cyclic-gmp and Respiratory-Distress-Syndrome

Topics: Administration, Inhalation; Cyclic GMP; Heart; Humans; Nitric Oxide; Pulmonary Gas Exchange; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

To compare hemodynamic and gasometric variables and the plasma concentrations of nitric oxide metabolites (cyclic guanosine monophosphate and nitrate and nitrite), endothelin-1, and renin-angiotensin metabolites before and after the start of nitric oxide inhalation, after prolonged nitric oxide inhalation, and before and after nitric oxide withdrawal.. Prospective study.. Surgical intensive care unit, university hospital.. Patients with acute lung injury and right ventricular failure.. Nitric oxide inhalation (10-12 ppm) during a median of 2.9 days (12 hrs to 6.5 days).. The pulmonary vasodilator effects of inhaled nitric oxide improved arterial oxygenation in patients with acute lung injury (p < .05) and reduced right atrial pressure in patients with right ventricular dysfunction (p < .01). These beneficial effects lasted the whole period of prolonged inhaled nitric oxide therapy up to 6.5 days. However, when inhaled nitric oxide was withdrawn, pulmonary vasodilator effects rapidly disappeared, and Pao2/Fio2 ratio markedly deteriorated in all studied patients to return to pre-inhaled nitric oxide levels. Changes in plasma cyclic guanosine monophosphate and nitrate and nitrite paralleled those of pulmonary vasodilatory effects. An immediate increase in plasma cyclic guanosine monophosphate with a slightly delayed increase in plasma nitrate and nitrite was observed at inhaled nitric oxide start with no attenuation during the prolonged inhaled nitric oxide therapy. A marked decrease toward pre-inhaled nitric oxide levels was seen within hours of inhaled nitric oxide withdrawal. In addition, no alteration of plasma endothelin-1 or renin-angiotensin mediators was observed during or after inhaled nitric oxide therapy.. Our study showed a lack of attenuation in the beneficial effects of inhaled nitric oxide and a lack of alteration of endogenous nitric oxide, endothelin-1, and renin-angiotensin pathways during prolonged nitric oxide inhalation.

Topics: Administration, Inhalation; Adult; Aged; Atrial Natriuretic Factor; Cyclic GMP; Endothelin-1; Endothelium-Dependent Relaxing Factors; Female; Humans; Intensive Care Units; Male; Middle Aged; Nitric Oxide; Respiratory Distress Syndrome; Ventricular Dysfunction, Right

To study the effects of infusion of atrial natriuretic peptide (ANP) versus the inhalation of nitric oxide (NO) in patients with an early acute respiratory distress syndrome (ARDS).. Ten patients with severe ARDS were studied in a crossover study design, within 72 hours after starting mechanical ventilation. We studied the effects of ANP infusion (10 ng/kg/min for 1 hour) and of inhalation of NO (20 ppm for 1 hour) on hemodynamic and respiratory patient parameters, as well as the effects on plasma levels of ANP, guanosine 3',5'-cyclic monophosphate, nitrate and endothelin-1.. Despite an approximate 50% increase in mixed venous ANP plasma concentration (from 86 +/- 21 to 123 +/- 33 ng/l, P < 0.05) during ANP infusion, there were no changes in mean pulmonary artery pressure, pulmonary vascular resistance index, extravascular lung water index, or in pulmonary gas exchange. NO inhalation, in contrast, lowered mean pulmonary artery pressure (from 26 +/- 1.9 to 23.9 +/- 1.7 mmHg, P < 0.01), pulmonary vascular resistance index (from 314 +/- 37 to 273 +/- 32 dynes/cm5/m2, P < 0.05) and central venous pressure (from 8.2 +/- 1.2 to 7.3 +/- 1.1 mmHg, P < 0.02). Furthermore, NO inhalation improved pulmonary gas exchange, reflected by a decrease in alveolar-arterial oxygen gradient (from 41.9 +/- 3.9 to 40.4 +/- 3.6 kPa, P < 0.05), a small increase in oxygenation (PaO2/FiO2 from 17.7 +/- 1.4 to 19.7 +/- 1.1 kPa, P = 0.07) and a small decrease in venous admixture (Qs/Qt from 35.7 +/- 2.0 to 32.8 +/- 2.7%, P = 0.11).. This study shows that, in contrast to NO inhalation, infusion of ANP neither improves oxygenation nor attenuates pulmonary hypertension or pulmonary edema in patients with severe ARDS.

Topics: Administration, Inhalation; Adult; Aged; Atrial Natriuretic Factor; Cross-Over Studies; Cyclic GMP; Endothelin-1; Female; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Nitrates; Nitric Oxide; Pulmonary Gas Exchange; Respiration, Artificial; Respiratory Distress Syndrome; Vasodilator Agents

Luteolin (Lut) was recently identified as the major active ingredient of Mosla scabra, which was a typical representative traditional Chinese medicine and had been used to treat pulmonary diseases for thousands of years.. This study was to explore the effects and relative mechanisms of Lut in LPS-induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). The main characteristic of ALI/ARDS is pulmonary edema, and epithelial sodium channel (ENaC) is a key factor in effective removal of excessive alveolar edematous fluid, which is essential for repairing gas exchange and minimizing damage to the peripheral tissues. However, whether the therapeutic effects of Lut on respiratory diseases are relative with ENaC is still unknown.. Alveolar fluid clearance was calculated in BALB/c mice and ENaC function was measured in H441 cells. Moreover, ENaC membrane protein and mRNA were detected by Western blot and real-time PCR, respectively. We also studied the involvement of cGMP/PI3K pathway during the regulation of Lut on ENaC during LPS-induced ALI/ARDS by ELISA method and applying cGMP/PI3K inhibitors/siRNA.. The beneficial effects of Lut in ALI/ARDS were evidenced by the alleviation of pulmonary edema, and enhancement of both amiloride-sensitive alveolar fluid clearance and short-circuit currents. Lut could alleviate the LPS decreased expression levels of ENaC mRNA and membrane protein in H441 cells and mouse lung. In addition, cGMP concentration was increased after the administration of Lut in ALI/ARDS mice, while the inhibition of cGMP/PI3K pathway could abrogate the enhanced AFC and ENaC protein expression of Lut.. These results implied that Lut could attenuate pulmonary edema via enhancing the abundance of membrane ENaC at least partially through the cGMP/PI3K pathway, which could provide a promising therapeutic strategy for treating ALI/ARDS.

Topics: Alveolar Epithelial Cells; Animals; Chromones; Cyclic GMP; Gene Expression Regulation; Lipopolysaccharides; Lung Injury; Luteolin; Male; Mice; Mice, Inbred BALB C; Morpholines; Phosphatidylinositol 3-Kinases; Random Allocation; Respiratory Distress Syndrome; Sodium Channels; Up-Regulation

Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR).. To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation.. Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake.. The ET-1-induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial-epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Exposing transgenic rats deficient in ETB receptors in the pulmonary vasculature (ET-B(-/-)) to ET-1 did not decrease AFR or Na,K-ATPase protein abundance at the plasma membrane of AECs. Exposing HMVEC-L to ET-1 led to increased NO, and the ET-1-induced down-regulation of Na,K-ATPase was prevented by the NO synthase inhibitor l-NAME, but not by a guanylate cyclase inhibitor.. We provide the first evidence that ET-1, via an endothelial-epithelial interaction, leads to decreased AFR by a mechanism involving activation of endothelial ETB receptors and NO generation leading to alveolar epithelial Na,K-ATPase down-regulation in a cGMP-independent manner.

Topics: Adenosine Triphosphatases; Animals; Cyclic GMP; Disease Models, Animal; Endothelin-1; Endothelium, Vascular; Extravascular Lung Water; Female; Humans; In Vitro Techniques; Lung Injury; Male; Nitric Oxide; Pulmonary Alveoli; Rats; Rats, Transgenic; Receptor, Endothelin A; Receptor, Endothelin B; Respiratory Distress Syndrome

Carbon monoxide (CO) is currently being evaluated as a therapeutic modality in the treatment of patients with acute lung injury and acute respiratory distress syndrome. No study has assessed the effects of CO on transepithelial ion transport and alveolar fluid reabsorption, two key aspects of alveolocapillary barrier function that are perturbed in acute lung injury/acute respiratory distress syndrome. Both CO gas (250 ppm) and CO donated by the CO donor, CO-releasing molecule (CORM)-3 (100 microM in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked (22)Na(+) clearance from the alveolar compartment, and blocked alveolar fluid reabsorption after fluid challenge. Apical application of two CO donors, CORM-3 or CORM-A1 (100 microM), irreversibly inhibited amiloride-sensitive short-circuit currents in H441 human bronchiolar epithelial cells and primary rat alveolar type II cells by up to 40%. Using a nystatin permabilization approach, the CO effect was localized to amiloride-sensitive channels on the apical surface. This effect was abolished by hemoglobin, a scavenger of CO, and was not observed when inactive forms of CO donors were employed. The effects of CO were not blocked by 8-bromoguanosine-3',5'-cyclic guanosine monophosphate, soluble guanylate cyclase inhibitors (methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), or inhibitors of trafficking events (phalloidin oleate, MG-132, and brefeldin A), but the amiloride affinity of H441 cells was reduced after CO exposure. These data indicate that CO rapidly inhibits sodium absorption across the airway epithelium by cyclic guanosine monophosphate- and trafficking-independent mechanisms, which may rely on critical histidine residues in amiloride-sensitive channels or associated regulatory proteins on the apical surface of lung epithelial cells.

Topics: Acute Lung Injury; Amiloride; Animals; Body Fluids; Boranes; Carbon Monoxide; Carbonates; Cell Line; Cyclic GMP; Energy Metabolism; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels; Guanylate Cyclase; Heme Oxygenase-1; Histidine; Humans; In Vitro Techniques; Ion Transport; Organometallic Compounds; Pulmonary Alveoli; Rabbits; Rats; Respiratory Distress Syndrome; Signal Transduction; Sodium-Potassium-Exchanging ATPase

Superoxide (O(2)(*-)), derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, is associated with acute respiratory distress syndrome (ARDS). NADPH oxidase activity and expression are blocked by nitric oxide (NO) and sildenafil. As another gas, hydrogen sulphide (H(2)S) is formed by blood vessels, the effect of sodium hydrosulphide (NaHS) and the H(2)S-donating derivative of sildenafil, ACS6, on O(2)(*-) formation and the expression of gp91(phox) (a catalytic subunit of NADPH oxidase) in porcine pulmonary arterial endothelial cells (PAECs) was investigated.. PAECs were incubated with 10 ng mL(-1) tumour necrosis factor-alpha (TNFalpha) (+/-NaHS or ACS6), both of which released H(2)S, for 2 h or 16 h. O(2)(*-) was measured. Expression of gp91(phox) was measured by western blotting and the role of cyclic AMP (cAMP) and/or cyclic GMP was assessed using protein kinase inhibitors.. After either 2- or 16-h incubations, O(2)(*-) formation by PAECs was inhibited by NaHS or ACS6, with IC(50) values of about 10 nM and less than 1 nM, respectively. Both 100 nM NaHS and 1 nM ACS6 completely inhibited gp91(phox) expression induced by TNFalpha. The effects of NaHS were blocked by the inhibition of protein kinase A (PKA), but not PKG, and not by the inhibition of guanylyl cyclase. Effects of ACS6 were blocked by inhibition of both PKA and PKG. Both NaHS and ACS6 augmented cAMP formation.. H(2)S inhibited O(2)(*-) formation and upregulation of NADPH oxidase in PAECs through the adenylyl cyclase-PKA pathway. ACS6 may be effective in treating ARDS through both elevation of cAMP and inhibition of phosphodiesterase type 5 activity.

Topics: Adenylyl Cyclases; Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Endothelial Cells; Gene Expression Regulation; Guanylate Cyclase; Hydrogen Sulfide; Inhibitory Concentration 50; Male; NADPH Oxidases; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Respiratory Distress Syndrome; Sulfides; Sulfones; Superoxides; Swine; Time Factors; Tumor Necrosis Factor-alpha

Ischemia-reperfusion (IR) causes human lung injury in association with the release of atrial and brain natriuretic peptides (ANP and BNP), but the role of ANP/BNP in IR lung injury is unknown. ANP and BNP bind to natriuretic peptide receptor-A (NPR-A) generating cGMP and to NPR-C, a clearance receptor that can decrease intracellular cAMP. To determine the role of NPR-A signaling in IR lung injury, we administered the NPR-A blocker anantin in an in vivo SWR mouse preparation of unilateral lung IR. With uninterrupted ventilation, the left pulmonary artery was occluded for 30 min and then reperfused for 60 or 150 min. Anantin administration decreased IR-induced Evans blue dye extravasation and wet weight in the reperfused left lung, suggesting an injurious role for NPR-A signaling in lung IR. In isolated mouse lungs, exogenous ANP (2.5 nM) added to the perfusate significantly increased the filtration coefficient sevenfold only if lungs were subjected to IR. This effect of ANP was also blocked by anantin. Unilateral in vivo IR increased endogenous plasma ANP, lung cGMP concentration, and lung protein kinase G (PKG(I)) activation. Anantin enhanced plasma ANP concentrations and attenuated the increase in cGMP and PKG(I) activation but had no effect on lung cAMP. These data suggest that lung IR triggered ANP release and altered endothelial signaling so that NPR-A activation caused increased pulmonary endothelial permeability.

Topics: Animals; Atrial Natriuretic Factor; Cell Adhesion Molecules; Cyclic AMP; Cyclic GMP; Guanylate Cyclase; Lung; Male; Mice; Mice, Inbred Strains; Microfilament Proteins; Perfusion; Phosphoproteins; Receptors, Atrial Natriuretic Factor; Reperfusion Injury; Respiratory Distress Syndrome; Signal Transduction

Soluble guanylyl cyclase (sGC) is a cGMP-generating enzyme implicated in the control of smooth muscle tone that also regulates platelet aggregation. Moreover, sGC activation has been shown to reduce leukocyte adherence to the endothelium. Herein, we investigated the expression of sGC in a murine model of LPS-induced lung injury and evaluated the effects of sGC inhibition in the context of acute lung injury (ALI). Lung tissue sGC alpha1 and beta1 subunit protein levels were determined by Western blot and immunohistochemistry, and steady-state mRNA levels for the beta1 subunit were assessed by real-time PCR. LPS inhalation resulted in a decrease in beta1 mRNA levels, as well as a reduction in both sGC subunit protein levels. Decreased alpha1 and beta1 expression was observed in bronchial smooth muscle and epithelial cells. TNF-alpha was required for the LPS-triggered reduction in sGC protein levels, as no change in alpha1 and beta1 levels was observed in TNF-alpha knockout mice. To determine the effects of sGC blockade in LPS-induced lung injury, mice were exposed to 1H-[1,2,4]oxodiazolo[4,3-a]quinoxalin-l-one (ODQ) prior to the LPS challenge. Such pretreatment led to a further increase in total cell number (mainly due to an increase in neutrophils) and protein concentration in the bronchoalveoalar lavage fluid; the effects of ODQ were reversed by a cell-permeable cGMP analog. We conclude that sGC expression is reduced in LPS-induced lung injury, while inhibition of the enzyme with ODQ worsens lung inflammation, suggesting that sGC exerts a protective role in ALI.

Topics: Aerosols; Animals; Blotting, Western; Bronchi; Bronchoalveolar Lavage Fluid; Cyclic GMP; Enzyme Inhibitors; Epithelial Cells; Guanylate Cyclase; Immunohistochemistry; Inflammation; Inhalation; Lipopolysaccharides; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth; Oxadiazoles; Protein Subunits; Quinoxalines; Respiratory Distress Syndrome; RNA, Messenger; Solubility; Tumor Necrosis Factor-alpha

1. Air embolism the in lungs induces microvascular obstruction, mediator release and acute lung injury (ALI). Nitrite oxide (NO) plays protective and pathological roles in ALI produced by various causes, but its role in air embolism-induced ALI has not been fully investigated. 2. The purpose of the present investigation was to elucidate the involvement of NO and pro-inflammatory cytokines in the pathogenesis of ALI following air infusion into isolated perfused lungs from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. 3. The extent of ALI was evaluated by changes in lung weight, Evans blue dye leakage, the protein concentration in the bronchoalveolar lavage and pathological examination. We also measured nitrite/nitrate (NO(x)), tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations in lung perfusate and determined cGMP in lung tissue. 4. The NO synthase (NOS) inhibitors N(G)-nitro-l-arginine methyl ester (l-NAME) and l-N(6)-(1-iminoethyl)-lysine (l-Nil), as well as the NO donors sodium nitroprusside (SNP) and s-nitroso-N-acetylpenicillamine (SNAP), were administered 30 min before air embolism at a concentration of 10(-3) mol/L in the lung perfusate. 5. Air embolism-induced ALI was enhanced by pretreatment with l-NAME or l-Nil, but was alleviated by SNP or SNAP pretreatment, in both SHR and WKY rats. In both SHR and WKY rats, AE elevated levels of NO(x) (2.6 and 28.7%, respectively), TNF-alpha (52.7 and 158.6%, respectively) and IL-1beta (108.4 and 224.1%, respectively) in the lung perfusate and cGMP levels in lung tissues (35.8 and 111.2%, respectively). Pretreatment with l-LAME or l-Nil exacerbated, whereas SNP or SNAP abrogated, the increases in these factors, except in the case of NO(x) (levels were decreased by l-LAME or l-Nil pretreatment and increased by SNP or SNAP pretreatment). 6. Air embolism caused increases in the lung weight (LW)/bodyweight ratio, LW gain, protein concentration in bronchoalveolar lavage and Evans blue dye leakage. These AE-induced changes were less in lungs isolated from SHR compared with normotensive WKY rats. 7. The results suggest that ALI and associated changes following air embolism in lungs isolated from SHR are less than those in WKY rats. Nitric oxide production through inducible NOS isoforms reduces air embolism-induced lung injury and associated changes. Spontaneously hypertensive rats appear to be more resistant than WKY rats to air embolism challenge.

Topics: Animals; Blood Pressure; Capillary Permeability; Cyclic GMP; Disease Models, Animal; Embolism, Air; Enzyme Inhibitors; Hypertension; Interleukin-1beta; Lung; Lysine; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type II; Nitroprusside; Organ Size; Perfusion; Proteins; Pulmonary Artery; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Respiratory Distress Syndrome; S-Nitroso-N-Acetylpenicillamine; Tumor Necrosis Factor-alpha

An impaired generation of cGMP may account for the pulmonary hypertension seen in acute lung injury (ALI). We investigated the hemodynamic changes and the plasma levels of cGMP during air embolism-induced ALI in two different models: venous air infusion (VAI) and massive air embolism (MAE).. After a baseline hemodynamic evaluation, anesthetized dogs received a VAI (0.2 mL/kg/min, n = 10) or a bolus of air (MAE, 2.5 mL/kg, n = 10) intravenously. A group of control dogs (n = 5) received no further treatment. Hemodynamic evaluation was performed 5 to 60 minutes after the VAI was initiated or after the MAE. Blood samples were drawn for plasma cGMP determinations.. The VAI increased the pulmonary artery pressure (by 181%, P<.05) after 15 minutes of air infusion without changing the cardiac index. The MAE increased the pulmonary artery pressure (by 252%) and decreased the cardiac index (by 31%) 5 minutes after the air injection (both P<.05). These variables returned to baseline 15 to 30 minutes thereafter. The cGMP concentrations remained unaltered during the VAI. In contrast, cGMP levels increased 26% (P<.05) by 15 minutes after the MAE and returned to basal levels thereafter.. These findings suggest that a lack of increase in the production of the cGMP may account for the pulmonary hypertension seen in air embolism-induced ALI. Additionally, the small increase in cGMP levels after the MAE may reflect the more severe hemodynamic derangement in this setting.

Topics: Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Dogs; Embolism, Air; Hemodynamics; Hypertension, Pulmonary; Respiratory Distress Syndrome

As inhaled nitric oxide (iNO) may differently increase bleeding time (BT) and inhibit platelet aggregation in normal and lung-injured patients or experimental models, we studied the effects of iNO on hemostasis in presence and absence of an endotoxic lung injury in the rat. Eight hours after intratracheal administration of endotoxin (lipopolysaccharide [LPS]) or its solvent (phosphate-buffered solution [PBS]), four groups of rats were randomized according to the presence or absence of 15 ppm iNO added for an additional 10 h. We measured BT, ex vivo platelet aggregation, plasma fibrinogen, euglobulin clot lysis time (ECLT), and platelet and aortic cyclic guanosine 5'-monophosphate (cGMP) contents. Acute lung inflammation did not influence BT, but increased platelet aggregability, fibrinogen levels, and platelet and aortic cGMP. In control and endotoxic rats, iNO increased BT, reduced platelet aggregability, and increased platelet cGMP. iNO increased aortic cGMP only in healthy rats. ECLT was increased by LPS and unchanged with iNO. These results suggest that the extrapulmonary "systemic" effects induced by iNO on hemostasis were not strictly similar in healthy and LPS rats, inflammation inducing proper changes in coagulation parameters. However, iNO attenuated the procoagulant activity induced by acute lung inflammation, suggesting a potentially beneficial effect of this therapy.

Topics: Administration, Inhalation; Animals; Aorta; Blood Coagulation; Blood Coagulation Tests; Blood Platelets; Buffers; Cyclic GMP; Disease Models, Animal; Endotoxins; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Hemostasis; Lipopolysaccharides; Male; Nitric Oxide; Platelet Aggregation; Platelet Aggregation Inhibitors; Random Allocation; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome

Production of cGMP is impaired in endotoxin-induced acute lung injury. This results in dysfunction of endothelium-dependent and -independent cGMP-mediated pulmonary vasorelaxation and, therefore, pulmonary hypertension. We hypothesized that cyclic nucleotide phosphodiesterase (PDE) inhibition would attenuate endotoxin-induced impairment to cGMP-mediated mechanisms of pulmonary vasorelaxation. The purpose was to examine the effect of stimulating cGMP production with concurrent inhibition of cGMP catabolism by PDE inhibition following endotoxin-induced acute lung injury. Isolated pulmonary arterial rings from rats (n = 5) were studied 6 hrs after endotoxin (20 mg/kg ip) or saline. In a third group (n = 5), PDE inhibition was accomplished with in vitro 3-isobutyl-1-methylxanthine (IBMX, 1 microM for 30 min). Cyclic GMP-mediated relaxation was interrogated by stimulating (1) endothelium-dependent mechanisms with the receptor-dependent agonist acetylcholine and the receptor-independent agonist A23187, a calcium ionophore, and an (2) endothelium-independent mechanism with sodium nitroprusside. PDE inhibition attenuated endotoxin-induced vasomotor dysfunction. A two-pronged approach-stimulating cGMP production and preventing cGMP catabolism with PDE inhibition-may offer a therapeutically accessible mechanism to overcome vasomotor dysfunction in acute lung injury.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Calcimycin; Cyclic GMP; Endothelium, Vascular; Endotoxins; Male; Muscle, Smooth, Vascular; Nitroprusside; Phosphodiesterase Inhibitors; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Vasodilation

The major hemodynamic feature of acute lung injury (ALI) is pulmonary hypertension. Both endothelial-dependent and -independent pulmonary vasorelaxation is impaired in ALI due to endotoxemia. We hypothesized that endotoxemia selectively impairs relaxation of the pulmonary artery but does not impair contractility of pulmonary vascular smooth muscle (VSM). Our purpose was to determine the effect of endotoxemia (ETX) on the contractile response of pulmonary VSM to (1) tubular depolarization (KCl), (2) alpha 1-adrenoreceptor stimulation (phenylephrine, PE), (3) 5HT2 receptor stimulation (serotonin, 5HT), and (4) prostaglandin F2 alpha receptor stimulation. Pulmonary artery rings were isolated from rats 6 hr after injection of ETX, 20 mg/kg ip (n > or = 6), or saline (n > or = 6) and suspended on tensiometers in individual organ baths. Endothelial-dependent cGMP-mediated relaxation was determined using the receptor agonist acetylcholine (ACh) in rings preconstricted with PE. Dose-response curves were generated to each contractile agonist. Statistical comparison was performed using one-way ANOVA with post hoc Bonferonni-Dunn, P < 0.05 accepted as significant. Relaxation to ACh was 96.4 +/- 1.3% in controls vs 21.4 +/- 3.1% (P < 0.05) in endotoxin-treated rats. Endotoxin did not affect the maximal tension in response to the contractile agonists nor did it change the concentration required to produce 50% contraction (EC50). From these data we conclude that endotoxemia causes a decrease in vasorelaxation to the endothelial-dependent receptor agonist acetylcholine but does not impair agonist-induced contractility of pulmonary VSM. This suggests that pulmonary hypertension in ALI is mediated by impairment of pulmonary vasodilation with preservation of VSM contractility.

Topics: Acute Disease; Animals; Calcium; Cyclic GMP; Endotoxins; Hypertension, Pulmonary; In Vitro Techniques; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Vasoconstriction; Vasodilation

Inhaling low concentrations of nitric oxide (NO) gas causes selective pulmonary vasodilation of ventilated lung regions. NO activates soluble guanylate cyclase, increasing guanosine 3',5'-cyclic monophosphate (cGMP). Inhibition of NO synthesis enhances hypoxic pulmonary vasoconstriction. Therefore we examined independent and combined effects of NO inhalation and infusion of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthesis inhibitor, on pulmonary vascular pressure-flow relationships, gas exchange, and plasma cGMP levels in anesthetized and mechanically ventilated sheep with acute lung injury induced by bilateral lavage. After lavage, inhaling 60 ppm by volume of NO decreased pulmonary arterial pressure (PAP) and resistance without any systemic hemodynamic effects, increased arterial PO2, and decreased venous admixture (Qva/QT; all P < 0.05) without altering cardiac output (QT), mixed venous PO2, or O2 uptake, major determinants of intrapulmonary shunt. During NO inhalation, PAP-left atrial pressure gradient (PAP-LAP) and Qva/QT were reduced (both P < 0.05) independently of QT, which was varied mechanically. L-NAME infusion produced systemic and pulmonary vasoconstriction and increased PAP-LAP gradient across the entire range of QT, whereas Qva/QT, was not changed. NO inhalation after L-NAME infusion produced pulmonary vasodilation and decreased Qva/QT to the same degree as NO inhalation alone. Five to 10 min after inhalation of 60 ppm NO, before and after L-NAME infusion, arterial plasma cGMP levels were increased by 80% (both P < 0.05). With NO breathing after L-NAME, we measured a consistent transpulmonary cGMP arteriovenous gradient [31 +/- 8 and 33 +/- 7 (SE) pmol/ml at 5 and 10 min, respectively; both P < 0.05]. NO inhalation before or after L-NAME administration in this acute lung injury model reduced Qva/QT, most likely by increasing cGMP concentration in ventilated lung regions and causing selective pulmonary vasodilation.

Topics: Administration, Inhalation; Animals; Arginine; Cyclic GMP; Disease Models, Animal; Hemodynamics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxygen Consumption; Pulmonary Circulation; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Respiratory Mechanics; Sheep; Therapeutic Irrigation