Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice

2005 ◽  
Vol 289 (2) ◽  
pp. H823-H831 ◽  
Author(s):  
Fabian Spöhr ◽  
Annemiek J. M. Cornelissen ◽  
Cornelius Busch ◽  
Martha M. Gebhard ◽  
Johann Motsch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
No Production ◽  
Wild Type ◽  
Pulmonary Vasodilation ◽  
Congenital Deficiency ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Endogenous Nitric Oxide ◽  
Deficient Mice

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific ( NG-nitro-l-arginine methyl ester, l-NAME) and NOS2-specific [l- N6-(1-iminoethyl)lysine, l-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without l-NAME or l-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 ± 17 vs. 3 ± 7%, respectively, P < 0.001). Perfusion with l-NAME or l-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.

NG-monomethyl-L-arginine does not restore loss of hypoxic pulmonary vasoconstriction induced by TNF-alpha

1993 ◽  
Vol 75 (2) ◽  
pp. 618-625 ◽  
Author(s):  
D. Johnson ◽  
T. Hurst ◽  
T. Wilson ◽  
F. Murphy ◽  
A. Saxema ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Tnf Alpha ◽  
No Production ◽  
Vascular Effects ◽  
Necrosis Factor Alpha ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Factor Alpha ◽  
Systemic Manifestations ◽  
Necrosis Factor

Tumor necrosis factor-alpha (TNF-alpha) causes systemic hypotension, pulmonary vasodilation, and loss of hypoxic pulmonary vasoconstriction. NG-monomethyl-L-arginine (L-NMMA) inhibits nitric oxide (NO) production and prevents some systemic manifestations of TNF-alpha. We tested using an isolated perfused canine lobe whether NO also mediates the pulmonary vascular effects of TNF-alpha. Total resistance (RT) was measured during control and hypoxic ventilation over a 90-min period in six control lobes, five lobes treated with TNF-alpha (250 micrograms), six lobes treated with L-NMMA (200 mg), and five lobes treated with L-NMMA (200 mg) + TNF-alpha (250 micrograms). In the control lobes RT increased (P < 0.02) from 0.0474 +/- 0.0105 to 0.0677 +/- 0.0133 cmH2O.ml-1 x min during normoxic and hypoxic ventilation, respectively. RT decreased (P < 0.05) from a baseline of 0.0593 +/- 0.0133 to 0.0449 +/- 0.0176 cmH2O.ml-1 x min 30 min after TNF-alpha administration and did not further change during hypoxic ventilation (0.0475 +/- 0.0107 cmH2O.ml-1 x min). L-NMMA pretreatment did not prevent the TNF-alpha-induced loss of hypoxic pulmonary vasoconstriction, with values of RT unchanged from normoxic (0.0541 +/- 0.0067 cmH2O.ml-1 x min) to hypoxic (0.0545 +/- 0.0078 cmH2O.ml-1.min) ventilation (P > 0.10) in the L-NMMA + TNF-alpha group after TNF-alpha administration. We conclude that NO is not the mediator responsible for the acute pulmonary vascular effects of TNF-alpha.

Role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide

2001 ◽  
Vol 91 (3) ◽  
pp. 1121-1130 ◽  
Author(s):  
Yasushi Yamamoto ◽  
Hitoshi Nakano ◽  
Hiroshi Ide ◽  
Toshiyuki Ogasa ◽  
Toru Takahashi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
No Synthase ◽  
No Production ◽  
Pulmonary Vasoconstriction ◽  
Exhaled No ◽  
Progressive Hypoxia ◽  
Pulmonary Arterial

The effects of hypercapnia (CO2) confined to either the alveolar space or the intravascular perfusate on exhaled nitric oxide (NO), perfusate NO metabolites (NOx), and pulmonary arterial pressure (Ppa) were examined during normoxia and progressive 20-min hypoxia in isolated blood- and buffer-perfused rabbit lungs. In blood-perfused lungs, when alveolar CO2concentration was increased from 0 to 12%, exhaled NO decreased, whereas Ppa increased. Increments of intravascular CO2levels increased Ppa without changes in exhaled NO. In buffer-perfused lungs, alveolar CO2 increased Ppa with reductions in both exhaled NO from 93.8 to 61.7 (SE) nl/min ( P < 0.01) and perfusate NOx from 4.8 to 1.8 nmol/min ( P < 0.01). In contrast, intravascular CO2 did not affect either exhaled NO or Ppa despite a tendency for perfusate NOx to decline. Progressive hypoxia elevated Ppa by 28% from baseline with a reduction in exhaled NO during normocapnia. Alveolar hypercapnia enhanced hypoxic Ppa response up to 50% with a further decline in exhaled NO. Hypercapnia did not alter the apparent K m for O2, whereas it significantly decreased the V max from 66.7 to 55.6 nl/min. These results suggest that alveolar CO2 inhibits epithelial NO synthase activity noncompetitively and that the suppressed NO production by hypercapnia augments hypoxic pulmonary vasoconstriction, resulting in improved ventilation-perfusion matching.

Role of nitric oxide in vasopressinergic pulmonary vasodilatation

1992 ◽  
Vol 262 (3) ◽  
pp. H743-H747 ◽  
Author(s):  
R. D. Russ ◽  
B. R. Walker
Keyword(s):  
Nitric Oxide ◽  
Pressor Response ◽  
Pulmonary Vasculature ◽  
No Production ◽  
Synthesis Inhibitor ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Significant Augmentation ◽  
Excess Substrate ◽  
Pulmonary Arterial

Experiments were performed to determine the mechanism of vasopressinergic pulmonary vasodilation in isolated, salt-perfused rat lungs. Administration of a 50-ng bolus of arginine vasopressin (AVP) to lungs preconstricted with the synthetic thromboxane analogue U-46619 resulted in a 66% reversal of pulmonary vasoconstriction. Administration of the known endothelium-dependent vasodilator ATP resulted in a parallel decrease in pressure. The vasodilatory responses to both agents were significantly attenuated by pretreatment with the nitric oxide synthesis inhibitor N omega-nitro-L-arginine (L-NNA). In addition to attenuating the vasodilatory response to these agents, L-NNA pretreatment caused a significant augmentation of the pressor response to U-46619 without affecting baseline pulmonary arterial pressure. The attenuation of vasopressinergic pulmonary vasodilation by L-NNA was completely reversed by addition of excess substrate for NO production (50 mM L-arginine) but was unaffected by addition of equimolar amounts of D-arginine. Finally, L-NNA pretreatment failed to attenuate the vasodilatory actions of sodium nitroprusside and isoproterenol. We conclude that AVP dilates the preconstricted pulmonary vasculature via the release of nitric oxide.

Contributions of nitric oxide synthase isozymes to exhaled nitric oxide and hypoxic pulmonary vasoconstriction in rabbit lungs

2003 ◽  
Vol 284 (5) ◽  
pp. L834-L843 ◽  
Author(s):  
David J. Vaughan ◽  
Thomas V. Brogan ◽  
Mark E. Kerr ◽  
Steven Deem ◽  
Daniel L. Luchtel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Exhaled Nitric Oxide ◽  
No Production ◽  
Rabbit Lung ◽  
Pulmonary Vasoconstriction ◽  
Exhaled No ◽  
Nos Inhibitors ◽  
Oxide Synthase

We investigated the source(s) for exhaled nitric oxide (NO) in isolated, perfused rabbits lungs by using isozyme-specific nitric oxide synthase (NOS) inhibitors and antibodies. Each inhibitor was studied under normoxia and hypoxia. Only nitro-l-arginine methyl ester (l-NAME, a nonselective NOS inhibitor) reduced exhaled NO and increased hypoxic pulmonary vasoconstriction (HPV), in contrast to 1400W, an inhibitor of inducible NOS (iNOS), and 7-nitroindazole, an inhibitor of neuronal NOS (nNOS). Acetylcholine-mediated stimulation of vascular endothelial NOS (eNOS) increased exhaled NO and could only be inhibited by l-NAME. Selective inhibition of airway and alveolar epithelial NO production by nebulized l-NAME decreased exhaled NO and increased hypoxic pulmonary artery pressure. Immunohistochemistry demonstrated extensive staining for eNOS in the epithelia, vasculature, and lymphatic tissue. There was no staining for iNOS but moderate staining for nNOS in the ciliated cells of the epithelia, lymphoid tissue, and cartilage cells. Our findings show virtually all exhaled NO in the rabbit lung is produced by eNOS, which is present throughout the airways, alveoli, and vessels. Both vascular and epithelial-derived NO modulate HPV.

Effects of endogenous nitric oxide on pulmonary vascular tone in intact dogs

1994 ◽  
Vol 266 (6) ◽  
pp. H2343-H2347 ◽  
Author(s):  
M. Leeman ◽  
V. Z. de Beyl ◽  
M. Delcroix ◽  
R. Naeije
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Balloon Catheter ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Endogenous Nitric Oxide ◽  
Anesthetized Dogs

The interaction between inspiratory fraction of O2 (FIO2) and endogenous nitric oxide (NO) regulation of pulmonary vascular tone was examined in intact anesthetized dogs. Stimulus (FIO2 of 1, 0.4, 0.21, 0.12, and 0.1)-response (changes in pulmonary artery pressure minus pulmonary artery occlusion pressure) curves were constructed with cardiac output kept constant (by opening a femoral arteriovenous bypass or inflating an inferior vena cava balloon catheter), before and after administration of compounds acting at different levels of the L-arginine-NO pathway, NG-nitro-L-arginine (L-NNA, 10 mg/kg iv, n = 16), a NO synthase inhibitor, and methylene blue (8 mg/kg iv, n = 16), a guanylate cyclase inhibitor. L-NNA and methylene blue did not influence pulmonary vascular tone in hyperoxic and in normoxic conditions, but they increased it during hypoxia, thus enhancing the vasopressor response to hypoxia (from 4.5 +/- 0.9 to 10.4 +/- 1.2 mmHg and from 4.2 +/- 0.8 to 9 +/- 1.5 mmHg, respectively, both P < 0.01). Hypoxic pulmonary vasoconstriction was augmented in dogs with a baseline hypoxic response (“responders”) and restored in dogs without hypoxic response (“nonresponders”). These results suggest that endogenous NO does not influence hyperoxic and normoxic pulmonary vascular tone, but that it inhibits hypoxic pulmonary vasoconstriction in intact anesthetized dogs.

Protective roles of nitric oxide and testosterone in endotoxemia: evidence from NOS-2-deficient mice

1998 ◽  
Vol 275 (6) ◽  
pp. H2211-H2218 ◽  
Author(s):  
Victor E. Laubach ◽  
Patricia L. Foley ◽  
Kim S. Shockey ◽  
Curtis G. Tribble ◽  
Irving L. Kron
Keyword(s):  
Nitric Oxide ◽  
Sex Hormones ◽  
Protective Role ◽  
Multiple Organ ◽  
No Synthase ◽  
Serum Enzymes ◽  
No Production ◽  
Multiple Organ Dysfunction ◽  
Wild Type ◽  
Deficient Mice

Lipopolysaccharide (LPS)-induced septic shock, which triggers nitric oxide (NO) overproduction, multiple organ dysfunction, and death, can be affected by gender and sex hormones. We hypothesized that NO is beneficial during endotoxemia and that this beneficial effect is influenced by sex hormones. C57BL/6 wild-type (WT) mice and congenic inducible NO synthase knockout (KO) mice were injected with LPS, and mortality was recorded for 4 days. After 5 mg/kg LPS, female KO mice had significantly higher mortality than WT. After 12.5 mg/kg LPS, both male and female KO mice had significantly higher mortality than WT. Ovariectomy did not alter mortality, but orchiectomy dramatically increased mortality in KO mice. After 5 mg/kg LPS, exogenous testosterone completely prevented the increased mortality in KO female and orchiectomized KO male mice. WT survival was not affected by exogenous testosterone. After 12.5 mg/kg LPS, exogenous testosterone significantly improved survival of female KO mice. Serum enzymes and organ edema, which may not correlate with mortality, were significantly and similarly increased in both WT and KO endotoxemic mice; however, edema was not observed in KO hearts. Thus, NO plays a protective role in endotoxemia while having differential effects on different organs. Importantly, testosterone is beneficial in endotoxemia when NO production is deficient, and may be therapeutic in certain septic patients.

NOS3 deficiency augments hypoxic pulmonary vasoconstriction and enhances systemic oxygenation during one-lung ventilation in mice

2005 ◽  
Vol 98 (2) ◽  
pp. 748-752 ◽  
Author(s):  
Rong Liu ◽  
Oleg V. Evgenov ◽  
Fumito Ichinose
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Left Lung ◽  
Lung Ventilation ◽  
Gas Analysis ◽  
Wild Type ◽  
One Lung Ventilation ◽  
Pulmonary Vasoconstriction ◽  
Arterial Blood ◽  
Deficient Mice

Nitric oxide (NO), synthesized by NO synthases (NOS), plays a pivotal role in regulation of pulmonary vascular tone. To examine the role of endothelial NOS (NOS3) in hypoxic pulmonary vasoconstriction (HPV), we measured left lung pulmonary vascular resistance (LPVR), intrapulmonary shunting, and arterial Po2 (PaO2) before and during left mainstem bronchus occlusion (LMBO) in mice with and without a deletion of the gene encoding NOS3. The increase of LPVR induced by LMBO was greater in NOS3-deficient mice than in wild-type mice (151 ± 39% vs. 109 ± 36%, mean ± SD; P < 0.05). NOS3-deficient mice had a lower intrapulmonary shunt fraction than wild-type mice (17.1 ± 3.6% vs. 21.7 ± 2.4%, P < 0.05) during LMBO. Both real-time PaO2 monitoring with an intra-arterial probe and arterial blood-gas analysis during LMBO showed higher PaO2 in NOS3-deficient mice than in wild-type mice ( P < 0.05). Inhibition of all three NOS isoforms with Nω-nitro-l-arginine methyl ester (l-NAME) augmented the increase of LPVR induced by LMBO in wild-type mice (183 ± 67% in l-NAME treated vs. 109 ± 36% in saline treated, P < 0.01) but not in NOS3-deficient mice. Similarly, systemic oxygenation during one-lung ventilation was augmented by l-NAME in wild-type mice but not in NOS3-deficient mice. These findings indicate that NO derived from NOS3 modulates HPV in vivo and that inhibition of NOS3 improves systemic oxygenation during acute unilateral lung hypoxia.

Effects of inhaled nitric oxide on pulmonary hemodynamics and gas exchange in an ovine model of ARDS

1994 ◽  
Vol 76 (1) ◽  
pp. 345-355 ◽  
Author(s):  
I. Rovira ◽  
T. Y. Chen ◽  
M. Winkler ◽  
N. Kawai ◽  
K. D. Bloch ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Gas Exchange ◽  
Lung Injury ◽  
Soluble Guanylate Cyclase ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Hemodynamics ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction ◽  
Selective Pulmonary 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.

Endothelin-1 is elevated in monocrotaline pulmonary hypertension

1999 ◽  
Vol 276 (2) ◽  
pp. L304-L310 ◽  
Author(s):  
H. Frederick Frasch ◽  
Carol Marshall ◽  
Bryan E. Marshall
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
No Production ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Before And After ◽  
Nos Inhibitor ◽  
Oxide Synthase

These studies document striking pulmonary vasoconstrictor response to nitric oxide synthase (NOS) inhibition in monocrotaline (MCT) pulmonary hypertension in rats. This constriction is caused by elevated endothelin (ET)-1 production acting on ETA receptors. Isolated, red blood cell plus buffer-perfused lungs from rats were studied 3 wk after MCT (60 mg/kg) or saline injection. MCT-injected rats developed pulmonary hypertension, right ventricular hypertrophy, and heightened pulmonary vasoconstriction to ANG II and the NOS inhibitor N G-monomethyl-l-arginine (l-NMMA). In MCT-injected lungs, the magnitude of the pulmonary pressor response to NOS inhibition correlated strongly with the extent of pulmonary hypertension. Pretreatment of isolated MCT-injected lungs with combined ETA (BQ-123) plus ETB (BQ-788) antagonists or ETA antagonist alone prevented thel-NMMA-induced constriction. Addition of ETA antagonist reversed establishedl-NMMA-induced constriction; ETB antagonist did not. ET-1 concentrations were elevated in MCT-injected lung perfusate compared with sham-injected lung perfusate, but ET-1 levels did not differ before and after NOS inhibition. NOS inhibition enhanced hypoxic pulmonary vasoconstriction in both sham- and MCT-injected lungs, but the enhancement was greater in MCT-injected lungs. Results suggest that in MCT pulmonary hypertension, elevated endogenous ET-1 production acting through ETA receptors causes pulmonary vasoconstriction that is normally masked by endogenous NO production.

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