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.

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

1996 ◽  
Vol 8 (3) ◽  
pp. 431 ◽  
Author(s):  
V DeMarco ◽  
JW Skimming ◽  
TM Ellis ◽  
S Cassin
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Circulation ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Minimum Concentration ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inhaled No

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs

1995 ◽  
Vol 78 (4) ◽  
pp. 1509-1515 ◽  
Author(s):  
F. Grimminger ◽  
R. Spriestersbach ◽  
N. Weissmann ◽  
D. Walmrath ◽  
W. Seeger
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Sharp Drop ◽  
Pulmonary Vasoconstriction ◽  
Exhaled No ◽  
Pressor Responses ◽  
Hypoxic Vasoconstriction ◽  
Alveolar Hypoxia

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78(4): 1509–1515, 1995.--We investigated the role of nitric oxide (NO) generation in hypoxic pulmonary vasoconstriction in buffer-perfused rabbit lungs. Exhaled NO was detected by chemiluminescence, and intravascular NO release was quantified as perfusate accumulation of nitrite, peroxynitrite, and nitrate (NOx). Under baseline conditions, exhaled NO was 45.3 +/- 4.1 parts per billion (1.8 +/- 0.2 nmol/min), and lung NOx release into the perfusate was 4.1 +/- 0.4 nmol/min. Alveolar hypoxia (alveolar PO2 of approximately 23 Torr) induced readily reproducible pressor responses preceded by a sharp drop in exhaled NO concentration. In contrast, perfusate NOx accumulation was not affected. Vasoconstrictor responses to U-46619 and angiotensin II were not accompanied by a decrease in NO exhalation. NG-monomethyl-L-arginine dose-dependently suppressed NO exhalation and amplified pressor responses to hypoxia > U-46619 and angiotensin II. In conclusion, portions of baseline NO generation originating from sites with ready access to the gaseous space sharply decrease in response to alveolar hypoxia, whereas the intravascular release of NO is unchanged. Such differential regulation of lung NO synthesis in response to hypoxia may suggest a complex role in the regulation or modulation of hypoxic pulmonary vasoconstriction.

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.

Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells

2004 ◽  
Vol 287 (1) ◽  
pp. L60-L68 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Tamara L. Young ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
No Synthase ◽  
No Production ◽  
Urea Production ◽  
Pulmonary Arterial ◽  
Factor Α ◽  
Arterial Endothelial Cells ◽  
Regular Medium ◽  
Necrosis Factor

Nitric oxide (NO) is produced by NO synthase (NOS) from l-arginine (l-Arg). Alternatively, l-Arg can be metabolized by arginase to produce l-ornithine and urea. Arginase (AR) exists in two isoforms, ARI and ARII. We hypothesized that inhibiting AR with l-valine (l-Val) would increase NO production in bovine pulmonary arterial endothelial cells (bPAEC). bPAEC were grown to confluence in either regular medium (EGM; control) or EGM with lipopolysaccharide and tumor necrosis factor-α (L/T) added. Treatment of bPAEC with L/T resulted in greater ARI protein expression and ARII mRNA expression than in control bPAEC. Addition of l-Val to the medium led to a concentration-dependent decrease in urea production and a concentration-dependent increase in NO production in both control and L/T-treated bPAEC. In a second set of experiments, control and L/T bPAEC were grown in EGM, EGM with 30 mM l-Val, EGM with 10 mM l-Arg, or EGM with both 10 mM l-Arg and 30 mM l-Val. In both control and L/T bPAEC, treatment with l-Val decreased urea production and increased NO production. Treatment with l-Arg increased both urea and NO production. The addition of the combination l-Arg and l-Val decreased urea production compared with the addition of l-Arg alone and increased NO production compared with l-Val alone. These data suggest that competition for intracellular l-Arg by AR may be involved in the regulation of NOS activity in control bPAEC and in response to L/T treatment.

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs

2001 ◽  
Vol 91 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Toshiyuki Ogasa ◽  
Hitoshi Nakano ◽  
Hiroshi Ide ◽  
Yasushi Yamamoto ◽  
Nobuhiko Sasaki ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Baseline Level ◽  
Pulmonary Arterial Pressure ◽  
Blood Perfusion ◽  
No Production ◽  
Perfusion Study ◽  
Capillary Recruitment ◽  
Physiological Conditions ◽  
Perfusate Flow ◽  
Pulmonary Arterial

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N G-monomethyl-l-arginine (l-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 ± 3 (SE) to 83 ± 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 ± 2 to 73 ± 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia.l-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However,l-NMMA blocked the flow-dependent increase in conductance over the range of 50–150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.

Endothelium-derived relaxing factor activity in rat lung during hypoxic pulmonary vascular remodeling

1993 ◽  
Vol 74 (3) ◽  
pp. 1061-1065 ◽  
Author(s):  
L. Zhao ◽  
D. E. Crawley ◽  
J. M. Hughes ◽  
T. W. Evans ◽  
R. J. Winter
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Exposure ◽  
Control Group ◽  
Pulmonary Vascular Remodeling ◽  
Relaxing Factor ◽  
Pulmonary Vasoconstriction ◽  
O2 Concentration ◽  
Pulmonary Arterial ◽  
Endothelium Derived Relaxing Factor

We have investigated the role of endothelium-derived relaxing factor in modulating hypoxic pulmonary vasoconstriction by inhibiting its synthesis with the false substrate NG-monomethyl-L-arginine (L-NMMA) in the isolated blood-perfused lungs of Wistar rats after chronic hypoxia (CH, fractional inspiratory O2 concentration 10%) for 15 h, 2 days, and 7 days. Lungs were perfused with blood of normal hematocrit at constant flow (18 ml/min) ventilated with 1) 95% air-5% CO2 (normoxia) and 2) 2% O2–5% CO2-93% N2 (hypoxia) and were studied in the absence and presence of L-NMMA (30 and 300 microM) or L-arginine (L-Arg, 1 and 6 mM) in separate groups. Pulmonary arterial pressure (Ppa) rose incrementally with hypoxic exposure (all P < 0.05 vs. normoxic control group). Hypoxic pulmonary vasoconstriction (HPV) was markedly reduced after 15 h and 2 days of CH: the mean increases in Ppa (delta Ppa) in hypoxia were 15.3, 3.5, 3.8, and 13.6 mmHg in control rats and rats exposed to 15 h (P < 0.05 vs. control and 7 days of CH), 2 days (P < 0.001 vs. control and 7 days of CH), and 7 days of CH, respectively. Ppa in control rats and rats exposed to 15 h, 2 days, and 7 days of CH were 137, 179, 184, and 166% of control, respectively, after 30 microM L-NMMA (all P < 0.05 when expressed as percent change vs. no L-NMMA). Similar augmentation in HPV was seen after 30 microM L-NMMA, with all hypoxic groups having a greater response than control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Does leukotriene C4 mediate hypoxic vasoconstriction in isolated ferret lungs?

1990 ◽  
Vol 68 (1) ◽  
pp. 253-259 ◽  
Author(s):  
C. M. Tseng ◽  
M. McGeady ◽  
T. Privett ◽  
A. Dunn ◽  
J. T. Sylvester
Keyword(s):  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Physiological Salt Solution ◽  
Leukotriene C4 ◽  
Prostaglandin F2 Alpha ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Hypoxic Vasoconstriction ◽  
Pulmonary Arterial

To evaluate leukotriene (LT) C4 as a mediator of hypoxic pulmonary vasoconstriction, we examined the effects of FPL55712, a putative LT antagonist, and indomethacin, a cyclooxygenase inhibitor, on vasopressor responses to LTC4 and hypoxia (inspired O2 tension = 25 Torr) in isolated ferret lungs perfused with a constant flow (50 ml.kg-1.min-1). Pulmonary arterial injections of LTC4 caused dose-related increases in pulmonary arterial pressure during perfusion with physiological salt solution containing Ficoll (4 g/dl). FPL55712 caused concentration-related inhibition of the pressor response to LTC4 (0.6 micrograms). Although 10 micrograms/ml FPL55712 inhibited the LTC4 pressor response by 61%, it did not alter the response to hypoxia. At 100 microgram/ml, FPL55712 inhibited the responses to LTC4 and hypoxia by 73 and 71%, respectively, but also attenuated the vasoconstrictor responses to prostaglandin F2 alpha (78% at 8 micrograms), phenylephrine (68% at 100 micrograms), and KCl (51% at 40 mM). At 0.5 microgram/ml, indomethacin significantly attenuated the pressor response to arachidonic acid but did not alter responses to LTC4 or hypoxia. These results suggest that in isolated ferret lungs 1) the vasoconstrictor response to LTC4 did not depend on release of cyclooxygenase products and 2) LTC4 did not mediate hypoxic vasoconstriction.

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog

1994 ◽  
Vol 76 (3) ◽  
pp. 1350-1355 ◽  
Author(s):  
J. A. Romand ◽  
M. R. Pinsky ◽  
L. Firestone ◽  
H. A. Zar ◽  
J. R. Lancaster
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Canine Model ◽  
Systemic Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Nitric oxide (NO) inhaled during a hypoxia-induced increase in pulmonary vasomotor tone decreases pulmonary arterial pressure (Ppa). We conducted this study to better characterize the hemodynamic effects induced by NO inhalation during hypoxic pulmonary vasoconstriction in 11 anesthetized ventilated dogs. Arterial and venous systemic and pulmonary pressures and aortic flow probe-derived cardiac output were recorded, and nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) were measured. The effects of 5 min of NO inhalation at 0, 17, 28, 47, and 0 ppm during hyperoxia (inspiratory fraction of O2 = 0.5) and hypoxia (inspiratory fraction of O2 = 0.16) were observed. NO inhalation has no measurable effects during hyperoxia. Hypoxia induced an increase in Ppa that reached plateau levels after 5 min. Exposure to 28 and 47 ppm NO induced an immediate (< 30 s) decrease in Ppa and calculated pulmonary vascular resistance (P < 0.05 each) but did not return either to baseline hyperoxic values. Increasing the concentration of NO to 74 and 145 ppm in two dogs during hypoxia did not induce any further decreases in Ppa. Reversing hypoxia while NO remained at 47 ppm further decreased Ppa and pulmonary vascular resistance to baseline values. NO inhalation did not induce decreases in systemic arterial pressure. MetHb remained low, and NO-Hb was unmeasurable. We concluded that NO inhalation only partially reversed hypoxia-induced increases in pulmonary vasomotor tone in this canine model. These effects are immediate and selective to the pulmonary circulation.

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