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Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO-deficient mice (96+/-20% and 94+/-19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27+/-7%; P<0.05) but not in 5-LO-deficient mice (72+/-9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76+/-10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO-deficient mice. Administration of MK571, a selective cysteinyl LT(1) receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.

Background: Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction., Methods: In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6)., Results: Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation., Conclusions: Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO.

Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing arterial oxygenation and enhancing hypoxemia. Endotoxin induces nitric oxide (NO) production by NO synthase 2 (NOS2). To assess the role of NO and NOS2 in the impairment of HPV during endotoxemia, we measured in vivo the distribution of total pulmonary blood flow (QPA) between the right (QRPA) and left (QLPA) pulmonary arteries before and after left mainstem bronchus occlusion (LMBO) in mice with and without a congenital deficiency of NOS2. LMBO reduced QLPA/QPA equally in saline-treated wild-type and NOS2-deficient mice. However, prior challenge with Escherichia coli endotoxin markedly impaired the ability of LMBO to reduce QLPA/QPA in wild-type, but not in NOS2-deficient, mice. After endotoxin challenge and LMBO, systemic oxygenation was impaired to a greater extent in wild-type than in NOS2-deficient mice. When administered shortly after endotoxin treatment, the selective NOS2 inhibitor L-NIL preserved HPV in wild-type mice. High concentrations of inhaled NO attenuated HPV in NOS2-deficient mice challenged with endotoxin. These findings demonstrate that increased pulmonary NO levels (produced by NOS2 or inhaled at high levels from exogenous sources) are necessary during the septic process to impair HPV, ventilation/perfusion matching and arterial oxygenation in a murine sepsis model.

Sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NO; Et2N-[N(O)NO]Na) is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (< or = 10(-2)M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR(-5%), but nonselectively dilated the systemic circulation at larger doses (> 10(-2)M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

Objectives: Inhalation of nitric oxide (NO) selectively dilates pulmonary vessels in well-ventilated regions. Prostaglandin F2 alpha (PGF2 alpha) is a vasoconstrictor and is reported to enhance hypoxic pulmonary vasoconstriction. The objective of this study was to examine whether the combination of intravenous PGF2 alpha and inhaled NO in ARDS lungs has a beneficial effect on oxygenation., Design: We investigated the effect of intravenous PGF2 alpha infusion (0.05-10.0 micrograms/kg per min) with and without NO inhalation (60 ppm) on the hemodynamics and gas exchange in an ovine ARDS model, examining the pulmonary artery pressure versus the flow plot by varying cardiac output., Measurements and Results: After lung lavage, NO inhalation reduced the mean pulmonary arterial pressure (MPAP) by decreasing the zero-flow pressure intercept from 10.6 +/- 3.8 (mean +/- SD) to 8.5 +/- 3.8 mmHg (p < 0.05) with no significant change in slope. NO inhalation improved PaO2 from 56 +/- 12 to 84 +/- 38 mmHg (p < 0.005) and reduced pulmonary shunt from 65 +/- 5 to 53 +/- 8% (Qs/Qt) (p < 0.001). The dose-dependent effects of PGF2 alpha infusion were: (1) increased MPAP attributed to an increased slope in pulmonary artery pressure-flow plot; (2) decreased cardiac index; (3) decreased Qs/Qt with unchanged PaO2. The dose-dependent decrease in Qs/Qt after PGF2 alpha infusion was attributed to the decreased cardiac output., Conclusions: It is suggested that inhalation of NO reduced the critical vascular pressure near alveoli without affecting upstream vessels, while infused PGF2 alpha constricted the larger upstream pulmonary artery vessels without appreciably affecting the critical pressure. Inhalation of NO into well-ventilated lung areas shifted perfusion to well-oxygenated areas, and there was no supplemental shift in blood flow by adding an infusion of PGF2 alpha.

Background: Nitric oxide (NO) inhalation selectively decreases pulmonary artery hypertension and improves arterial oxygenation in patients with the adult respiratory distress syndrome (ARDS). In this study of patients with severe ARDS, we sought to determine the effect of inhaled NO dose and time on pulmonary artery pressure and oxygen exchange and to determine which patients with ARDS are most likely to show this response., Methods: Thirteen patients with severe ARDS (hospital mortality 67%) inhaled 0-40 parts per million (ppm) NO. Seven of these patients continued to breathe 2-20 ppm NO for 2-27 days., Results: Inhaling 5-40 ppm NO decreased mean pulmonary artery pressure in a dose-related fashion (from 34 +/- 7 to 30 +/- 7 mmHg at 20 ppm NO). Systemic arterial pressure did not change. The ratio of arterial oxygen tension to inspired oxygen fraction increased (from 126 +/- 36 to 149 +/- 38 mmHg) and the venous admixture decreased (from 31.2 +/- 5.5 to 28.2 +/- 5.2%) without a clear dose-response effect. During prolonged NO inhalation, 2-20 ppm NO effectively reduced mean pulmonary artery pressure (38 +/- 7 vs. 31 +/- 6 mmHg) and increased arterial oxygen tension (79 +/- 10 vs. 114 +/- 27 mmHg) without evidence of tachyphylaxis. The decrease of pulmonary vascular resistance during NO inhalation correlated with the level of pulmonary vascular resistance without NO (r = -0.72). The reduction of venous admixture correlated with the level of venous admixture without NO (r = -0.78)., Conclusions: Long-term NO inhalation at low concentrations selectively decreases mean pulmonary artery pressure and improves arterial oxygen tension in patients with ARDS. The selective pulmonary vasodilation effect is most pronounced in ARDS patients with the greatest degree of pulmonary vasoconstriction.

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.

The cross-protective effects of a murine immunoglobulin M monoclonal antilipid A antibody (E5 MAb) were tested by challenging awake sheep with mixtures of in vitro incubated E5 MAb (0.02 mg/kg) with lipopolysaccharide (LPS, 0.02 micrograms/kg) derived from Escherichia coli O111:B4, E. coli O55:B5, or Serratia marcescens. Intravenous infusion of these LPS preparations without antibody into awake sheep produced a similar pattern of fever, leukopenia, plasma thromboxane B2 (TxB2) release, and acute pulmonary vasoconstriction with pulmonary hypertension. The addition of MAb E5 to LPS from E. coli O111:B4 reduced these responses to the LPS in a fashion comparable to that achieved with an MAb specific to the E. coli O111:B4 O-side chain. Incubation of LPS derived from E. coli O55:B5 with the E5 MAb only slightly diminished acute pulmonary hypertension, the delayed temperature increase, and the degree of leukopenia (all P = NS) but reduced the mean peak TxB2 at 60 min (P < 0.05) compared with a control infusion of E. coli O55:B5 LPS. We were unable to demonstrate any protective effects on the pulmonary circulation from incubating E5 with LPS derived from S. marcescens. Preincubation of B55 MAb (a murine immunoglobulin M MAb directed against a human milk fat globulin), the control antibody, with LPS from E. coli 0111:B4 decreased the mean peak TxB2 but had no effect on the other parameters. We conclude that incubating E5 with LPS protects the pulmonary circulation of sheep from challenge with LPS derived from the parent E. coli strain. There were trends toward protection by E5 against LPS from 055:B5 E. coli, but these did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal antibodies (MAbs) directed to endotoxin can protect in some animal models against the pathophysiological effects of endotoxin infusion. When 0.02 microgram/kg of lipopolysaccharide (LPS) derived from Escherichia coli O111:B4 was incubated in vitro for 2 h with the murine immunoglobulin G MAb, 5B10, directed against the O-polysaccharide antigenic domain of E. coli O111:B4 and then the mixture was infused into sheep, we noted significant protection. The second temperature peak was decreased (P < 0.05 vs. LPS control). The acute pulmonary arterial pressure elevation was diminished (mean peak pulmonary arterial pressure 23.2 +/- 2.5 mmHg, P < 0.05 vs. LPS control), and the peak plasma thromboxane B2 level was reduced (mean peak thromboxane B2 level 0.50 +/- 0.15 ng/ml, P < 0.05 vs. LPS control). In contrast, preincubation of the LPS with a human immunoglobulin M MAb, HA-1A, directed against the core glycolipid of the LPS molecule provided no protective effects in this sheep model. This finding is in agreement with recent studies reporting HA-1A may bind to antibiotic-treated bacteria but not to purified smooth LPS.

Background. The gas nitric oxide (NO) is an important endothelium-derived relaxing factor, inactivated by rapid combination with heme in hemoglobin. Methods and Results. Awake spontaneously breathing lambs inhaled 5-80 ppm NO with an acutely constricted pulmonary circulation due to either infusion of the stable thromboxane endoperoxide analogue U46619 or breathing a hypoxic gas mixture. Within 3 minutes after adding 40 ppm NO or more to inspired gas, pulmonary hypertension was reversed. Systemic vasodilation did not occur. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. During U46619 infusion pulmonary vasodilation was maintained up to 1 hour without tolerance. In the normal lamb, NO inhalation produced no hemodynamic changes. Breathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels nor modify lung histology compared with control lambs. Conclusions. Low dose inhaled NO (5-80 ppm) is a selective pulmonary vasodilator reversing both hypoxia- and thromboxane-induced pulmonary hypertension in the awake lamb [corrected].

We infused recombinant human tumor necrosis factor alpha (rhTNF alpha), lymphotoxin (rhLT), and Escherichia coli 0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF alpha (25-150 micrograms/kg, n = 6 sheep), but not rhLT (25 micrograms/kg, n = 3), rapidly increased lung lymph and plasma levels of 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 micrograms/kg rhTNF alpha prevented the increase of lymph and plasma 6-k-PGF1 alpha levels, systemic vasodilation, and the early (less than 2 hrs) but not the late (4-6 hours) hypotension caused by rhTNF alpha. LPS (1 micrograms/kg, n = 11) induced a briefer increase of lymph 6-k-PGF1 alpha levels than did rhTNF alpha while plasma 6-k-PGF1 alpha levels did not increase. LPS induced more gradual hypotension than did rhTNF alpha but did not cause systemic vasodilation. LPS and rhTNF alpha, but not rhLT, increased lymph thromboxane B2 (TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2 levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF alpha or rhLT. Whereas LPS-treated sheep required less fluid transfusion than rhTNF alpha-treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF alpha caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF alpha cannot account for all of the LPS-induced hemodynamic, lung lymph, and eicosanoid responses in sheep.

In this report, the authors present the results of 34 estimates of pulmonary capillary pressure (Pcap) in 15 adult patients receiving intensive care for acute respiratory failure (ARF). Within the pulmonary artery pressure profile during transient balloon occlusion, the authors identified two exponential pressure decay components-the slower one representing the discharge of the pulmonary capillary pressure through the pulmonary venous resistance. By extrapolating this exponential to its origin at the moment of pulmonary artery occlusion, a pressure within the pulmonary vascular bed which approximates pulmonary capillary pressure (Pcap) was identified. Pcap, and not the pulmonary artery occlusion pressure (PAOP), is the major driving pressure forcing fluid from the pulmonary microvasculature. The results indicate that a discrete value for pulmonary capillary pressure can be reproducibly measured in paralyzed ventilated patients. The data report that mean pulmonary artery pressure, pulmonary capillary pressure, and total pulmonary vascular resistance (PVR) are increased in acute respiratory failure, but there is considerable variation in the distribution of pulmonary vascular resistance between the arterial and venous beds. The data suggest that there is unequal and variable partitioning of the increased PVR during acute respiratory failure. Bedside pressure profile Pcap measurements will allow optimum reduction of Pcap during ARF by infusing vasoactive agents to modify the distribution of PVR or reducing the PAOP.

The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.

To investigate the quantity and pathophysiological relationship of pulmonary and bronchial artery supply to the tracheobronchial tree in dogs in absence and in presence of increased tissue metabolic requirements, pulmonary and bronchial blood flow to the trachea and bronchi was determined by the radioactive microsphere method in nine adult mongrel dogs. Microspheres were injected into the right atrium of three dogs (pulmonary injection group) and into the left ventricle of four dogs (systemic injection group) just before and three, eight and fourteen days after resection and anastomosis of the right main bronchus. The remaining two dogs served as controls without surgery. After the fourth injection, the tracheobronchial tree was harvested, divided into segments, and the radioactivity counted in each segment. At baseline the systemic flow to the tracheobronchial tree expressed as percentage of cardiac output was 0.188% +/- 0.121 and the pulmonary blood flow was 0.007% +/- 0.004 (mean +/- S.D.). Three, eight and fourteen days after transection and anastomosis of the right main stem bronchus, the systemic blood flow to the bronchial segments proximal and distal to the anastomosis increased significantly whereas pulmonary blood flow did not change. Depending on the anatomical segment considered the systemic contribution was between 5 and 100 times larger than the pulmonary one, both at baseline and after transection and anastomosis of the right main stem bronchus, but the ratio diminished in more distal segments where pulmonary blood flow was larger. It is concluded that the systemic blood contribution to the canine tracheobronchial tree is larger than the pulmonary one and that, in the presence of increased metabolic needs, it responds more promptly with increased blood flow.

Mild pulmonary artery hypertension (PAP, 29.6 +/- 10.6 mm Hg, mean +/- SD) due to a 3-fold elevation of pulmonary vascular resistance (PVR, 2.2 +/- 1.1 mm Hg X L/min) is a common finding in severe ARDS. A vasodilator such as nitroprusside (151 micrograms/kg X min) can be administered in early ARDS and will lower PAP and PAOP (capillary wedge pressure) while increasing cardiac output (CO) from 6.9 to 8.75 L/min X M2 and venous admixture from 23% to 31.6%. This suggests diffuse vasoconstriction is present in early ARDS. In 19 patients with severe ARDS, 13 had vascular occlusions on balloon occlusion angiography, and these occlusions correlated with increased post mortem counts of PA thrombi. At autopsy, there was a considerable increase of PA medial thickness and a reduction of lumen diameter. This hemodynamic and morphologic evidence suggests both vasoconstrictor and anatomic changes play major roles elevating the PVR in ARDS.

Dose response and tolerance to a small intravenous dose of Serratia marcescens lipopolysaccharide (LPS) were studied in awake sheep. Core temperature significantly increased after a dose of 0.002 micrograms/kg; changes in pulmonary arterial pressure, pulmonary vascular resistance, plasma thromboxane B2, and circulating leukocyte concentration occurred after 0.02 micrograms/kg; plasma 6-keto-prostaglandin F1 alpha increased after 0.2 micrograms/kg. Development of acute tolerance was studied by injection of S. marcescens LPS (0.02 micrograms/kg iv) on 3 consecutive days: pulmonary arterial pressure and thromboxane B2 levels were significantly lower than controls after the second dose, whereas fever and the degree of leukopenia were not diminished until the third dose. After intravenous administration of LPS given in increasing doses from 0.1 to 3.2 micrograms/kg three times weekly over 7 wk, there were no measurable changes in any of the above parameters after challenge with S. marcescens LPS (0.02 micrograms/kg) after a 1-wk rest period. In awake sheep, small intravenous doses of LPS can cause physiologically important changes of the pulmonary circulation and can alter the hemodynamic and eicosanoid mediator responses to subsequent challenges with LPS. Large intravenous doses of LPS can ablate the physiological responses to subsequent small doses of LPS.

In six awake sheep the control heparin-protamine reaction was associated with a 150-fold rise in arterial plasma thromboxane B2 (TxB2) levels, a 4.5-fold increase in pulmonary vascular resistance, a 20% decrease in cardiac output, a 30% decrease in arterial PO2, and a 30% reduction in arterial white blood cell concentrations. Depletion of 99% of circulating platelets by antibodies did not prevent either acute and severe pulmonary hypertension or increased plasma TxB2 levels induced by heparin-protamine administration. We produced sheep platelet aggregation in vitro with bovine thrombin and measured marked TxB2 release (36.3 +/- 16.3 ng/10(9) platelets). In contrast, neither heparin, protamine, nor heparin-protamine complexes over a 10,000-fold range of concentrations induced platelet aggregation and release of thromboxane in vitro. Therefore sheep platelets are not the source of thromboxane production associated with acute pulmonary hypertension during the heparin-protamine reaction, and other cells must produce the thromboxane.

Objectives: Inhalation of nitric oxide (NO) selectively dilates pulmonary vessels in well-ventilated regions. Prostaglandin F (PGF) is a vasoconstrictor and is reported to enhance hypoxic pulmonary vasoconstriction. The objective of this study was to examine whether the combination of intravenous PGF and inhaled NO in ARDS lungs has a beneficial effect on oxygenation. Design: We investigated the effect of intravenous PGF infusion (0.05-10.0 μg/kg per min) with and without NO inhalation (60 ppm) on the hemodynamics and gas exchange in an ovine ARDS model, examining the pulmonary artery pressure versure the flow plot by varying cardiac output. Measurements and results: After lung lavage, NO inhalation reduced the mean pulmonary arterial pressure (MPAP) by decreasing the zero-flow pressure intercept from 10.6±3.8 (mean±SD) to 8.5±3.8 mmHg ( p<0.05) with no significant change in slope. NO inhalation improved PaO from 56±12 to 84±38 mmHg ( p<0.005) and reduced pulmonary shunt from 65±5 to 53±8% ( $$\dot Qs/\dot Qt$$ ) ( p<0.001). The dose-dependent effects of PGF infusion were: (1) increased MPAP attributed to an increased slope in pulmonary artery pressure-flow plot; (2) decreased cardiac index; (3) decreased $$\dot Qs/\dot Qt$$ with unchanged PaO. The dose-dependent decrease in $$\dot Qs/\dot Qt$$ after PGF infusion was attributed to the decreased cardiac output. Conclusions: It is suggested that inhalation of NO reduced the critical vascular pressure near alveoli without affecting upstream vessels, while infused PGF constricted the larger upstream pulmonary artery vessels without appreciably affecting the critical pressure. Inhalation of NO into well-ventilated lung areas shifted perfusion to well-oxygenated areas, and there was no supplemental shift in blood flow by adding an infusion of PGF. [ABSTRACT FROM AUTHOR]