Preliminary report: effects of artificial blood on hypoxic pulmonary vasoconstriction

BACKGROUND: We examined the effects of artificial blood on hypoxic pulmonary vasoconstriction (HPV). METHODS: Pump-perfused rabbit lungs were reperfused and ventilated with a mixture of 21% O2, 5% CO2, and balance N2. HPV was induced by reduction of O2 concentration from 21 to 3% for 5 min. Pulmonary arterial pressure (PAP) was measured using a low-pressure transducer. Two perfusion solutions, (1) a mixture of autologous red blood cells and physiological salt solution supplemented with 5% albumin and (2) artificial red blood cells (liposome-encapsulated hemoglobin) and physiological saline supplemented with 5% albumin, were made. Using each solution, HPV was evaluated by PAP increase with and without inhalation of nitric oxide (NO). RESULTS: (1) With both autologous and artificial perfusion solutions, hypoxic stimulation (HS) increased PAP. (2) With the autologous solution, NO inhalation suppressed the HS-induced PAP increase, but with the artificial solutions no such a phenomenon was observed. CONCLUSIONS: NO inhalation failed to suppress HPV with the artificial solution, probably since the liposome-encapsulated hemoglobin strongly inactivated NO.     

Inhibition of nitric oxide synthase prevents hyporesponsiveness to inhaled nitric oxide in lungs from endotoxin-challenged rats.

BACKGROUND: Inhalation of nitric oxide (NO) selectively dilates the pulmonary circulation and improves arterial oxygenation in patients with adult respiratory distress syndrome (ARDS). In approximately 60% of patients with septic ARDS, minimal or no response to inhaled NO is observed. Because sepsis is associated with increased NO production by inducible NO synthase (NOS2), the authors investigated whether NOS inhibition alters NO responsiveness in rats exposed to gram-negative lipopolysaccharide (LPS). METHODS: Sprague-Dawley rats were treated with 0.4 mg/kg Escherichia coli O111:B4 LPS with or without dexamethasone (inhibits NOS2 gene expression; 5 mg/kg), L-NAME (a nonselective NOS inhibitor; 7 mg/kg), or aminoguanidine (selective NOS2 inhibitor; 30 mg/kg). Sixteen hours after LPS treatment, lungs were isolated-perfused; a thromboxane-analog U46619 was added to increase pulmonary artery pressure (PAP) by 5 mmHg, and the pulmonary vasodilator response to inhaled NO was measured. RESULTS: Ventilation with 0.4, 4, and 40 ppm NO decreased the PAP less than in lungs of LPS-treated rats (0.75+/-0.25, 1.25+/-0.25, 1.75+/-0.25 mmHg) than in lungs of control rats (3+/-0.5, 4.25+/-0.25, 4.5+/-0.25 mmHg; P < 0.01). Dexamethasone treatment preserved pulmonary vascular responsiveness to NO in LPS-treated rats (3.75+/-0.25, 4.5+/-0.25, 4.5+/-0.5 mmHg, respectively; P < 0.01 vs. LPS, alone). Responsiveness to NO in LPS-challenged rats was also preserved by treatment with L-NAME (3.0+/-1.0, 4.0+/-1.0, 4.0+/-0.75 mmHg, respectively; P < 0.05 vs. LPS, alone) or aminoguanidine (1.75+/-0.25, 2.25+/-0.5, 2.75+/-0.5 mmHg, respectively; P < 0.05 vs. LPS, alone). In control rats, treatment with dexamethasone, L-NAME, and aminoguanidine had no effect on inhaled NO responsiveness. CONCLUSION: These observations demonstrate that LPS-mediated increases in pulmonary NOS2 are involved in decreasing responsiveness to inhaled NO.     

Inhaled nitric oxide does not alter pulmonary or cardiac effects of fat embolism in dogs after cemented arthroplasty

PURPOSE: We examined the effect of inhaled nitric oxide (NO) on the acute pulmonary hypertension and right ventricular (RV) dilation after fat embolism. METHODS: A bilateral cemented arthroplasty (BCA), created fat embolism in 20 dogs. In Part A, 12 dogs were randomized to an NO group (n=6, inhaled NO 40 ppm before BCA and throughout the study) or a control group (n=6). In Part B, a third group of dogs (n=8) were given NO 20-40 ppm 2-3 min after BCA when pulmonary artery pressure (PAP) increased. Transesophageal echocardiography (TEE) and invasive hemodynamic monitoring evaluated the hemodynamic response to BCA. Postmortem, quantitative morphometry was used to estimate the number of fat emboli and diameter of lung vessel occluded by fat. RESULTS: Part A: The increase in PAP in the NO group (16 +/- 1 to 34 +/- 9 mmHg) within three minutes of BCA was not different from that in the control group (14 +/- 4 to 35 +/- 9 mmHg). Within three minutes of BCA, TEE demonstrated RV dilation in all groups (P < 0.05) but there was no difference in the change in RV area in the NO and control groups. When NO was given after BCA, no difference in PAP or RV dilation was noted from that in the control group. There were no differences, at post mortem, between the groups in the diameter of lung vessel occluded by fat CONCLUSION: Whether given before the embolic insult or two to three minutes after the onset of pulmonary hypertension, inhaled NO did not attenuate the acute pulmonary hypertension or RV dilation after cemented arthroplasty.     

Inhibition of Nitric Oxide Synthase Prevents Hyporesponsiveness to Inhaled Nitric Oxide in Lungs from Endotoxin-challenged Rats

Background: Inhalation of nitric oxide (NO) selectively dilates the pulmonary circulation and improves arterial oxygenation in patients with adult respiratory distress syndrome (ARDS). In approximately 60% of patients with septic ARDS, minimal or no response to inhaled NO is observed. Because sepsis is associated with increased NO production by inducible NO synthase (NOS2), the authors investigated whether NOS inhibition alters NO responsiveness in rats exposed to gram-negative lipopolysaccharide (LPS).

Methods: Sprague-Dawley rats were treated with 0.4 mg/kg Escherichia coli 0111:B4 LPS with or without dexamethasone (inhibits NOS2 gene expression; 5 mg/kg), L-NAME (a nonselective NOS inhibitor; 7 mg/kg), or aminoguanidine (selective NOS2 inhibitor; 30 mg/kg). Sixteen hours after LPS treatment, lungs were isolated-perfused; a thromboxane-analog U46619 was added to increase pulmonary artery pressure (PAP) by 5 mmHg, and the pulmonary vasodilator response to inhaled NO was measured.

Results: Ventilation with 0.4, 4, and 40 ppm NO decreased the PAP less than in lungs of LPS-treated rats (0.75 +/- 0.25, 1.25 +/- 0.25, 1.75 +/- 0.25 mmHg) than in lungs of control rats (3 +/- 0.5, 4.25 +/- 0.25, 4.5 +/- 0.25 mmHg; P < 0.01). Dexamethasone treatment preserved pulmonary vascular responsiveness to NO in LPS-treated rats (3.75 +/- 0.25, 4.5 +/- 0.25, 4.5 +/- 0.5 mmHg, respectively; P < 0.01 vs. LPS, alone). Responsiveness to NO in LPS-challenged rats was also preserved by treatment with L-NAME (3.0 +/- 1.0, 4.0 +/- 1.0, 4.0 +/- 0.75 mmHg, respectively; P < 0.05 vs. LPS, alone) or aminoguanidine (1.75 +/- 0.25, 2.25 +/- 0.5, 2.75 +/- 0.5 mmHg, respectively; P < 0.05 vs. LPS, alone). In control rats, treatment with dexamethasone, L-NAME, and aminoguanidine had no effect on inhaled NO responsiveness.     

Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats.

Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with N(G)-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO. IMPLICATIONS: High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.     

Intermittent nitric oxide combined with intravenous dipyridamole in a piglet model of acute pulmonary hypertension

Continuous administration of inhaled nitric oxide is now widely used as a potent and selective pulmonary vasodilator. We have evaluated the effects of IV dipyridamole, a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, on the magnitude and duration of action of inhaled nitric oxide (NO)-mediated pulmonary vasodilation. We hypothesized that inhibition of cGMP degradation could augment and prolong the pulmonary vasodilating effects of NO and allow for intermittent NO inhalation. In eight anesthetized and mechanically ventilated piglets, IV U-46619, a thromboxane A(2) analog, was used to induce pulmonary hypertension. The effects of 2, 5, and 10 ppm of NO, delivered during 4 min for each concentration and followed by a 10-min NO-free interval after each NO concentration, were evaluated without and with dipyridamole. Pulmonary vascular resistance decreased from 825 +/- 49 dynes. s. cm(-5) (U-46619) to 533 +/- 48 dynes. s. cm(-5) (10 ppm NO) (P < 0.05 versus U-46619) and 396 +/- 42 dynes. s. cm(-5) (dipyridamole 10 microg kg-1x min-1 and 10 ppm NO) (P <0.05 versus NO), and cardiac output increased from 1.93 +/- 0.09 L/min to 2.03 +/- 0.13 L/min and 2.60 +/- 0.30 L/min (P < 0.05 versus NO). Mean arterial blood pressure decreased from 90 +/- 5 mm Hg (10 ppm NO) to 75 +/- 3 mm Hg (dipyridamole plus 10 ppm NO) (P < 0.01). The pulmonary vasodilation obtained with NO alone could be prolonged from 12 to 42 min when inhaled NO was combined with IV dipyridamole, accounting for a time-weighted reduction in NO exposure by 72%. We conclude that dipyridamole augments the effects of NO on right ventricular afterload, allows for intermittent NO inhalation, and can significantly reduce exposure to NO. IMPLICATIONS: IV dipyridamole prolongs the action of inhaled nitric oxide (NO) in a piglet model of acute pulmonary hypertension. Intermittent NO inhalation combined with IV dipyridamole decreases pulmonary artery pressure for a prolonged period of time and reduces exposure to NO.     

吸入一氧化氮对室间隔缺损手术后肺动脉高压的疗效观察

目的　观察吸入一氧化氮(nitricoxide,NO)治疗室间隔缺损 (ventricularseptaldefect,VSD)术后肺动脉高压 (pulmonaryhypertension ,PH)的疗效。 方法　 2 0例VSD术后PH病人分别吸入 2 0×10 -6 、6× 10 -6 NO ,监测吸入前后的血流动力学、氧合指标。结果　吸入 2 0× 10 -6 NO后明显降低肺动脉压、肺循环阻力、肺内分流率、肺泡动脉血氧分压差 ,提高动脉血氧分压、氧供指数 ;以上指标停吸NO后恢复吸入NO前水平 ;再吸入 6× 10 -6 NO后恢复吸入 2 0× 10 -6 NO后水平 ,并维持至停吸NO后。吸入前后体循环压及阻力无变化。结论　吸入NO是治疗VSD手术后PH的一种有效的方法。     

Hypoxic pulmonary vasoconstriction increases during endotoxemia in the perfused rat lung

BACKGROUND: Several investigations have studied hypoxic pulmonary vasoconstriction (HPV) during endotoxemia, as in this situation there is an increase in the activation of the inducible nitric oxide synthases, producing a greater liberation of nitric oxide (NO) in the pulmonary vessels. However, these studies yielded conflicting or at times contradictory results, since reference has been made to both enhancement and inhibition of HPV. Our objective was to determine the effect of hypoxia on the isolated blood-perfused lung of endotoxemic rats, and to give at least a partial explanation of its production mechanism. METHODS: Pulmonary arterial pressure (PAP) was measured in a blood-perfused lung preparation from Wistar rats in normoxia (O2, 20%; CO2, 5%; N, 75%) and hypoxia (O2, 2%; CO2, 5%; N, 93%). There were three experimental protocols. We studied the effect of hypoxia in a control group (CG) and an endotoxemic group (EG). Second, we studied the effect of hypoxia in endotoxemic rats pretreated with indomethacin (E+IG). Third, we assessed the effect of two inhibitors of NO synthesis: N-methyl-l-arginine (NMLA) and methylene blue (MB) on two subgroups of groups CG (CGnmla and CGmb) and EG (EGnmla and EGmb). With the exception of the CG, all specimens were pretreated with a 20-mg/kg intraperitoneal injection of Escherichia coli lipopolysaccharide. RESULTS: DeltaPAP elicited by hypoxia in the EG group (15.90 +/- 4.75 mm Hg) was 2.30 times higher than in the CG (6.89 +/- 1.96 mm Hg). In the E+IG group, hypoxia produced a DeltaPAP of 15.20 +/- 3.56 mm Hg, similar to that in the EG. The addition of MB in the EGmb subgroup increased base PAP during normoxia from 19.1 +/- 1.23 mm Hg to 32.2 +/- 6.1 mm Hg (p < 0.05). CONCLUSION: In an isolated-perfused rat model, E. coli lipopolysaccharide (20 mg/kg) significantly increased HPV. This response is maintained over time. Inhibition of NO release by hypoxia may be responsible for the enhanced HPV after endotoxin.     

Low-dose phosphodiesterase inhibition improves responsiveness to inhaled nitric oxide in isolated lungs from endotoxemic rats

BACKGROUND: Inhalation of nitric oxide (NO) and inhibition of phosphodiesterase type 5 (PDE5) selectively dilate the pulmonary circulation in patients with acute lung injury (ALI) associated with pulmonary hypertension. PDE5 inhibitors administered at doses that decrease pulmonary artery pressures have been shown to worsen arterial oxygenation. We investigated the efficacy of doses of PDE5 inhibitors that do not reduce pulmonary artery pressure alone (subthreshold doses) to improve the response to inhaled NO in an animal model of ALI. MATERIALS AND METHODS: Adult Sprague-Dawley rats were pre-treated with 0.5 mg/kg Escherichia coli 0111:B4 endotoxin and 16 to 18 h later, their lungs were isolated perfused and ventilated. The thromboxane mimetic U46619 was used to induce pulmonary hypertension. After the determination of subthreshold doses of two different PDE5 inhibitors, either 50 microg zaprinast or 10 ng sildenafil was added to the perfusate and the decrease of pulmonary artery pressure measured in the presence and absence of inhaled NO. RESULTS: In the presence of 4 or 10 ppm NO, zaprinast (-1.6 +/- 0.4 and -2.9 +/- 0.6 mmHg, respectively) and sildenafil (-1.9 +/- 0.4 and -2.4 + 0.3 mmHg, respectively) improved responsiveness to inhaled NO compared to lungs from rats treated with LPS only (0.7 +/- 0.1 and -1.0 +/- 0.1 mmHg, respectively; P<0.05). Neither zaprinast nor sildenafil prolonged the pulmonary vasodilatory response to inhaled NO. CONCLUSIONS: Subthreshold doses of PDE5 inhibitors improved responsiveness to inhaled NO. Combining inhaled NO with subthreshold doses of PDE5 inhibitors may offer a therapeutic strategy with minimal side-effects in ALI associated with pulmonary hypertension.     

Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy.

BACKGROUND: The inhalation of nitric oxide (NO) in patients with heart failure decreases pulmonary vascular resistance (PVR) and is associated with an increase in pulmonary artery wedge pressure (PAWP). The mechanism for this effect remains unclear. METHODS: In dogs rapid-paced for 8 weeks to induce cardiac dysfunction, we performed left ventricular pressure-volume analysis of unpaced hearts in situ to determine whether during NO inhalation (80 ppm), the mechanism for the rise in PAWP is due to: 1) primary pulmonary vasodilation; 2) a direct negative inotropic effect; or 3) impairment of ventricular relaxation. RESULTS: Inhalation of NO decreased PVR by 51%+/-3.8% (257+/-25 vs 127+/-18 dynes x sec x cm(-5) [NO 80 ppm]; p < 0.001) and increased PAWP (15.4+/-2.4 vs 18.1+/-2.6 mm Hg [NO 80 ppm]; p < 0.001). Calculated systemic vascular resistance remained unchanged. Left ventricular (LV) end-diastolic pressure rose (16.4+/-1.9 vs 19.1+/-1.8 mm Hg [NO 80 ppm]; p < 0.001), as did LV end-diastolic volume (83.5+/-4.0 vs 77.0+/-3.4 mL [NO 80 ppm]; p = 0.006). LV peak +dP/dt was unchanged by NO (1,082+/-105 vs 1,142+/-111 mm Hg/sec [NO 80 ppm]; p = NS). There was a trend toward a stroke volume increase (17.4+/-1.2 vs 18.8+/-1.3 mL; p = NS), but the relaxation time constant and end-diastolic pressure-volume relation were both unchanged. CONCLUSIONS: In this canine model of cardiomyopathy, inhaled NO decreases pulmonary vascular resistance. The associated increase in left ventricular filling pressure appears to be secondary to a primary pulmonary vasodilator effect of NO without primary effects on the contractile or relaxation properties of the left ventricle.     

Inhaled nitric oxide. A selective pulmonary vasodilator of heparin-protamine vasoconstriction in sheep.

Nitric oxide (NO) has recently been discovered to be an important endothelium-derived relaxing factor and produces profound relaxation of vascular smooth muscle. To learn if NO could be a potent and selective pulmonary vasodilator, NO was inhaled by 16 awake lambs in an attempt to reduce the increase in pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) induced by either the infusion of an exogenous pulmonary vasoconstrictor (the thromboxane analog U46619) or the endogenous release of thromboxane that occurs during the neutralization of heparin anticoagulation by protamine sulfate. Inhaling greater than or equal to 40 ppm of NO during a continuous U46619 infusion returned the PAP to a normal value, without affecting systemic blood pressure or vascular resistance. Pretreatment with the cyclooxygenase inhibitor indomethacin before infusing U46619 did not reduce the pulmonary vasodilatory effect of inhaled NO, and we conclude that the dilatory effect of NO on the lung's circulation is independent of cyclooxygenase products such as prostacyclin. Continuously inhaling NO at 180 ppm did not significantly reduce the mean peak thromboxane B2 concentration at 1 min after protamine injection; however, the mean values of pulmonary hypertension and vasoconstriction at 1 min were markedly reduced below the levels in untreated heparin-protamine reactions. Breathing NO at lower concentrations (40-80 ppm) did not decrease the mean peak PAP and PVR at 1 min after protamine but decreased the PAP and PVR values at 2, 3, and 5 min below those of control heparin-protamine reactions. Intravenous infusion of nitroprusside completely prevented the transient increase of PAP and PVR during the heparin-protamine reaction; however, marked concomitant systemic vasodilation occurred. Inhaled NO is a selective pulmonary vasodilator that can prevent thromboxane-induced pulmonary hypertension during the heparin-protamine reaction in lambs and can do so without causing systemic vasodilation.     

Selective Pulmonary Vasodilation Induced by Aerosolized Zaprinast

Background: Zaprinast, an inhibitor of guanosine-3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators (including inhaled nitric oxide [NO]). The present study was designed to examine the effects of inhaled nebulized zaprinast, alone, and combined with inhaled NO.

Methods: Eight awake lambs with U46619-induced pulmonary hypertension sequentially breathed two concentrations of NO (5 and 20 ppm), followed by inhalation of aerosols generated from solutions containing four concentrations of zaprinast (10, 20, 30, and 50 mg/ml). The delivered doses of nebulized zaprinast at each concentration (mean +/- SD) were 0.23 +/- 0.06, 0.49 +/- 0.14, 0.71 +/- 0.24, and 1.20 +/- 0.98 mg [center dot] kg sup -1 [center dot] min sup -1, respectively. Each lamb also breathed NO (5 and 20 ppm) and zaprinast (0.23 +/- 0.06 mg [center dot] kg sup -1 [center dot] min sup -1) in combination after a 2-h recovery period.

Results: Inhaled NO selectively dilated the pulmonary vasculature. Inhaled zaprinast selectively dilated the pulmonary circulation and potentiated and prolonged the pulmonary vasodilating effects of inhaled NO. The net transpulmonary release of cGMP was increased by inhalation of NO, zaprinast, or both. The duration of the vasodilation induced by zaprinast inhalation was greater than that induced by NO inhalation.     

Effect of increased intracranial pressure on regional hypoxic pulmonary vasoconstriction

The effects of increased intracranial pressure (ICP) and increased cardiac output (QT) on the pulmonary vascular response to regional alveolar hypoxia were compared in pentobarbital-anesthetized, closed-chested dogs. A bronchial divider was inserted, the right lung (RL) was continuously ventilated with 100% O2, and the left lung (LL) was ventilated with either 100% O2 (hyperoxia) or a hypoxic gas mixture (hypoxia). Sulfur hexafluoride (SF6) was used to measure differential lung blood flow and the multiple inert gas technique assessed gas exchange. The response to LL alveolar hypoxia (hypoxic pulmonary vasoconstriction, HPV) was studied in each animal prior to, during, and after the ICP was increased by infusing mock cerebrospinal fluid (CSF) into a lateral ventricle so that cerebral perfusion pressure was 25 mmHg. During both control periods, QT was randomly altered by opening (high QT) or closing (normal QT) two arteriovenous fistulas. Increasing ICP significantly increased QT (P less than 0.01), pulmonary artery pressure (PAP) (P less than 0.05), and mixed venous oxygen tension (PVO2) (P less than 0.05), compared with normal QT controls. Opening the arteriovenous fistulas achieved similar increases in QT (P less than 0.01), PAP (P less than 0.05), and PVO2 (P less than 0.05). The percentage of blood flow to the LL (QL/QT%) during hyperoxia was 43.9 +/- 0.8% (mean +/- SE) and did not vary with manipulation of QT or ICP. QL/QT% during LL hypoxia was significantly increased by both increased ICP (24.6 +/- 3.5%) and high QT (23.1 +/- 1.0%) compared with normal QT (16.8 +/- 2.1) controls (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Responsiveness to inhaled NO in isolated-perfused lungs from endotoxin-challenged rats is dependent on endogenous nitrite/nitrate synthesis

BACKGROUND AND OBJECTIVES: In isolated-perfused lungs of lipopolysaccharide (LPS)-challenged rats, vasodilatation to inhaled nitric oxide (NO) is impaired. Inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) prevented hyporesponsiveness to inhaled NO. Here, we investigated whether NOS2-mediated nitrite/nitrate synthesis modulates responsiveness to inhaled NO. METHODS: Sprague-Dawley rats received intraperitoneally 0.5 mg kg(-1) LPS. Four hours later, LPS-treated rats received 3, 10 or 30 mg kg(-1) AG or 0.01, 0.1 or 1 mg kg(-1) S-methylisothiourea (SMT) by intraperitoneal injection. Sixteen to eighteen hours later, lungs were isolated and perfused, and pulmonary artery pressure (PAP) was elevated by 6-8 mmHg using the thromboxane analogue U46619. The decrease of PAP in response to inhaled NO and nitrate/nitrite levels in serum and perfusate was measured. RESULTS: In rats treated with LPS alone or 0.01 or 0.1 mg kg(-1) SMT, 40 ppm NO decreased PAP less than in rats treated with AG and 1 mg kg(-1) SMT (-1.8 mmHg (95% confidence interval: -1.5 to -2.1) vs. -6.0 mmHg (-5.7 to -6.3), P < 0.01). Improved NO responsiveness was associated with lower serum and perfusate nitrite/nitrate levels than in rats with hyporesponsiveness to inhaled NO (102 micromol (82-122) vs. 282 micromol (261-303) and 8.1 micromol (6.9-9.3) vs. 19.8 micromol (17.2-22.4), respectively, P < 0.01). CONCLUSIONS: These observations demonstrate that in isolated-perfused lungs of LPS-treated rats, NOS2 inhibition improved responsiveness to inhaled NO. Here, responsiveness to inhaled NO is dependent on the ability of NOS2 inhibitors to reduce nitrite and nitrate levels in serum and released in the lung.     

Intravenous PGF2 alpha infusion does not enhance hypoxic pulmonary vasoconstriction during canine one-lung hypoxia

The effect of prostaglandin F2 alpha (PGF2 alpha) on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in 12 closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was either ventilated with 100% O2 ("hyperoxia") or ventilated with an hypoxic gas mixture ("hypoxia:" end-tidal PO2 approximately equal to 50.0 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 2.89 +/- 0.26 1.min-1 to a "high" value of 3.55 +/- 0.26 1.min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were performed in the absence of, and in the presence of, PGF2 alpha administered as a constant peripheral intravenous infusion of 1.0 microgram.kg-1.min-1. During left lung hypoxia, mean pulmonary artery pressure (PAP) increased significantly when compared to hyperoxia. With PGF2 alpha administration, mean PAP increased significantly during both hyperoxia and hypoxia. The presence or absence of PGF2 alpha had no effect on cardiac output or PaO2 during hypoxia. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 45 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 29 +/- 3%. However, with the administration of PGF2 alpha, the %QL-VCO2 during left lung hypoxia did not change significantly 26 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of isoflurane on hypoxic pulmonary vasoconstriction in dogs

The authors studied the influence of locally administered isoflurane anesthesia on the pulmonary vascular response to regional alveolar hypoxia (hypoxic pulmonary vasoconstriction [HPV]) over a range of cardiac outputs (COs) in seven mechanically ventilated, closed-chest dogs. The right lung was ventilated with 100% O2 throughout the study. The left lung was ventilated with either 100% O2 (normoxia) or an hypoxic gas mixture (hypoxia). Different alveolar concentrations of isoflurane (0, 1, and 2.5 MAC) were administered to the left lung in a randomized sequence. The CO was altered by opening and closing surgically produced arteriovenous fistulae, at all isoflurane concentrations, and by hemorrhage at 0 MAC isoflurane. The magnitude of the HPV response was measured by differential CO2 elimination in the absence of isoflurane and by venous admixtures in all phases. During normoxia, the left lung effective flow (QL%) measured from differential CO2 excretion was 39.9 +/- 1.2% of the total blood flow and decreased to 18.8 +/- 2.6% when ventilated with the hypoxic gas mixture. Venous admixture (QVA/QT%) was significantly correlated with QL% during hypoxic ventilation in the absence of isoflurane. QVA/QT% was 22.3 +/- 2.7% during hypoxia with normal CO, and it increased significantly to 27.7 +/- 1.1% when the CO was increased 43%. It was not significantly altered (23.6 +/- 3.6%) when the CO was decreased by 54%. Isoflurane 2.5 MAC significantly increased QVA/QT% during hypoxic ventilation of the left lung to 33.9 +/- 2.6% with low CO and 35.4 +/- 1.7% with normal CO. Isoflurane 1 MAC increased QVA/QT% to 27.2 +/- 2.7% with normal CO and 28.1 +/- 2.6% with high CO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined therapy with inhaled nitric oxide and intravenous vasodilators during acute and chronic experimental pulmonary hypertension.

Both inhaled nitric oxide (NO) and IV vasodilators decrease pulmonary hypertension, but the effects of combination therapy are unknown. We studied the response to inhaled NO (100 ppm) alone, IV vasodilator alone, and combined therapy during acute (U46619-induced) and chronic (monocrotaline-induced) pulmonary hypertension in the pentobarbital-anesthetized rat. Vasodilator doses were 1.0, 3.2, 10, and 32 microg x kg(-1) x min(-1) sodium nitroprusside (SNP); 50, 100, 150, 200, and 300 microg x kg(-1) x min(-1) adenosine; or 25, 50, 150, 200, and 300 ng x kg(-1) x min(-1) prostacyclin. In the absence of IV vasodilator therapy, inhaled NO decreased mean pulmonary artery pressure without decreasing mean systemic arterial pressure. In both acute and chronic pulmonary hypertension, the addition of inhaled NO to the largest dose of adenosine or prostacyclin, but not of SNP, decreased pulmonary artery pressure. Because inhaled NO and SNP activate guanylyl cyclase and adenosine and prostacyclin activate adenylyl cyclase, the results suggest that adding inhaled NO to a vasodilator not dependent on guanylyl cyclase may produce additional selective pulmonary vasodilation. IMPLICATIONS: In therapy of pulmonary hypertension, inhaled nitric oxide should produce additional selective pulmonary vasodilation when combined with a vasodilator whose mechanism of action is not dependent on cyclic guanosine 3',5'-monophosphate.     

Repair of ventricular septal defect in a child with severe pulmonary hypertension—response to inhaled nitric oxide

Nitric oxide (NO), was administered successfully, to a child with severe pulmonary hypertension, following surgical repair of a large ventricular septal defect. Inhalation of NO, 20–25 parts per million (ppm) was continued for 24 h, resulting in mean pulmonary artery pressure (PAP) of 25 mmHg and permitting a reduction in both ventilatory and inotropic support. Weaning of NO was commenced. At 5 ppm, administration was discontinued. An immediate and dramatic increase in PAP occurred. A similar pattern resulted on further attempts, demonstrating the extreme sensitivity of the pulmonary vasculature to the effects of inhaled low dose NO and the selectivity of the response.     

Treatment of pulmonary hypertension during surgery with nitric oxide and vasodilators

PURPOSE: To describe the effects of the combination of several therapies on the pulmonary circulation and cardiac function in a patient with severe pulmonary hypertension. CLINICAL FEATURES: We report the case of a female patient with chronic secondary pulmonary hypertension and cardiac failure who underwent right hemicolectomy under general anesthesia. Insertion of a pulmonary artery catheter before the operation revealed pulmonary artery pressure (PAP) of 55/24 mm Hg which was lowered moderately by 40 parts per million (ppm) inhNO. During surgery, the patient presented an episode of atrial fibrillation with a slow, irregular heart rate of 45-50 min(-1) and variable systemic pressure. A dipyridamole DPD (0.2 mg x kg(-1)) bolus stabilized systemic pressure and increased heart rate and cardiac output. However, PAP did not change. Nitroglycerine infusion was started at 10 mg x hr(-1) shortly after the initiation of DPD. The patient responded favourably to combined inhNO, intravenous DPD and NTG therapy with a marked and sustained reduction of PAP and a systemic hemodynamic stability. CONCLUSION: We conclude that: 1) in combination with inhNO, DPD does not augment the inhNO-induced decrease in PAP; 2) DPD improves the hemodynamic profile and elevates cardiac output; 3) therapeutic combination (inhaled NO, NTG, DPD) has a potent effect on pulmonary pressure in cardiac failure patients.     

Inhaled nitric oxide administration during one-lung ventilation in patients undergoing thoracic surgery

OBJECTIVE: To evaluate the effects of inhaled nitric oxide (iNO) on hemodynamics and oxygenation during one-lung ventilation (OLV) in the lateral decubitus position in patients undergoing elective thoracic surgery. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Thirty consecutive patients scheduled for thoracotomy. INTERVENTIONS: Anesthesia consisted of thoracic epidural analgesia combined with general anesthesia (isoflurane, fentanyl, and vecuronium bromide). Systemic and pulmonary circulations were monitored with a radial artery catheter and a pulmonary artery catheter. Inhaled NO, 40 ppm, was administered during OLV, and the inhaled gas mixture was monitored for NO and nitrogen dioxide (NO2). Hemodynamic and oxygenation data were collected before and during inhaled NO administration. MEASUREMENTS AND MAIN RESULTS: Inhaled NO caused a reduction of pulmonary vascular resistance index from 249 +/- 97.6 dyne. sec. cm(-5) to 199.3 +/- 68.9 dyne. sec. cm(-5) (p < 0.05), without effects on systemic hemodynamics or impairment of oxygenation. A stratification of the patients according to values of QS/QT (< 30%, 30% to 44%, > or = 45%), PaO(2)/fraction of inspired oxygen (> or = 200, 100 to 199, < 100), and pulmonary hypertension (mean pulmonary arterial pressure < 24 or > or = 24 mmHg) showed that inhaled NO causes a significant reduction of mean pulmonary artery pressure in patients with pulmonary hypertension, mainly as a result of a reduction of pulmonary vascular resistance index, and improves oxygenation by reducing intrapulmonary shunt in patients with severe hypoxemia during OLV. CONCLUSIONS: Inhaled NO administration neither significantly decreased mean pulmonary arterial pressure in patients with normal pulmonary artery pressure nor improved oxygenation in nonhypoxic patients. Nevertheless, inhaled NO is effective in patients with pulmonary hypertension and hypoxemia during OLV.