cyclic-gmp and Pulmonary-Edema

OBJECTIVE AND DATA SOURCE: Experimental and clinical data reported in the international literature have been collected and critically reviewed to summarize knowledge of the role of atrial natriuretic factor (ANF) in lung physiology and pathophysiology.. Lung contribution to circulating ANF concentration is modest, whereas its capability of degrading ANF is very high, the lung being one of the major sites of ANF catabolism. The impairment of ANF protease activity in lung tissue by hypoxia and pulmonary hypertension could be responsible for the increase in ANF plasma levels observed in several pulmonary pathological conditions. ANF-specific binding sites in lung are reportedly greater than in any other tissue. ANF induces a cGMP-mediated relaxation of central (rather than peripheral) bronchi. ANF bronchodilating effect has also been clinically demonstrated; eg, asthmatic patients show increased plasma ANF levels and exogenous ANF infusion provokes bronchial relaxation comparable with the salbutamol-induced effect. Moreover, ANF determines pulmonary artery vasodilation, thus contributing to improved pulmonary circulation. When pathophysiological levels are present in plasma, ANF influences pulmonary fluid regulation provoking protein mobilization from arteries to the alveolar space whereas ANF pharmacological concentrations re-equilibrate the transwall gradient. A remarkable enhancement of guanylate cyclase activity in lung tissue before hemodynamic modifications by both endogenous end exogenous ANF has been reported in pneumocytes of cardiomyopathic hamsters. On the other hand, ANF infusion provokes a reduction of pulmonary edema induced by pneumotoxic chemicals through a mechanism independent of the natriuretic/hypotensive action of the peptide and not mediated by cGMP.. The modest amount of specific research on ANF effects on lung does not permit a final assessment of natriuretic peptides in pulmonary physiology and pathophysiology. In particular, further investigations are needed to determine the potential clinical relevance of ANF in asthma and pulmonary edema.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Humans; Lung; Lung Diseases; Pulmonary Edema

Topics: Adolescent; Albuterol; Asthma; Beclomethasone; Bronchodilator Agents; Carboxylic Acids; Child; Child, Preschool; Cromolyn Sodium; Cyclic AMP; Cyclic GMP; Humans; Hypertension, Pulmonary; Immunoglobulin E; Metaproterenol; Phenols; Prostaglandins; Pulmonary Atelectasis; Pulmonary Edema; Radiography; Respiratory Function Tests; Terbutaline; Tetrazoles; Xanthenes

Decrease in lung compliance is one of the major causes of respiratory failure. We investigated whether amrinone could improve lung compliance.. We selected 20 consecutive patients with respiratory failure due to severe cardiogenic pulmonary edema to receive mechanical ventilation. Patients were administered a bolus injection (1 mg.kg-1) over 10 min followed by continuous intravenous infusion (10 micrograms.kg-1.min-1) of amrinone. Lung compliance, blood gas values, hemodynamic parameters, and sample plasma amrinone levels were assessed over a 120-min period after the onset of the continuous infusion of amrinone.. Ten min following amrinone infusion, dynamic compliance (Cdyn) and static compliance (Cst) increased from 30 +/- 11 to 36 +/- 12 ml/cm H2O and from 37 +/- 12 to 42 +/- 13 ml/cm H2O, respectively (P < 0.01). Plasma amrinone levels reached a therapeutic level as vasodilator and positive inotropic effects at 10 min after amrinone infusion. The significant change in mean pulmonary artery pressure and pulmonary artery wedge pressure occurred later than the change in compliance of respiratory system. However, there were significant correlations between the mean pulmonary artery pressure and Cdyn (r = 0.36, P < 0.01) and Cst (r = 0.44, P < 0.01), as well as between plasma amrinone levels and Cdyn (r = 0.30, P < 0.05) and Cst (r = 0.41, P < 0.01).. Amrinone-induced improvement in lung compliance was considered mainly to be due to an increase in the number of functioning lung units by improvement of the hemodynamics and a direct positive effect of amrinone on respiratory muscle contraction.

Topics: Aged; Amrinone; Blood Gas Analysis; Cyclic AMP; Cyclic GMP; Female; Heart Failure; Hemodynamics; Humans; Lung Compliance; Male; Myocardial Contraction; Pulmonary Edema; Respiration, Artificial; Respiratory Mechanics; Vasodilator Agents

Atrial Natriuretic Peptide (ANP) is secreted in response to hypoxia and pulmonary vasoconstriction. The hormone modulates pulmonary vascular tone in vivo and decreases pulmonary edema in isolated lungs exposed to several toxic agents. In addition, ANP improves the barrier function of endothelial cell monolayers in vitro. The plasma levels of ANP are elevated in patients with high-altitude pulmonary edema. We hypothesized that under these circumstances, ANP improves pulmonary gas exchange by attenuating the transvascular permeation of plasma (water). Therefore, we studied the effect of low-dose ANP in 11 healthy mountaineers exposed to hypoxia in a single-blind, placebo-controlled, cross-over design. During four 1-h periods, the subjects were stepwise exposed to decreasing barometric pressure, with a minimum of 456 mm Hg (simulated altitude, 4,115 m). Infusion of 5 ng/kg/min human-ANP increased the plasma ANP concentrations approximately twofold. The plasma concentrations of cyclic GMP, which is the second messenger of ANP, rose approximately threefold. Infusion of ANP did not affect the hemodynamic or ventilatory response to hypoxia. The hemoglobin concentration, however, rose from 9.0 +/- 0.1 to 9.4 +/- 0.1 mmol/L (p < 0.01) during ANP infusion but not during placebo infusion. The change in plasma volume calculated from this hemoconcentration indicated that approximately 10% of the plasma volume had permeated into the interstitium. Despite the observed whole-body hemoconcentration, oxygen saturation was significantly higher during ANP infusion than during placebo infusion (84.7 +/- 1.7 versus 79.6 +/- 1.8%, p < 0.05), and the alveolar-arterial oxygen difference was significantly lower (3.5 +/- 0.7 versus 7.3 +/- 0.8 mm Hg, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Blood Proteins; Carbon Dioxide; Cyclic GMP; Heart Rate; Hemoglobins; Humans; Hypoxia; Infusions, Intravenous; Mountaineering; Oxygen; Oxygen Consumption; Partial Pressure; Placebos; Plasma Volume; Pulmonary Edema; Pulmonary Gas Exchange; Single-Blind Method

Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.. CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (. The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Aorta; Carrier Proteins; Collagen; Constriction, Pathologic; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Fibrosis; Heart; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Lung; Male; Mice; Organ Size; Phosphodiesterase Inhibitors; Phosphorylation; Pulmonary Edema; Stroke Volume; Ventricular Remodeling

Nicorandil is a hybrid between nitrates and K. Nicorandil attenuated IR injury in isolated rat lungs. This protective effect appears to involve its activation as K

Topics: Animals; Capillary Permeability; Cyclic GMP; KATP Channels; Lung; Lung Injury; Male; Membrane Transport Modulators; Nicorandil; Perfusion; Pulmonary Circulation; Pulmonary Edema; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Soluble Guanylyl Cyclase; Vascular Resistance

Lungs from non-heart-beating donors (NHBDs) would enhance the donor pool. Ex vivo perfusion and ventilation of NHBD lungs allows functional assessment and treatment. Ventilation of rat NHBD lungs with nitric oxide (NO) during ischemia, ex vivo perfusion and after transplant reduced ischemia-reperfusion injury (IRI) and improved lung function posttransplant. One hour after death, Sprague-Dawley rats were ventilated for another hour with either 60% O2 or 60% O2/40 ppm NO. Lungs were then flushed with 20-mL cold Perfadex, stored cold for 1 h, perfused in an ex vivo circuit with Steen solution and warmed to 37 degrees C, ventilated 15 min, perfusion-cooled to 20 degrees C, then flushed with cold Perfadex and stored cold. The left lung was transplanted and ventilated separately. Recipients were sacrificed after 1 h. NO-ventilation was associated with significantly reduced wet:dry weight ratio in the ex vivo circuit, better oxygenation, reduced pulmonary vascular resistance, increased lung tissue levels of cGMP, maintained endothelial NOS eNOS, and reduced increases in tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS). NO-ventilation had no effect on MAP kinases or NF-kappaB activation. NO administration to NHBDs before and after lung retrieval may improve function of lungs from NHBDs.

Topics: Animals; Cyclic GMP; Lung; Lung Transplantation; Mitogen-Activated Protein Kinases; Myocardial Contraction; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Organ Preservation; Pulmonary Edema; Rats; Reperfusion Injury; Tissue Donors; Tumor Necrosis Factor-alpha

Although the formation of hydrostatic lung edema is generally attributed to imbalanced Starling forces, recent data show that lung endothelial cells respond to increased vascular pressure and may thus regulate vascular permeability and edema formation. In combining real-time optical imaging of the endothelial Ca(2+) concentration ([Ca(2+)](i)) and NO production with filtration coefficient (K(f)) measurements in the isolated perfused lung, we identified a series of endothelial responses that constitute a negative-feedback loop to protect the microvascular barrier. Elevation of lung microvascular pressure was shown to increase endothelial [Ca(2+)](i) via activation of transient receptor potential vanilloid 4 (TRPV4) channels. The endothelial [Ca(2+)](i) transient increased K(f) via activation of myosin light-chain kinase and simultaneously stimulated NO synthesis. In TRPV4 deficient mice, pressure-induced increases in endothelial [Ca(2+)](i), NO synthesis, and lung wet/dry weight ratio were largely blocked. Endothelial NO formation limited the permeability increase by a cGMP-dependent attenuation of the pressure-induced [Ca(2+)](i) response. Inactivation of TRPV4 channels by cGMP was confirmed by whole-cell patch-clamp of pulmonary microvascular endothelial cells and intravital imaging of endothelial [Ca(2+)](i). Hence, pressure-induced endothelial Ca(2+) influx via TRPV4 channels increases lung vascular permeability yet concomitantly activates an NO-mediated negative-feedback loop that protects the vascular barrier by a cGMP-dependent attenuation of the endothelial [Ca(2+)](i) response. The identification of this novel regulatory pathway gives rise to new treatment strategies, as demonstrated in vivo in rats with acute myocardial infarction in which inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil reduced hydrostatic lung edema.

Topics: Animals; Calcium; Capillary Permeability; Cyclic GMP; Electrophysiology; Endothelium, Vascular; Feedback, Physiological; Hydrostatic Pressure; In Vitro Techniques; Mice; Myocardial Infarction; Nitric Oxide; Patch-Clamp Techniques; Pulmonary Edema; Rats; TRPV Cation Channels

Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF.. In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 microg.kg body weight.min) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured.. In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation.. If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.

Topics: Administration, Inhalation; Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart Failure; Hypertension, Pulmonary; Male; Milrinone; Phosphodiesterase Inhibitors; Pulmonary Edema; Rats; Rats, Sprague-Dawley

Formation of cardiogenic pulmonary edema in acute left heart failure is traditionally attributed to increased fluid filtration from pulmonary capillaries and subsequent alveolar flooding. Here, we demonstrate that hydrostatic edema formation at moderately elevated vascular pressures is predominantly caused by an inhibition of alveolar fluid reabsorption, which is mediated by endothelial-derived nitric oxide (NO). In isolated rat lungs, we quantified fluid fluxes into and out of the alveolar space and endothelial NO production by a two-compartmental double-indicator dilution technique and in situ fluorescence imaging, respectively. Elevation of hydrostatic pressure induced Ca(2+)-dependent endothelial NO production and caused a net fluid shift into the alveolar space, which was predominantly attributable to impaired fluid reabsorption. Inhibition of NO production or soluble guanylate cyclase reconstituted alveolar fluid reabsorption, whereas fluid clearance was blocked by exogenous NO donors or cGMP analogs. In isolated mouse lungs, hydrostatic edema formation was attenuated by NO synthase inhibition. Similarly, edema formation was decreased in isolated mouse lungs of endothelial NO synthase-deficient mice. Chronic heart failure results in endothelial dysfunction and preservation of alveolar fluid reabsorption. These findings identify impaired alveolar fluid clearance as an important mechanism in the pathogenesis of hydrostatic lung edema. This effect is mediated by endothelial-derived NO acting as an intercompartmental signaling molecule at the alveolo-capillary barrier.

Topics: Absorption; Animals; Capillaries; Cyclic GMP; Endothelium, Vascular; Extravascular Lung Water; Guanylate Cyclase; Heart Failure; Hydrostatic Pressure; In Vitro Techniques; Indicator Dilution Techniques; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Pulmonary Alveoli; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Sprague-Dawley

Endothelial hyperpermeability induced by inflammatory mediators is a hallmark of sepsis and adult respiratory distress syndrome. Increased levels of the regulatory peptide adrenomedullin (ADM) have been found in patients with systemic inflammatory response. We analyzed the effect of ADM on the permeability of cultured human umbilical vein endothelial cell (HUVEC) and porcine pulmonary artery endothelial cell monolayers. ADM dose-dependently reduced endothelial hyperpermeability induced by hydrogen peroxide (H2O2), thrombin, and Escherichia coli hemolysin. Moreover, ADM pretreatment blocked H2O2-related edema formation in isolated perfused rabbit lungs and increased cAMP levels in lung perfusate. ADM bound specifically to HUVECs and porcine pulmonary artery endothelial cells and increased cellular cAMP levels. Simultaneous inhibition of cAMP-degrading phosphodiesterase isoenzymes 3 and 4 potentiated ADM-dependent cAMP accumulation and synergistically enhanced ADM-dependent reduction of thrombin-induced hyperpermeability. However, ADM showed no effect on endothelial cGMP content, basal intracellular Ca2+ levels, or the H2O2-stimulated, thrombin-stimulated, or Escherichia coli hemolysin-stimulated Ca2+ increase. ADM diminished thrombin- and H2O2-related myosin light chain phosphorylation as well as stimulus-dependent stress fiber formation and gap formation in HUVECs, suggesting that ADM may stabilize the barrier function by cAMP-dependent relaxation of the microfilament system. These findings identify a new function of ADM and point to ADM as a potential interventional agent for the reduction of vascular leakage in sepsis and adult respiratory distress syndrome.

Topics: Actin Cytoskeleton; Adrenomedullin; Animals; Calcium; Cell Membrane Permeability; Cells, Cultured; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Hydrogen Peroxide; Lung; Myosin Light Chains; Peptides; Phosphorylation; Pulmonary Edema; Rabbits; Swine

Substitution of the NO-pathway reduces ischemia/reperfusion injury following lung transplantation. 8-Br-cGMP is a membrane permeable analogue of cGMP, the second messenger of NO. In this study the effect of continuous administration of 8-Br-cGMP on early graft function was evaluated.. Unilateral left lung transplantation was performed in 10 weight-matched pigs (23-30 kg). Donor lungs were flushed with 1.51 cold (1 degree C) LPD solution and preserved for 20 hours. In Group I (n = 5), 8-Br-cGMP (0.2 mg/kg/h) was given continuously over the entire observation time starting 15 min before reperfusion. Group II served as control, no 8-Br-cGMP was administered. In both groups, 250 microg PGE1 was injected into the pulmonary artery (PA) before flush. One hour after reperfusion the recipients contralateral right PA and bronchus were ligated to assess isolated graft function only. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, mean systemic arterial pressure and gas exchange were assessed during a 5-hour observation period. Lipid peroxidation as indicator for free radical mediated injury and neutrophil migration to the allograft were measured at the end of the assessment.. EVLWI was significantly reduced in animals treated with 8-Br-cGMP (overall difference P = 0.024) with a peak 2 hours after reperfusion (Group I, 8.2+/-0.3 mg/ml vs Group II, 10.1+/-0.6 mg/ml; P = 0.039). Also in Group I the free radical mediated tissue injury was significantly lower when compared to Group II (Group I, 61.8+/-12.3 pmol/g vs Group II, 120.7+/-7.2 pmol/g; P = 0.006). A tendency towards a reduced neutrophil migration after 8-Br-cGMP infusion was shown; however, the changes in comparison to the control animals were not statistically significant (Group I, 1.0+/-0.2 deltaOD/mg/min vs Group II, 1.7+/-0.3 deltaOD/mg/min; P = 0.13). Pulmonary- and systemic hemodynamics, and allograft gas exchange did not differ between groups.. The results indicate that substitution of the NO pathway by administration of the second messenger cGMP at the time of reperfusion improves post-transplant lung allograft function.

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Extravascular Lung Water; Free Radicals; Lipid Peroxidation; Lung Transplantation; Postoperative Period; Pulmonary Edema; Random Allocation; Reperfusion Injury; Swine; Thiobarbituric Acid Reactive Substances; Transplantation, Homologous

Prevention of ischemia-reperfusion (IR) injury is crucial for successful lung transplantation. We investigated whether a nitric oxide donor, nitroglycerin (NTG), could suppress the oxidative stress of IR injury and improve pulmonary function after reperfusion in an ex vivo rat lung perfusion model. In Fresh group of animals, the lungs were flushed with perfusate, followed immediately by reperfusion, and no lung injury was observed. In NTG- and NTG+ groups of animals, the lungs were flushed with perfusate alone or perfusate containing NTG, respectively. Harvested lung and heart blocks from these latter two groups were immersed in the corresponding perfusate at 4 degrees C for 15 h, and were then reperfused for 60 min. Reperfusion induced pulmonary edema in the NTG- group, but not in the NTG+ group. Shunt fractions in NTG+ group were significantly lower than in the NTG- group throughout reperfusion. NTG had no effect on pulmonary arterial pressure or myeloperoxidase activity. In contrast, oxidative DNA damage assessed immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine (8-OHdG) was significantly increased in the NTG- group, in the order alveolar epithelium > pulmonary endothelium > bronchial epithelium. NTG treatment significantly decreased staining with the anti-8-OHdG antibody in all three areas of tissue. Therefore, administration of NTG attenuates the oxidative stress of IR injury, and may improve pulmonary function after reperfusion.

Topics: Animals; Cyclic GMP; DNA Damage; Immunoenzyme Techniques; Lung; Lung Transplantation; Male; Nitroglycerin; Organ Preservation; Oxidative Stress; Peroxidase; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Inbred Lew; Reperfusion Injury; Vasodilator Agents

Atrial natriuretic peptide (ANP) is a cardiac hormone which affects endothelial cell function through a receptor-mediated process. Pneumonectomy is a common thoracic surgical procedure that can cause pulmonary oedema in the remaining lung. Few reports have investigated the aetiology of this complication. The aim of this study was to determine the changes in ANP concentration and expression of its receptors following pneumonectomy as a possible aetiology for postpneumonectomy pulmonary oedema (PPE). We compared plasma ANP concentrations, cGMP concentrations, and natriuretic peptide receptor (NPR)-A mRNA and NPR-C mRNA expression in rat lung 3 h after pneumonectomy (n=5) or a sham operation (n=5). The ANP concentrations in plasma and lung tissue in the pneumonectomy group were significantly higher than in the control group (749.5 versus 202.7 pg x ml(-1), P<0.01; 33.1 versus 6.8 ng x g(-1) wet tissue, P<0.01 respectively). The level of ANP mRNA expression in the pneumonectomy group was significantly higher than in the control group (1.44 versus 0.41 relative ANP mRNA expression, P<0.05). The concentration of cGMP and the level of NPR-A mRNA expression were not significantly different between the pneumonectomy and control groups. The level of NPR-C mRNA expression in the pneumonectomy group was significantly higher than in the control group (4.17 versus 2.19 relative NPR-C mRNA expression, P<0.01). These findings suggest that changes in pulmonary ANP and NPR-C expression may contribute to the development of PPE in the remaining lung in the acute phase following pneumonectomy.

Topics: Animals; Atrial Natriuretic Factor; Cyclic GMP; Lung; Male; Pneumonectomy; Postoperative Complications; Pulmonary Edema; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; RNA, Messenger

Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation. Rats received intraperitoneal saline or Etx (Salmonella typhimurium; 20 mg/kg) and one of the PARS inhibitors, 3-aminobenzamide (3-AB; 10 mg/kg) or nicotinamide (Nic; 200 mg/kg), 90 min later. After 6 h, concentration-response curves were determined in isolated pulmonary arterial rings. Etx impaired endothelium-dependent (response to ACh and calcium ionophore) and -independent (sodium nitroprusside) cGMP-mediated vasorelaxation. 3-AB and Nic attenuated Etx-induced impairment of endothelium-dependent and -independent pulmonary vasorelaxation. 3-AB and Nic had no effect on Etx-induced increases in lung myeloperoxidase activity and edema. Lung ATP decreased after Etx but was maintained by 3-AB and Nic. Pulmonary arterial PARS activity increased fivefold after Etx, which 3-AB and Nic prevented. The beneficial effects were not observed with benzoic acid, a structural analog of 3-AB that does not inhibit PARS. Our results suggest that PARS inhibition with 3-AB or Nic improves pulmonary vasorelaxation and preserves lung ATP levels in acute lung injury.

Topics: Adenosine Triphosphate; Animals; Benzamides; Cyclic GMP; Endotoxemia; Endotoxins; Enzyme Inhibitors; Lung; Male; Niacinamide; Peroxidase; Poly(ADP-ribose) Polymerase Inhibitors; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Vasodilation

FK409 is the first spontaneous nitric oxide (NO) donor known to increase plasma cyclic guanosine 3',5'monophosphate levels. In this study, we evaluated the effect of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm ischemia canine model. Fourteen dogs were divided into two groups, and the FK409-treated group was given 5 micrograms/kg per min FK409. Warm ischemia was induced for 3 h. The arterial partial pressure of oxygen (PaO2), arterial oxygen saturation (SaO2), cardiac output (CO), left pulmonary vascular resistance (L-PVR), and endothelin-I (ET-I) were measured. A histologic study was performed, and polymorphonuclear neutrophils (PMNs) were also counted. The PaO2, SaO2, and L-PVR levels and PMNs after 30 min of reperfusion, ET-I after 2 h of reperfusion, and the 7-day survival rate were significantly (P < 0.05) better in the FK409-treated group than in the control group. The histologic damage was reduced in the FK409-treated group compared to the control group. FK409 appears to have a protective effect in ischemia-reperfusion injury of the lung.

Topics: Animals; Cardiac Output; Cyclic GMP; Dogs; Drug Evaluation, Preclinical; Endothelin-1; Ischemia; Lung; Nitric Oxide Donors; Nitro Compounds; Oxygen; Partial Pressure; Pulmonary Edema; Reperfusion Injury

Because atrial natriuretic peptide (ANP) is considered to play a role in lung physiology and pathology, our aim was to characterize natriuretic peptide receptors in cultured rat alveolar type II (ATII) cells. Guanylate cyclase A- and B-receptor but not clearance-receptor mRNAs were detected by reverse transcription-polymerase chain reaction. The absence of clearance-receptor expression in ATII cells was confirmed by competitive inhibition of ANP binding; ANP (0.1-100 nM) decreased the binding of 125I-ANP, whereas C-ANP-(4-23), a specific ligand of clearance receptors, was ineffective. ANP induced a dose-dependent increase in guanosine 3',5'-cyclic monophosphate (cGMP) production, with a threshold of 0.1 nM, whereas the response to C-type natriuretic peptide was weak and was observed only at high concentrations (100 nM). In ATII cells cultured on filters, 1) ANP receptors were present on both the apical and basolateral surfaces and 2) cGMP egression was polarized, as indicated by the greater ANP-induced cGMP accumulation in the basolateral medium, and was partially inhibited by probenecid, an organic acid transport inhibitor. Influx studies demonstrated that ANP decreased the amiloride-sensitive component of 22Na influx but did not change ouabain-sensitive 86Rb influx. In conclusion, ATII cells behave as a target for ANP. ANP activation of guanylate cyclase A receptors produces cGMP, which is preferentially extruded on the basolateral side of the cells and inhibits the amiloride-sensitive Na-channel activity.

Topics: Amiloride; Animals; Atrial Natriuretic Factor; Cells, Cultured; Cyclic GMP; Diuretics; Guanylate Cyclase; Peptide Fragments; Polymerase Chain Reaction; Pulmonary Alveoli; Pulmonary Edema; Rats; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Rubidium; Sodium

Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the "adult respiratory distress syndrome," and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Topics: Animals; Arginine; Benzamides; Cyclic GMP; Enzyme Inhibitors; In Vitro Techniques; Lung; Lung Injury; Magnesium; Male; Models, Biological; N-Methylaspartate; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Perfusion; Poly(ADP-ribose) Polymerase Inhibitors; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Vasoactive Intestinal Peptide

Previous studies reported that atrial natriuretic factor (ANF) decreased lung edema in guinea pigs. To determine whether ANF protects against lung edema by increasing active Na+ transport and lung edema clearance, ANF (10(-7) M) was instilled into the air spaces (n = 5) or perfused through the pulmonary circulation (n = 5) of isolated perfused liquid-filled rat lungs. These animals were compared with five control rats and four rats having amiloride (10(-5) M) instilled into the air space. Amiloride reduced lung edema clearance by 65%, perfused ANF reduced lung edema clearance by 32%, and instilled ANF did not change edema clearance compared with responses in control rats after 70 min of experimental protocol. Passive Na+ movement increased by 91% with perfused ANF and by 52% with instilled ANF compared with that in control rats. Albumin flux from the perfusate into the air space increased in ANF-perfused lungs compared with control lungs (P < 0.05) but not when ANF or amiloride was instilled into the air spaces. These results suggest that ANF instilled into rat air spaces or perfused through the pulmonary circulation increases lung epithelial permeability and that ANF perfused through the pulmonary circulation decreases lung edema clearance due to impaired active Na+ transport. Conceivably, the previously observed protective effect of ANF was due to reduced pressures across the pulmonary circulation, which resulted in less edema formation.

Topics: Amiloride; Animals; Atrial Natriuretic Factor; Biological Transport, Active; Blood Pressure; Capillary Permeability; Cyclic GMP; Epithelium; Male; Perfusion; Pulmonary Alveoli; Pulmonary Edema; Rats; Rats, Sprague-Dawley; RNA; Sodium; Time Factors

The postdialytic plasma level of cGMP, a marker for the release of atrial natriuretic peptide (ANP) in humans, is closely related to hypervolemia in chronic hemodialysis patients. In order to test the practicability of routine postdialysis cGMP determination for the detection of fluid overload, ANP and cGMP levels in the total hemodialysis population of 81 patients were measured with blood samples drawn immediately after hemodialysis. Twenty-three patients had a cGMP level of more than 20 pmol/mL. In 13 of these, pulmonary congestion was present on the chest roentgenogram. Two of these patients refused a gradual reduction of their dry body weight. In the remaining 21 patients, the weight reduction was associated with a decrease in cGMP levels in all cases and with a decrease in ANP levels in all but two cases. Fourteen of the 21 patients reached a cGMP level below 20 pmol/mL after weight reduction, and at that time, none of these showed signs of pulmonary congestion on chest x-ray. All seven patients, whose cGMP levels remained above 20 pmol/mL despite the reduction, had documented heart disease with impairment of left ventricular function. These results suggest that the plasma cGMP level after hemodialysis is more apt for the determination of dry body weight than is ANP or a chest roentgenogram.

Topics: Adult; Aged; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Body Weight; Cardiovascular Diseases; Cyclic GMP; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitric Oxide; Predictive Value of Tests; Pulmonary Edema; Radiography; Renal Dialysis; Ventricular Function, Left; Water-Electrolyte Imbalance

Bovine pulmonary microvessel endothelial cells grown on a flexible substrate contract upon the addition of angiotensin II, thrombin, bradykinin, and U44069, a stable analogue of thromboxane A2. All these agents promote inflammation and increase paracellular permeability in vivo or in vitro. The contractile response is mediated by intracellular and extracellular free calcium: the response is inhibited by TMB-8, an intracellular Ca2+ chelator, and EGTA. Contraction is inhibited by trifluoroperazine, a Ca2(+)-calmodulin antagonist, and by ML-7, an inhibitor of myosin light-chain kinase. Preincubation with PMA, a protein kinase C activator, prevents contraction by angiotensin II. The inactive analogue 4-alpha-phorbol 12,13-didecanoate does not inhibit contraction. In contrast cAMP, carbacyclin (a stable PGI2 analogue), and isoproterenol, agonists known to stabilize the microvascular barrier against inflammatory agents, relax pulmonary microvessel EC. This direct evidence of the contractile potential of microvessel endothelial cells lends support to the theory that endothelial contraction leads to increased junctional permeability.

Topics: Angiotensin II; Animals; Bradykinin; Calcium; Capillary Permeability; Cattle; Cells, Cultured; Cyclic GMP; Edetic Acid; Endothelium, Vascular; Epoprostenol; Gallic Acid; Indomethacin; Intercellular Junctions; Isoproterenol; Myosin-Light-Chain Kinase; Prostaglandin Endoperoxides, Synthetic; Protein Kinase C; Pulmonary Edema; Second Messenger Systems; Tetradecanoylphorbol Acetate; Thrombin; Trifluoperazine

It has been established that alpha-hANP, the newly discovered peptide extracted from human cardiac atria, has potent natriuretic and hypotensive actions. Our present investigation is the first to demonstrate that alpha-hANP is capable of protecting against pulmonary edema caused by various chemicals, using isolated perfused guinea pig lung system. Lungs were perfused via pulmonary artery with Krebs-Ringer bicarbonate buffer at 5.0 ml/min, and wet weight of lungs and perfusion pressure of pulmonary artery (Pa) were monitored. Bolus injection of Triton-X or CHAPS into cannulated pulmonary artery produced edema as indicated by a massive increase in wet weight and a slight increase in Pa. Constant infusion of alpha-hANP through pulmonary artery at 200 ng/ml was effective in causing decrease in wet weight of lung. Perfusion of lung with paraquat or PGF2 alpha, and repeated bolus injection of arachidonic acid or PGE2 caused elevation in both wet weight of lung and Pa. The treatment with alpha-hANP similar to that described above also protected against edema caused by paraquat or arachidonic acid. Bolus administration of epinephrine induced a slight increase in wet weight and Pa, and alpha-hANP was effective in decreasing the elevated lung wet weight and Pa of lungs. Infusion or bolus administration of alpha-hANP into control lungs increased cGMP level in outflow perfusate as well as in lung tissue significantly. In lungs with edema which were induced by Triton-X or paraquat, there was a slight increase in cGMP level in Triton-X treated and no increase in paraquat treated lung tissues. In either cases, was there any increase in cGMP level in perfusate. The specific binding study of [125I]alpha-hANP revealed that the lack of increase in cGMP was not due to a loss of receptor in Triton-X or paraquat treated lungs. Thus our study demonstrated that alpha-hANP had a direct anti-edematic action(s) in lung which was not secondary to the systemic natriuretic and/or hypotensive action(s).

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Atrial Natriuretic Factor; Blood Pressure; Cholic Acids; Cyclic GMP; Dinoprost; Dinoprostone; Epinephrine; Guinea Pigs; Humans; Indicator Dilution Techniques; Lung; Male; Norepinephrine; Octoxynol; Organ Size; Paraquat; Peptide Fragments; Polyethylene Glycols; Prostaglandins E; Prostaglandins F; Pulmonary Artery; Pulmonary Edema

Topics: Animals; Cyclic AMP; Cyclic GMP; Dinoprost; Dogs; Lung; Male; Prostaglandins E; Pulmonary Edema; Smoke Inhalation Injury

Topics: Alprostadil; Animals; Burns, Inhalation; Complement System Proteins; Cyclic AMP; Cyclic GMP; Dogs; Histamine; Male; Prostaglandins E; Pulmonary Edema

Cyclic nucleotide content of lung tissue is altered by anesthesia, ventilatory pattern, and pharmacologic manipulation (e.g., isoproterenol). In addition the lung releases cyclic nucleotides into its circulation, but little is known about factors that might alter this release. We isolated and perfused rat lungs (IPL) to determine: 1) if cyclic nucleotides are released into the perfusate in the control state; and 2) if their release changes after alteration of the ventilatory pattern or the addition of isoproterenol. We demonstrated that the rat IPL releases both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) into the perfusate. Isoproterenol has no effect on cGMP release but increases cAMP release dramatically. Perfusate cAMP is not affected by ventilatory pattern, but perfusate cGMP is higher during high-pressure ventilation than it is in nonventilated or normally ventilated lungs.

Topics: Animals; Cyclic AMP; Cyclic GMP; DNA; In Vitro Techniques; Isoproterenol; Lung; Male; Perfusion; Positive-Pressure Respiration; Pulmonary Edema; Rats; Rats, Inbred Strains