results indicated that 3,4-dihydroxyacetophenone (DHAP) gives with an i.v. dose of 640mg could reduce (1) 15% of mean pulmonary arterial pressure, 39% of pulmonary vascular resistance and 21% of systemic vascular resistance; (2) but not effect on systemic arterial pressure and blood gas analysis; (3) decrease the plasma ET1 as well as cGMP level (P < 0.01, P < 0.05 respectively). The authors think that the decrease of pulmonary arterial pressure in COPD patients may be related to the lowering of plasma ET1 level and the change of the cAMP to cGMP ratio.

Topics: Acetophenones; Adult; Aged; Cyclic AMP; Cyclic GMP; Endothelins; Female; Hemodynamics; Humans; Lung Diseases, Obstructive; Male; Middle Aged

Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.

Topics: Airway Resistance; Animals; Benzoates; Cyclic GMP; Drug Evaluation, Preclinical; Enzyme Activation; Guanylate Cyclase; Lung Diseases, Obstructive; Lung Injury; Male; Mice, Inbred C57BL

In order to study the effect of dihydroxyacetophenone (DHAP) on pulmonary hemodynamics and its relationship to plasma ANP as well as cAMP/cGMP level in chronic obstructive pulmonary disease (COPD), 11 COPD patients were examined with the right heart catheterisation, and the plasma ANP and cAMP/cGMP were measured with radioimmunoassay at the same time. The results showed that intravenous given DHAP 640 mg could decrease mean pulmonary arterial pressure, pulmonary vascular resistance and systemic vascular resistance (P < 0.05), but increase the cardiac output from 4.10 +/- 1.08 L/min to 5.13 +/- 1.19 L/min (P > 0.05) and not affect systemic arterial pressure (P > 0.05) as well as blood gas analysis; it also reduce the plasma ANP and cGMP level from 0.73 +/- 0.42 pg/ml to 0.41 +/- 0.33 pg/ml (P < 0.01) and from 9.82 +/- 5.75 pm/ml to 8.01 +/- 4.80 pm/ml (P < 0.05) respectively, but did not affect the plasma cAMP level (P > 0.05). It is suggested that DHAP may relax pulmonary vessels by regulating the ratio of cAMP to cGMP, and the lowering of plasma ANP level might be a secondary reaction. So we consider that DHAP is a fast-acting, safe and potential drug in treating pulmonary arterial hypertension by COPD.

Topics: Acetophenones; Adult; Aged; Atrial Natriuretic Factor; Blood Pressure; Cyclic AMP; Cyclic GMP; Female; Hemodynamics; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Circulation; Vascular Resistance

The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control- respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55-93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 10(6) cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3-4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions.

Topics: 1-Methyl-3-isobutylxanthine; Adult; Albuterol; Bronchoalveolar Lavage Fluid; Cyclic AMP; Cyclic GMP; Dinoprostone; Female; Humans; Leukotriene B4; Lung; Lung Diseases, Obstructive; Macrophages, Alveolar; Male; Middle Aged; Nitroprusside; Smoking

The purpose of this study was to evaluate the pathophysiologic role of atrial natriuretic peptide (ANP) as a pulmonary artery vasodilator in patients with acute respiratory failure receiving artificial ventilation. Twenty-one consecutive patients were studied, 12 without and 9 with preexisting cardiopulmonary disease. Pulmonary artery plasma ANP levels were significantly higher than the levels obtained in the superior vena cava and radial artery. Plasma ANP levels correlated significantly with the plasma levels of its second messenger, guanosine 3',5'-cyclic monophosphate (cGMP). In the 12 patients without prior cardiopulmonary disease, plasma ANP levels correlated significantly with mean pulmonary arterial pressure (MPAP). This correlation was not found in the nine patients with preexisting cardiopulmonary disease. The cGMP/ANP ratio, indicating the biologic effect of ANP, was also higher in the patients without preexisting cardiopulmonary disease. These results are compatible with clearance and vasodilator activity of ANP in the pulmonary vascular bed, but only in patients without preexisting cardiopulmonary disease.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Atrial Function, Right; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Heart Failure; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Pulmonary Artery; Pulmonary Fibrosis; Radial Artery; Respiration, Artificial; Respiratory Insufficiency; Vena Cava, Superior

Topics: Aged; Arteries; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Humans; Lung Diseases, Obstructive; Male; Pulmonary Artery; Veins

Deeper insight into the pharmacodynamics and pharmacokinetics of theophylline during the past 10 years led to the wide-spread use of the substance in the treatment of obstructive airway diseases. The effect of theophylline can be explained by different mechanisms of action, namely increase in cAMP and prostaglandins, redistribution of calcium, and blockade of purinergic receptors. Besides the known antiobstructive activity of theophylline ethylenediamine, its influence on the respiratory muscles is an essential clinical quality. The results of pharmacokinetic studies and routine determination of theophylline levels contributed to greatly improve the efficacy of theophylline therapy. At adequate doses, theophylline or theophylline ethylenediamine in sustained-release form constitutes the most effective long-term treatment of chronic asthma today. The pharmacological properties of ethylenediamine reinforce some of the more important effects of theophylline and improve tolerance. Combining the substance with beta-sympathomimetics elicits additive effects, while side effects are kept low.

Topics: Calcium; Cyclic AMP; Cyclic GMP; Delayed-Action Preparations; Humans; Lung Diseases, Obstructive; Mast Cells; Prostaglandins E; Receptors, Histamine; Theophylline