Inhaled nitric oxide and pulmonary edema formation.
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Animals↗
Biomedical subjects
F Hinder
Publications and source records attributed to F Hinder.
Inhalation injury increases the anastomotic bronchial blood flow in the pouch model of the left ovine lung.
Pulmonary parenchymal damage often occurs after airway injury. Bronchial venous drainage empties into the pulmonary microvasculature. We developed an in vivo model to study the bronchopulmonary portal system after smoke inhalation injury. Eight ewes were instrumented with hydraulic occluders on the left pulmonary artery (LPA), the left pulmonary vein, and the bronchoesophageal artery (BEA); a catheter in the LPA; and Swan-Ganz and femoral artery catheters. The vasculature between the occluders was defined as pouch. At stable mean arterial and right pulmonary arterial pressures, LPA occlusion reduced the left pulmonary artery pressure (LPAP) from 17 +/- 1 mmHg to 8 +/- 1 mmHg (p < .05). After left pulmonary vein occlusion, LPAP rose to 28 +/- 4 mmHg (p < .05 vs. baseline), indicating that systemic blood had entered the pouch. Opening the pouch to atmospheric pressure revealed an anastomotic bronchial blood flow (anastomotic Qbr) of .76 +/- .11% of cardiac output (CO). BEA occlusion reduced the anastomotic Qbr to .32 +/- .06% of CO (p < .05). Smoke inhalation injury resulted in a further increase in the maximal LPAP to 38 +/- 5 mmHg (p < .05 vs. right pulmonary artery pressure). The anastomotic Qbr rose to 1.29 +/- .13% of CO (p < .05) and was reduced to .40 +/- .09% of CO (p < .05) by BEA occlusion. Inhalation injury increased the anastomotic Qbr mainly due to BEA vasodilatation. Because the BEA supplies the injured airway, it may deliver deleterious material to the lung parenchyma.
Anastomosis, Surgical↗
Nitric oxide and endothelial permeability.
Nitric oxide synthase inhibition reverses systemic vasodilation during sepsis but may increase endothelial permeability. To assess adverse effects on the pulmonary vasculature, 12 sheep were chronically instrumented with lung lymph fistulas and hydraulic pulmonary venous occluders. Escherichia coli endotoxin (lipopolysaccharide; 10 ng . kg-1 . min-1) was continuously infused for 32 h. After 24 h, six animals received 25 mg/kg of Nomega-nitro-L-arginine methyl ester (L-NAME), and six received saline. All sheep developed a hyperdynamic circulatory response and elevated lymph flows by 24 h of lipopolysaccharide infusion. L-NAME reversed systemic vasodilation, increased pre- and postcapillary pulmonary vascular resistance index, pulmonary arterial pressure, and, transiently, effective pulmonary capillary pressure. Lung lymph flows were not different between groups at 24 h or thereafter. Calculated as changes from baseline, however, lung lymph flow was higher in the L-NAME group than in the control animals, with a trend toward lower lymph-to-plasma protein concentration ratio at 25 h. Permeability analysis at 32 h by the venous occlusion technique showed normal reflection coefficients and elevated filtration coefficients without differences between groups. Reversal by L-NAME of the systemic vasodilation during endotoxemia was associated with high pulmonary vascular resistance without evidence of impaired pulmonary endothelial barrier function.
Animals↗
[Limitations of inhaled vasodilators].
Treatment of pulmonary hypertension is an important issue in intensive care. One therapeutic regimen involves the intravenous administration of prostacyclin (PGI2). This, however, is accompanied by diminished hypoxic pulmonary vasoconstriction, reduced arterial oxygenation, and systemic vasodilation. Thus, its clinical usefulness is limited. However, the inhalation of vasodilators such as nitric oxide (NO) or nebulized PGI2 causes a selective pulmonary vasodilation in ventilated alveoli and improved gas exchange, without any systemic vasodilation. It has therefore gained importance for the treatment of pulmonary failure associated with high shunt fractions. However, the inhalation of vasodilators may have adverse effects: in the case of NO, toxic side effects are predominant (MetHb, NOx), whereas in the case of PGI2, technical problems in terms of dosing and administration safety are of major interest. Furthermore, some patients do not respond to the treatment. In some individuals a reduction in pulmonary hypertension can be seen, while others lack even pulmonary vasodilation. The exact pathophysiological mechanisms remain to be investigated.
Administration, Inhalation↗
The effects of propofol on hemodynamics and renal blood flow in healthy and in septic sheep, and combined with fentanyl in septic sheep.
Sepsis is characterized by myocardial depression and systemic vasodilation, both of which are most likely mediated by nitric oxide. Propofol inhibits nitric oxide synthase and may therefore be beneficial in sepsis. On the other hand, renal blood flow, known to be only minimally affected by propofol in healthy subjects, may be drastically reduced in septic individuals, because the renal microvasculature is known to be very sensitive to nitric oxide. In this study, the effects of propofol in healthy and in septic sheep, and in combination with fentanyl, were analyzed and compared with nonanesthetized septic sheep. In healthy sheep, propofol caused only minor hemodynamic changes. In septic sheep, however, hemodynamics deteriorated. Renal blood flow was reduced to 60% +/- 10% of the preseptic baseline and to 39% +/- 4% of the septic value. This reduction was selective, since the cardiac output decreased significantly less. These adverse effects of propofol on hemodynamics and renal blood flow were reduced when propofol was combined with fentanyl.
Adjuvants, Anesthesia↗
Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide.
OBJECTIVE: To test whether renal excretory function decreases after nitric oxide synthase inhibition during experimental hyperdynamic sepsis. DESIGN: Prospective, randomized, controlled animal trial. SETTING: Research laboratory at a large university medical center. SUBJECTS: Chronically instrumented Merino breed ewes (n = 18). INTERVENTIONS: Continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) for the experimental period of 32 hrs. One group received a bolus of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (25 mg/kg), after 24 hrs, and the remaining sheep were given the carrier, sodium chloride 0.9%. MEASUREMENTS AND MAIN RESULTS: The sheep developed a hyperdynamic cardiovascular response characterized by a decrease in systemic vascular resistance index (p < .05), and an increased cardiac index (p < .05) by 24 hrs. The sheep retained fluid, with creatinine clearance decreasing in the presence of chronically increased atrial natriuretic peptide. After the administration of N omega-nitro-L-arginine methyl ester, systemic vascular resistance index and cardiac index returned to baseline values, fluid balance normalized, and glomerular filtration rate increased (p < .05), while the control animals continued to retain fluid and their creatinine clearance continued to decrease. The concentrations of atrial natriuretic peptide did not differ significantly between groups after N omega-nitro-L-arginine methyl ester administration. CONCLUSIONS: In this ovine model of experimental hyperdynamic sepsis, renal excretory function decreases in the presence of chronically increased concentrations of atrial natriuretic peptide. Administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, reverses the vasodilatory state, thereby improving fluid balance and glomerular filtration.
Animals↗
Nitric oxide synthase inhibition versus norepinephrine for the treatment of hyperdynamic sepsis in sheep.
OBJECTIVES: To investigate the effects of Nomega-mono-methyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on hemodynamics, oxygen transport, and regional blood flow in an ovine model of hyperdynamic sepsis and to compare these effects with the responses to norepinephrine. DESIGN: Prospective, nonrandomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Twenty-five female, healthy, adult sheep of the Merino breed, divided into three groups: nine control sheep; eight sheep treated with L-NMMA; and eight sheep treated with norepinephrine. INTERVENTIONS: All sheep were chronically instrumented. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) was started and maintained for the remainder of the experiment. After 24 hrs of sepsis, eight sheep received L-NMMA (7 mg/kg/hr), eight sheep received norepinephrine, and nine sheep received the vehicle alone (0.9% saline). The norepinephrine dosage was continuously and individually adjusted to achieve the same increase in blood pressure as was observed in a matched sheep of the L-NMMA group. MEASUREMENTS AND MAIN RESULTS: After 24 hrs of sepsis, all sheep developed a hyperdynamic circulatory state with increased cardiac indices and reduced arterial pressures, and systemic vascular resistances. L-NMMA reversed the hyperdynamic circulation, causing an increase in arterial pressure by peripheral vasoconstriction. Norepinephrine led to an increase in blood pressure by augmenting cardiac indices, leaving the systemic vascular resistance unaffected. The norepinephrine dose needed to keep the blood pressure high had to be continuously increased, reflecting the reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unaffected by all treatment forms. Norepinephrine and L-NMMA led to a dramatic increase in urine production. Blocking the nitric oxide synthase with L-NMMA did not interfere with the host's pulmonary ability to clear bacteria, nor did treatment with norepinephrine. CONCLUSIONS: Blocking nitric oxide synthase had a marked vasoconstrictive effect. Both norepinephrine and L-NMMA increased arterial pressure without reducing renal blood flow, leading to an improved renal function.
Animals↗
Effects of inhaled nitric oxide and nebulized prostacyclin on hypoxic pulmonary vasoconstriction in anesthetized sheep.
OBJECTIVES: Inhaled nitric oxide has been shown to be a selective pulmonary vasodilator, leading to reduced pulmonary arterial pressure and improved ventilation/perfusion ratio in the acute respiratory distress syndrome. This local pulmonary vasodilation theoretically can be achieved by the airway application of a short-acting vasodilator, such as prostacyclin. We hypothesized that nebulized prostacyclin has the same properties for selective pulmonary vasodilation as inhaled nitric oxide. DESIGN: Prospective, experimental study in sheep. SETTING: Investigational intensive care unit in a university hospital. SUBJECTS: Six adult ewes of the Merino breed. INTERVENTIONS: Sheep (n = 6) were surgically prepared for chronic study. After 5 days of recovery, the sheep had tracheostomies performed under anesthesia. Intubation with a modified Robert-Shaw tube allowed side-separated ventilation. The entire left lung was ventilated with pure nitrogen, whereas the right lung was ventilated with pure oxygen. Nitric oxide and prostacyclin were added in different concentrations to the nitrogen, with which the left lung was ventilated. MEASUREMENTS AND MAIN RESULTS: The blood flows to the left and right lungs were measured with ultrasonic flow probes on the common and left pulmonary artery. Measurements were taken after each compound had been administered for 10 mins at a predefined dose. Both inhaled nitric oxide and nebulized prostacyclin caused effective, selective, dose-dependent pulmonary vasodilation. Inhaled nitric oxide was able to abolish hypoxic pulmonary vasoconstriction when insufflated into the animals at a concentration of 50 ppm of nitrogen, but 100 ppm of nitric oxide had no further effect. Prostacyclin, at a dosage of 10 micrograms/min, showed maximum pulmonary vasodilation, which could not be further increased by doubling the dosage. However, prostacyclin produced less dilation than high doses of nitric oxide, and its maximum pulmonary vasodilation was comparable with that effect obtained under ventilation with 20 ppm of nitric oxide. CONCLUSIONS: Both drugs selectively dilated the pulmonary vasculature in ventilated alveoli. Prostacyclin nebulization is an excellent tool to reduce pulmonary hypertension and to improve the ventilation/perfusion ratio. Prostacyclin nebulization can be used without the highly sophisticated technical equipment that is needed for controlled nitric oxide inhalation, and may therefore become a new, noninvasive therapeutic approach for treatment of adult respiratory distress syndrome in hospitals that cannot provide nitric oxide inhalation.
Administration, Inhalation↗
Nitric oxide synthase inhibition versus norepinephrine in ovine sepsis: effects on regional blood flow.
Hypotension is a serious problem in septic patients. We investigated regional perfusion in several organs during treatment of hyperdynamic sepsis in sheep. Sepsis was induced and maintained for the entire experiment with a continuous infusion of live Pseudomonas aeruginosa. Treatment with either norepinephrine or the nitric oxide synthase inhibitor L omega-mono-methyl-arginine (L-NMMA) was begun after 24 h of sepsis and continued for 24 h. The norepinephrine dosage was adjusted to achieve the same increase in mean arterial pressure as that obtained by a fixed dose of L-NMMA (7 mg/kg/h). Blood flows were analyzed by the microsphere technique. Both compounds restored blood pressure effectively, but only L-NMMA caused a significant increase in systemic vascular resistance, concomitant with a significant fall in cardiac output. Sepsis caused an increase in myocardial blood flow and a redistribution of blood flow away from the pancreas and the stomach. Renal blood flow was not significantly elevated. During treatment with either compound, renal blood flow remained unchanged, despite a fall in cardiac output in the L-NMMA group. Unchanged renal blood flow combined with the restoration of arterial blood pressure caused a significant increase in urine output. Both L-NMMA and norepinephrine caused a redistribution of blood flow to the colon. Pancreatic blood flow was further reduced by L-NMMA but the oxygen extraction improved simultaneously, so that oxygen availability in the pancreas might have been unchanged. Because ischemic pancreatitis in sepsis is likely to trigger multiorgan failure, further investigations in that area are desirable.
Animals↗
Effects of L-arginine and L-nitro-arginine treatment on blood pressure and cardiac output in a rabbit endotoxin shock model.
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Amino Acid Oxidoreductases↗
S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep.
S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.
Animals↗
Effects of bafilomycin A1 on cytosolic pH of sheep alveolar and peritoneal macrophages: evaluation of the pH-regulatory role of plasma membrane V-ATPases.
The role of plasma membrane V-ATPase activity in the regulation of cytosolic pH (pHi) was determined for resident alveolar and peritoneal macrophages (m theta) from sheep. Cytosolic pH was measured using 2',7'-biscarboxyethyl-5,6-carboxyfluorescein (BCECF). The baseline pHi of both cell types was sensitive to the specific V-ATPase inhibitor bafilomycin A1. Bafilomycin A1 caused a significant (approximately 0.2 pH units) and rapid (within seconds) decline in baseline pHi. Further, bafilomycin A1 slowed the initial rate of pHi recovery (dpHi/dt) from intracellular acid loads. Amiloride had no effects on baseline pHi, but reduced dpHi/dt (acid-loaded pHi nadir < 6.8) by approximately 35%. Recovery of pHi was abolished by co-treatment of m theta with bafilomycin A1 and amiloride. These data indicate that plasma membrane V-ATPase activity is a major determinant of pHi regulation in resident alveolar and peritoneal m theta from sheep. Sheep m theta also appear to possess a Na+/H+ exchanger. However, Na+/H+ exchange either is inactive or can be effectively masked by V-ATPase-mediated H+ extrusion at physiological pHi values.
Animals↗
Use of nitric oxide synthase inhibitors in animal models of sepsis.
Sepsis, as a general inflammatory process, affects the whole organism, mainly because of the intense vasodilation and reduced perfusion pressures associated with it. The high mortality rates seen with sepsis are correlated with a reduction in mean arterial pressure. Therefore, the restoration of adequate arterial pressures is imperative. Nitric oxide (NO.) is at least partly responsible for the vasodilation. Inhibition of nitric oxide synthase (NOS) is, therefore, a logical approach for the treatment of sepsis. As with any other vasoconstrictive drug, NOS inhibitors are clinically indicated only in hyperdynamic sepsis. In animal models, their administration leads to an immediate restoration of blood pressure, accompanied by improved myocardial, pulmonary, and renal function. An increase in oxygen extraction prevents oxygen consumption from decreasing, despite a marked reduction in cardiac output to normal concentrations. In sepsis, virtually all regional blood flows are increased. In our experiments, no organ systems showed a reduction below preseptic baseline values when NOS inhibitors were administered. Furthermore, NOS inhibition did not cause an increase in lactate concentrations, indicating adequate nutritive organ blood flow. Consequently, NOS inhibitors seem to be beneficial and safe when administered under the right circumstances and in a controlled fashion.
Amino Acid Oxidoreductases↗
Endotoxin versus bacteremia: a comparison focusing on clinical relevance.
All phenomena seen under ovine endotoxemia or bacteremia are typically observed in septic humans as well. The lethality (approximately 20%) in both sepsis models underlines the severity of the experimental sepsis in these models. As mentioned above, both models are ideal to objectify the effects of new therapeutic approaches for the treatment of sepsis, because they provide stable conditions. We tested the inhibition of nitric oxide synthase in both models: Nitric oxide is the main mediator of the vasodilation and the hyperdynamic circulation seen in sepsis. Since the restoration of the perfusion pressure is the major therapeutic goal to prevent further tissue damage (Chernow et al. 1990), the blockade of the nitric oxide synthase seems to be a logical approach for the treatment of hyperdynamic sepsis. Therefore, we tested the nitric oxide synthase inhibitor N(W)-nitro-L-arginine methyl ester (L-NAME) in the endotoxemic sheep model as well as in the bacteremic model. L-NAME reversed the hyperdynamic circulation of sepsis (Meyer et al.1992; Dehring et al.1993). The cardiac output was lowered back to baseline, and at the same time, the arterial pressure was elevated to baseline niveau, both resulting in a marked increase in systemic vascular resistance (figure 3). The pulmonary artery pressure showed only a slight increase, but due to the marked reduction in cardiac output the pulmonary vascular resistance increased significantly. The oxygen extraction was elevated to an extent, which prevented the oxygen consumption to fall, although the oxygen delivery dropped significantly because of the lowered cardiac output (figure 4). The intrapulmonary shunt was brought back to baseline (Meyer et al.1994a), allowing an improved pulmonary oxygen uptake. The renal function improved significantly after nitric oxide synthase inhibition in endotoxemia as well as in bacteremia (Hinder et al.1994; Lingnau et al.1994). Not only was the creatinine clearance elevated, but the urine output also increased, lowering the positive fluid balance. Another inhibitor of nitric oxide synthase N(W)-Mono-Methyl-L-Arginine (L-NMMA) was recently tested in these models as well. This drug is now already in clinical trials. The fact that the effects of these nitric oxide synthase inhibitors in septic humans are similar to the effects in the described experimental sepsis models proves the clinical relevance of the endotoxemic and the bacterimic sheep model.
Animals↗
Increased organ blood flow in chronic endotoxemia is reversed by nitric oxide synthase inhibition.
We evaluated regional blood flows in a hyperdynamic sepsis model and the reversal of increased flows by blockade of nitric oxide (NO) synthase. Seven awake sheep were continuously infused with Escherichia coli endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1] for 48 h. The NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg) was injected after 24 h. Blood flows to systemic organs were determined with the radioactive microsphere technique. LPS induced elevation of cardiac index by 36% (P < 0.05) and a fall in systemic vascular resistance index by 37% (P < 0.05) at 0 h [time of L-NAME administration, 24 h after infusion of LPS had begun] L-NAME administration normalized cardiac index [6.1 +/- 0.5 at 4 h posttreatment, 6.1 +/- 0.5 l.min-1.m-2 at -24 h (baseline)] and systemic vascular resistance index (1,333 +/- 105 at 4 h posttreatment, 1,280 +/- 163 dyn.s.cm-5.m2 at -24 h) and reduced all regional blood flows to near-baseline levels for the remainder of the study period (24 h). O2 consumption was unaffected by treatment.
Amino Acid Oxidoreductases↗
Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release.
We have previously shown that infection of macrophages by influenza A virus is capable of priming for a high TNF-alpha production in response to LPS. The present study was designed to examine in more detail TNF-alpha gene expression and TNF-alpha protein release of virus-infected, murine PU5-1.8 macrophages in the presence or absence of low and by itself rather inefficient concentrations of LPS (10 ng/ml). Although influenza A virus infection alone induced a massive TNF-alpha mRNA accumulation, translation into the bioactive TNF-alpha protein was low as intra- and extracellularly determined by bioassay, specific ELISA and Western blot. However, when LPS was added simultaneously or up to 4 h after infection, a high TNF-alpha production was initiated. The virus-induced TNF-alpha mRNA accumulation appeared to be due to both transcriptional and post-transcriptional changes: an enhanced TNF-alpha gene transcription as determined by nuclear run-on transcription assay and a markedly prolonged half-life of TNF-alpha mRNA as shown in actinomycin D-treated macrophages. These findings imply that influenza A virus may 1) either directly or indirectly stimulate TNF-alpha gene transcription activators or may interfere with labile transcription repressor proteins and 2) may stabilize TNF-alpha mRNA by delaying its degradation. Both mechanisms, taken together, prime influenza A virus-infected macrophages for a high TNF-alpha release in response to LPS which, as clinical cases show, may adversely affect patients with combined influenza A virus and bacterial infections.
Animals↗
Influenza A virus infects macrophages and stimulates release of tumor necrosis factor-alpha.
The clinical picture of influenza A virus infections indicates that release of tumor necrosis factor-alpha (TNF-alpha) may be involved. In the present study we exposed the murine macrophage line PU5-1.8 to influenza A virus and observed a productive infection which was followed by subsequent cell death. Infection of macrophages was accompanied by TNF-alpha mRNA accumulation and TNF-alpha release. TNF-alpha production could only be induced by live virus whereas interferon release was also stimulated by inactivated virus. When virus-infected macrophages were exposed to low amounts of lipopolysaccharide (LPS; 1-10 ng/ml) TNF-alpha production was strongly potentiated. These data show that low LPS concentrations could readily trigger a high TNF-alpha release from influenza-A-virus-infected macrophages which could, at least partially, explain the serious complications of combined influenza A virus and bacterial infections.
Animals↗
Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccharides.
Influenza A virus infections are commonly associated with symptoms that suggest involvement of TNF-alpha. In this study, we exposed human monocytes, rat alveolar macrophages, and murine PU5-1.8 macrophages to influenza A virus, strain Puerto Rico 8. We observed a productive infection that was accompanied by TNF-alpha mRNA accumulation, TNF-alpha release and subsequent cell death. TNF-alpha production was dependent on exposure to live virus, in contrast to IFN release that was also induced by UV-inactivated virus. Most strikingly, low amounts of LPS (1 to 10 ng/ml) from Escherichia coli or Haemophilus influenzae were capable of strongly potentiating TNF-alpha production from virus-infected macrophages. The potentiating effect of LPS was neither due to increased survival of macrophages nor to altered virus multiplication, enhanced TNF-alpha gene expression, discharge of intracellular TNF-alpha stores, or shifts in the kinetics of TNF-alpha release. Thus, low amounts of LPS, which could easily be present in vivo, may serve as a potent trigger signal for TNF-alpha production from macrophages that have been primed by influenza A virus infection. These data suggest that the frequently observed serious complications of combined influenza A virus and bacterial infections may be partially due to a high TNF-alpha production.
Blotting, Northern↗