thromboxane-b2 and Hypoxia

Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arterioles; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Diethylcarbamazine; Dinoprost; Dinoprostone; Humans; Hypertension, Pulmonary; Hypoxia; Inflammation; Leukotriene D4; Lipoxygenase Inhibitors; Lung; Male; Prostaglandins F; Pulmonary Artery; Pyrazoles; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ventricular Function, Right

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

Topics: Adult; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Mass Index; Body Weight; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Gene Expression Regulation, Enzymologic; Hematocrit; Humans; Hypoxia; Male; Mice; Mice, Transgenic; Middle Aged; Pyrazoles; Risk Factors; Sleep Apnea, Obstructive; Thromboxane B2

Hypoxic pulmonary vasoconstriction (HPV) is a well known phenomenon to temporarily offset a ventilation-perfusion mismatch. Sustained HPV may lead to pulmonary hypertension. In this protocol, we studied the relationships between the HPV response and inducible cyclooxygenase II (COX II) activation after hypoxia-reoxygenation (H-R) challenge in an isolated perfused lung model.. An in situ isolated perfused rat lung model underwent inaction of hypoxia by ventilation with 5% CO(2)-95% N(2) for 10 minutes instead of 5% CO(2)-95% air; they were then reoxygenated with 5% CO(2)-95% air. We measured pulmonary arterial pressure (PAP) changes before, during, and after H-R challenge. We also estimated changes in blood concentrations of hydroxyl radicals, nitric oxide (NO) and thromboxane B(2) (TxB(2)) before and after H-R as well as mRNA expressions of COX II in lung tissue thereafter. A COX II inhibitor, celecoxib (10 mg/kg), was administered between 2 consecutive challenges.. Hypoxia induced pulmonary vasoconstriction by increasing PAP (4.1 ± 0.8 mm Hg). Consecutive hypoxic challenges did not show tachyphylaxis (P > .05). H-R of lung tissues induced significant increases in blood concentrations of hydroxyl radicals (48.5 ± 7.6 vs 75.8 ± 11.5 mmol/L; P < .01), NO (54.3 ± 12.3 vs 77.7 ± 15.7 pmol; P < .05), and TxB(2) (42.3 ± 6.9 vs 58.7 ± 8.6 pg/mL; P < .05). Lung tissue H-R also significantly increased COX II mRNA expression compared with sham tissues (1 ± 0 vs 4.0 ± 2.8; P < .001). The COX II inhibitor celecoxib significantly attenuated HPV responses (P < .05) and attenuated the elevated blood concentrations of TxB(2) (P < .05), hydroxyl radicals (P < .01), nitric oxide (P < .05), and COX II mRNA expression (P < .05) after H-R challenge.. Lung tissue H-R induced significant increases blood concentrations of inflammatory mediators and tissue mRNA expression of COX related to elevation of HPV responses. COX II inhibitor celecoxib attenuated the HPV responses by reducing TxB(2) release.

Topics: Animals; Biomarkers; Blood Pressure; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Hydroxyl Radical; Hypoxia; Inflammation Mediators; Nitric Oxide; Oxidative Stress; Perfusion; Pulmonary Artery; Pyrazoles; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Thromboxane B2; Time Factors; Vasoconstriction

Few studies have assessed the effects of stress on in vivo platelet activation. In the present study, hypobaric hypoxia induced by rapid decompression during high-altitude simulated flight in a hypobaric chamber was used to evaluate the effects of environmental stress on salivary cortisol and urinary thromboxane metabolite (TXM) excretion, a noninvasive marker of in vivo platelet function. Twenty-one male aviators (mean ± SD age = 36 ± 7 years) experiencing hypoxia by removing their oxygen mask for 4-5 min during a simulated flight to 25,000 ft (7,620 m; pO(2) = 59.17 mmHg) and a matched control group of thirteen flying instructors wearing oxygen masks during the challenge, were studied. Hypobaric hypoxia induced a transient significant increase (P < 0.001) in the aviators' salivary cortisol concentration; the overall pattern of diurnal cortisol fluctuation was maintained in both groups. Urinary TXM showed a significant ∼30% reduction (P < 0.01) after the chamber session in aviators exposed to hypobaric hypoxia, but not in controls. A significant inverse correlation was found between salivary cortisol and urinary TXM in aviators (r = - 0.64, P = 0.0015). Salivary cortisol was a significant predictor (P < 0.001) for urinary TXM concentrations in aviators. In conclusion, here we observed that an acute stress-induced salivary cortisol increase was associated with reduced urinary thromboxane biosynthesis, providing the first indirect evidence for an inhibitory effect of acute stress on in vivo platelet function.

Topics: Adult; Altitude Sickness; Dinoprost; Humans; Hydrocortisone; Hypoxia; Male; Saliva; Stress, Physiological; Thromboxane B2

Low-grade inflammation may potentially explain the relationship between obstructive sleep apnea syndrome (OSA) and cardiovascular events. However, the respective contribution of intermittent hypoxia and confounders, such as obesity, is still debated.. To monitor urinary leukotriene E(4) (U-LTE(4)), a validated marker of proinflammatory cysteinyl leukotriene production, in OSA; to determine the influence of obesity and other confounders on U-LTE(4) concentrations; to examine the mechanisms involved through transcriptional profiling of the leukotriene pathway in peripheral blood mononuclear cells (PBMCs); and to investigate the effect of continuous positive air pressure (CPAP) on U-LTE(4) concentrations.. We measured U-LTE(4) by liquid chromatography-tandem mass spectrometry.. The U-LTE(4) concentrations were increased (P = .019) in 40 nonobese patients with OSA carefully matched for age, sex, and body mass index (BMI) to 25 control subjects, and correlated (r = 0.0312; P = .017) to the percentage of time spent with mean oxygen saturation (SaO(2)) less than 90%. In a larger cohort of patients with OSA (n = 72), U-LTE(4) increased as a function of BMI (r = 0.445; P = .0002). In those patients, the expression levels of 5-lipoxygenase activating protein mRNA in mononuclear cells exhibited a similar pattern. A stepwise multiple linear regression analysis performed in this cohort identified BMI (P = .001; regression coefficient, 3.33) and percentage of time spent with SaO(2) <90% (P = .001; regression coefficient, 1.01) as independent predictors of U-LTE(4) concentrations. Compared with baseline, CPAP reduced by 22% (P = .006) U-LTE(4) concentrations only in patients with OSA with normal BMI.. Obesity, and to a lesser extent hypoxia severity, are determinant of U-LTE(4) production in patients with OSA.

Topics: 5-Lipoxygenase-Activating Proteins; Adult; Carrier Proteins; Chromatography, Liquid; Female; Humans; Hypoxia; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Obesity; Polysomnography; Prospective Studies; RNA, Messenger; Sleep Apnea, Obstructive; Tandem Mass Spectrometry; Thromboxane B2

To study the effect of Safflower injection (a compound of Chinese Traditional medicine) on pulmonary hypertension in rat during chronic hypoxia and hypercapnia.. Sprague-Dawley rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + Safflower injection group (C). The concentration of TXB2 and 6-keto-PGF18 in plasma and in lung homogenate were detected by the radioimmunoassay.. (1) mPAP, weight ratio of right ventricle (RV) to left ventricle plus septum (LV + S) were much higher in rats of hypoxic hypercapnic group than those of control group. Differences of mCAP among the three groups were not significant. (2) The concentration of TXB2 and the ratio of TXB2/6-keto-PGF1a were significantly higher in rats of B group than those of A and C group. (3) The results examined by light microscopy showed that WA/TA (vessel wall area/total area), SMC (the density of medial smooth muscle cell) and PAMT (the thickness of medial smooth cell layer) were significantly higher in rats of B group than those of A and C group. (4) The results examined by electron microscopy showed proliferation of medial smooth muscle cells and collagen fibers of pulmonary arterioles in rats of B group, and Safflower injection could reverse the changes mentioned above.. Safflower injection may inhibit hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling by decreasing the ratio of TXB2/6-keto-PGF1a.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carthamus tinctorius; Drugs, Chinese Herbal; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

Dobutamine, a beta-adrenoceptor agonist that is often used to treat myocardial dysfunction in asphyxiated neonates, may act on the adrenoceptors of platelets resulting in activation. Little information is available on the effect and mechanistic pathway of dobutamine on the platelet aggregatory function in neonatal asphyxia. Newborn piglets were acutely instrumented and exposed to hypoxia for 2 h and reoxygenation for 4 h. Piglets were randomized to receive dobutamine infusion (5, 10, or 20 microg/kg per min) or saline (hypoxic-control) at 2 to 4 h of reoxygenation (n = 8 each), and sham-operated animals were not exposed to hypoxia and reoxygenation (n = 6). Platelet number, collagen-stimulated whole blood aggregation, and plasma concentrations of thromboxane B2 were studied. The effects of alpha- and beta-adrenoceptor antagonists (phentolamine and propranolol, respectively) on platelet aggregation to in vitro administration of dobutamine (3 microM) were also examined. Shock and metabolic acidosis developed similarly in all hypoxia-reoxygenated groups. At 4 h of reoxygenation, platelet numbers in all groups decreased, with no differences among groups. Platelet aggregation deteriorated significantly with a rightward shift of concentration-response curve in piglets receiving 10 and 20 microg/kg per min of dobutamine. The group that received 20 microg/kg per min of dobutamine had increased plasma thromboxane B2 concentrations from baseline (P < 0.05). The platelet aggregatory response induced by 3 microM of dobutamine was improved by the coadministration of the beta-but not the alpha-adrenoceptor antagonist. We observed platelet aggregatory dysfunction in hypoxic-reoxygenated newborn piglets treated with high-dose dobutamine. Further investigation is needed to examine the differential effects of dobutamine and hypoxia-reoxygenation in platelet aggregation in newborns.

Topics: Adrenergic beta-Agonists; Animals; Animals, Newborn; Blood Platelets; Collagen; Dobutamine; Heart Rate; Hydrogen-Ion Concentration; Hypoxia; Models, Biological; Oxygen; Platelet Aggregation; Respiration Disorders; Swine; Thromboxane B2

An imbalance of vaso-constrictor and -dilator mediators has been implicated in the pathogenesis of the pulmonary hypertension accompanying neonatal hypoxemic respiratory failure (NHRF).. To characterize plasma PGE2, TXB2 and their ratio in normal newborns and in those with NHRF.. Twenty newborns with NHRF received inhaled PGE1 (IPGE1) by jet nebulizer in doses of 25, 50, 150 and 300 ng/kg/min followed by weaning. Blood for PGE2 and TXB2 assay using EIA was available in 8 neonates with NHRF prior to IPGE1. Umbilical cord arterial samples were also obtained at delivery from 10 normal newborns to serve as controls.. Compared to normal newborns, those with NHRF had significantly lower PGE2/TXB2 ratios after controlling for preterm gestation (< 37 weeks) and postnatal age (p < 0.05). Notably, all subjects except one in the NHRF group had a value of < 1.0 (range 0.1-1.2) compared to a value of > 1.0 in all subjects in the Control group (range 1.1-5.2).. Lower PGE2/TXB2 ratio in subjects with NHRF compared with controls reflects a predominance of vaso-constrictor activity in these patients as the basis of pulmonary hypertension. Plasma PGE2/TXB2 ratio may have important implications for the diagnosis and treatment of NHRF.

Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dinoprostone; Female; Humans; Hypoxia; Infant, Newborn; Male; Pilot Projects; Respiratory Insufficiency; Thromboxane B2

Our purpose was to determine whether production of arachidonic acid metabolites, particularly cyclooxygenase (COX) metabolites, is altered in 100-400-microm-diameter pulmonary arteries of piglets at an early stage of pulmonary hypertension. Piglets were raised in either room air (control) or hypoxia for 3 days. A cannulated artery technique was used to measure responses of 100-400-microm-diameter pulmonary arteries to arachidonic acid, a prostacyclin analog, or the thromboxane mimetic. Radioimmunoassay was used to determine pulmonary artery production of thromboxane B(2) (TxB(2)) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), the stable metabolites of thromboxane and prostacyclin, respectively. Assessment of abundances of COX pathway enzymes in pulmonary arteries was determined by immunoblot technique. Arachidonic acid induced less dilation in pulmonary arteries from hypoxic than in pulmonary arteries from control piglets. Pulmonary artery responses to prostacyclin and were similar for both groups. 6-Keto-PGF(1alpha) production was reduced, whereas TxB(2) production was increased in pulmonary arteries from hypoxic piglets. Abundances of both COX-1 and prostacyclin synthase were reduced, whereas abundances of both COX-2 and thromboxane synthase were unaltered in pulmonary arteries from hypoxic piglets. At least partly due to altered abundances of COX pathway enzymes, a shift in production of arachidonic acid metabolites, away from dilators toward constrictors, may contribute to the early phase of chronic hypoxia-induced pulmonary hypertension in newborn piglets.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Arachidonic Acid; Chronic Disease; Cyclooxygenase 1; Cyclooxygenase 2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Hypertension, Pulmonary; Hypoxia; Intramolecular Oxidoreductases; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Reference Values; Swine; Thromboxane B2; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

This study explored the effect of chronic hypoxia on the elevation of pulmonary vascular resistance caused by ischemia-reperfusion (IR) in anesthetized rats. Experiments were separated into five parts. In Part 1, we examined the increase in left pulmonary vascular resistance (Rpl) after ischemia of the left lung and localized the major site for the increased resistance of the left pulmonary vasculature in both the normoxic and chronic hypoxia groups. Here, IR induced a significant increase in Rpl in the normoxic but not the chronic hypoxia group. This increased Rpl in the normoxic group was attributed to contraction of pulmonary arterial segments. Part 2 and Part 3 were focused on the changes in plasma nitrate/nitrite (NOx) and thromboxane B(2) (TxB(2)) levels. TxB(2) increased significantly in the normoxic group, whereas NOx increased significantly in the chronic hypoxia group, following ischemia. Indomethacin (Part 4) prevented IR-induced increase in Rpl in the normoxic group, whereas the IR-induced increase in Rpl appeared in the chronic hypoxia group after N(G)-nitro-L-arginine methyl ester treatment (Part 5). We conclude that IR elicited increases in the cyclooxygenase products such as TxB(2), which in turn caused an increase in Rpl. However, this increased Rpl was attenuated by elevated NOx in the chronic hypoxia group.

Topics: Animals; Hypoxia; Intubation, Intratracheal; Lung; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Size; Pulmonary Circulation; Rats; Rats, Wistar; Reperfusion Injury; Thromboxane B2; Vascular Resistance

To investigate the effects of prostaglandins (PGs) and leukotrienes (LTs) on hypoxic pulmonary vasoconstriction (HPV), in vivo rats experiment and in vitro perfused lung experiment were conducted. The effect of hypoxia on hemodynamics, concentrations of TXB2 and 6-keto-PGF1 alpha in serum and lung tissue during hypoxia and effects of PGs and LTs on HPV were observed. The results showed that pulmonary arterial pressure (Ppa) and pulmonary vascular resistance were increased during hypoxia, but cardiac output and systemic arterial pressure were decreased. There were increases of the concentrations of TXB2 and 6-keto-PGF1 alpha and their ratio in serum and lung tissue during hypoxia. After use of cyclooxygenase inhibitor (indomethacin) in vivo and in vitro, HPV was augmented respectively, but after use of lipoxygenase inhibitor (diethylcorbamazine) or leukotriene receptor blocker (LY-171883), HPV was attenuated. It was suggested that LTs mediated pulmonary vasoconstriction, PGs inhibited pulmonary vasoconstriction and they played a modulating role during hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Hypoxia; Leukotrienes; Prostaglandins; Pulmonary Artery; Rats; Rats, Wistar; Thromboxane B2; Vasoconstriction

We have previously shown a sequence of events after unilateral pulmonary contusion that suggests the release of blood-borne prostanoid mediators and that culminates in refractory bilateral pulmonary failure.. To determine the role of platelet-derived thromboxane and endothelial-derived prostacyclin in the primary and secondary injury after unilateral blunt chest trauma, and to determine whether pretreatment with the cyclooxygenase inhibitor indomethacin alters the progression of secondary injury.. Anesthetized, ventilated (FIO2 = 0.50) pigs received a unilateral, blunt injury to the right thorax (n = 20) or sham injury (n = 5) and were monitored for 24 hours. Either indomethacin (5 mg/kg i.v.; n = 10) or its saline vehicle (n = 10) were administered 15 minutes before injury. Serial bronchoalveolar lavages of each lung were analyzed for protein and neutrophil (polymorphonuclear neutrophil (PMN)) content.. Contusion caused profound hypoxemia; PaO2 partially recovered within 1 hour of injury to 50% of baseline. Thereafter, worsening hypoxemia required positive end-expiratory pressure. With indomethacin compared with vehicle, PaO2 was higher at any given level of positive end-expiratory pressure (p < 0.05). There was an early increase in serial bronchoalveolar lavage protein on the injured side (peak at 2 hours), with a delayed pulmonary capillary leak on the contralateral side (peak at 6 hours), which correlated with increasing PMN infiltration; this was reduced by 40 to 60% with indomethacin (p < 0.05). Thromboxane peaked within 1 hour after contusion at 800% baseline, then fell off rapidly. This peak preceded the maximal increase in permeability and was completely blocked by indomethacin. Prostacyclin slowly rose to 300% baseline by 3 hours and remained elevated; this change was blocked by indomethacin for 18 hours.. Contusion of the right thorax induced a delayed pulmonary capillary leak in the left lung, which reflects a progressive secondary inflammatory response. Elevations in thromboxane and prostacyclin preceded progressive bilateral PMN infiltration. Indomethacin blocked thromboxane and prostacyclin and attenuated, but did not prevent, the progression to pulmonary failure. Overall, these data suggest that prostanoids are released soon after unilateral contusion and initiate an inflammatory response in both lungs that is sustained by PMN infiltration.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Contusions; Cyclooxygenase Inhibitors; Epoprostenol; Hemodynamics; Hydrocortisone; Hypoxia; Indomethacin; Inflammation Mediators; Leukocytes; Lung; Lung Injury; Positive-Pressure Respiration; Prostaglandins; Swine; Thromboxane B2

We examined the effect on 6-Keto-PGF1a and TXB2 (the stable metabolites of PGI2 and TXA2) outflow of pretreatment with tetramethylpyrazine in the hypoxic isolated rat heart. In control hearts, 6-Keto-PGF1a was increased from 185 +/- 46 pg/ml of baseline value to 335 +/- 76 pg/ml after 2 min of hypoxia and TXB2 increased from 136 +/- 28 pg/ml of baseline value to 230 +/- 43 pg/ml at 20 min of hypoxia and 252 +/- 32 pg/ml after 5 min of reoxygenation. Pretreatment with tetramethylpyrazine increased the 6-Keto-PGF1a concentration to 266 +/- 51 pg/ml (143% of control heart), 471 +/- 89 pg/ml (150% of control heart) and 332 +/- 47 pg/ml (195% of control heart) at 15 min of normoxia, 2 min of hypoxia and 5 min of reoxygenation, respectively (p < 0.05 vs control). On the other hand, tetramethylpyrazine diminished the release of TXB2 to 78 +/- 21 pg/ml (174% of control heart), 160 +/- 30 pg/ml (144% of control heart), and 196 +/- 23 pg/ml (128% of control heart) at 15 min of normoxia, 20 min of hypoxia and 5 min of reoxygenation, respectively (p < 0.05 vs control). These data show that pretreatment with tetramethylpyrazine enhances PGI2 outflow and attenuates release of TXA2 in the rat heart during normoxia, hypoxia and reoxygenation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Coronary Circulation; Epoprostenol; Heart; Hypoxia; In Vitro Techniques; Male; Myocardium; Perfusion; Platelet Aggregation Inhibitors; Pyrazines; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane B2; Time Factors; Vasodilator Agents

The action of phospholipase A2 (PLA2) and related inflammatory mediators on the formation of hypoxic pulmonary arterial hypertension was studied. 30 Sprague-Dawley rats were equally divided into three groups at random: normal control group, hypoxic group and the group pretreated with dexamethasone plus hypoxia. The pulmonary arterial pressure (PAP) was measured by inserting a microcatheter into the pulmonary artery. After 30 min of hypoxia, the activity of PLA2, platelet activating factor (PAF), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were measured in blood and lung tissue, and it was found that the mean pulmonary arterial pressure (mPAP), the PLA2 activity, PGE2, TXB2 and PAF in blood and lung tissue were significantly increased; but pretreatment with dexamethasone relieved the changes mentioned above. In hypoxia, a positive correlations was found between the PLA2 activity and mPAP, PAF, PGE2, TXB2 respectively; positive correlations were also found between PAF, PGE2, TXB2 and mPAP. In conclusion, PLA2 induced the release of inflammation mediators, which may play roles in the formation of the acute hypoxic pulmonary arterial hypertension.

Topics: Animals; Dinoprostone; Female; Hypertension, Pulmonary; Hypoxia; Male; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

We postulated that the attenuated pulmonary and systemic vascular contractility observed in sepsis was secondary to the release of vasodilator prostaglandins. We used the cyclooxygenase inhibitor meclofenamate to inhibit prostaglandin synthesis in an unanesthetized, chronically instrumented model of hyperdynamic sepsis. Sixteen male Sprague-Dawley rats (300-350 g) were randomized to either sepsis induced by cecal ligation and perforation (CLP, n = 8) or a sham procedure (Sham, n = 8). Vascular reactivity was assessed by measuring the hypoxic (FiO2 = 0.08) pulmonary pressor response (HPV), and the systemic pressor response to an intravenous infusion of phenylephrine (1.5-7.5 micrograms/kg/min) before and after the administration of meclofenamate (5 mg/kg intravenously, i.v.). Twenty-four hours postoperatively, CLP animals had significantly increased cardiac output (CO) as compared with Sham animals (204 +/- 12 vs. 148 +/- 5 ml/min, p < 0.05), slightly decreased mean arterial pressure (MAP) (109 +/- 4 vs. 118 +/- 3 mm Hg, p < 0.05), and decreased total systemic vascular resistance (TSVR) (0.546 +/- 0.046 vs. 0.805 +/- 0.030 mm Hg.min.ml-1, p < 0.05). Mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance (TPVR) were similar in both groups (p > 0.05). In response to hypoxia, the change in MPAP (delta MPAP) was 3.6 +/- 1.0 and 6.9 +/- 0.8 (mm Hg) in CLP and Sham animals, respectively (p < 0.05). Similarly, the change in TPVR (delta TPVR) during hypoxia was 0.012 +/- 0.006 and 0.038 +/- 0.009 mm Hg.min.ml-1 in CLP and Sham (p < 0.05). The pulmonary and systemic blood pressure (BP) response to phenylephrine was also attenuated in CLP as compared with Sham animals. After treatment with meclofenamate, differences were no longer apparent in the HPV response between CLP and Sham animals, due to a slight increase in the HPV response of CLP animals and a slight decrease in the HPV response in Sham animals. The attenuated pressor response to phenylephrine was not changed in either the pulmonary or the systemic circulation after the administration of meclofenamate. These data suggest that vasodilator prostaglandins may contribute to the attenuated pulmonary pressor response in sepsis. However, the mechanism of the attenuated HPV may be different than the attenuated response to exogenous catecholamines since meclofenamate had no effect on either the pulmonary or systemic response to a phenylephrine infusion in septic animals.

Topics: Animals; Cyclooxygenase Inhibitors; Dinoprostone; Hemodynamics; Hypoxia; Male; Meclofenamic Acid; Phenylephrine; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sepsis; Thromboxane B2; Vasoconstriction; Vasoconstrictor Agents

The changes of some factors of blood coagulation system in rats following frost-bite of both hind feet under hypoxia were investigated. Male Wistar rats weighed 200 +/- 20g were divided into four groups: normal control (C); frostbite at normoxia (FN); frostbite during acute hypoxia (FAH) and frostbite during hypoxia after altitude acclimation (FHAC). Bleeding time and clotting time, rate of clot-retraction, plasma content of 6-keto-PGF1 alpha and TXB2 were determined following exposure to cold. The results showed that bleeding time and clotting time were shortened, and rate of clot-retraction was decreased, plasma content of 6-keto-PGF1 alpha and TXB2, T/P ratio were increased significantly after exposure to cold in all frostbite groups, but these changes were more prominent in FHAC than those in FN and FAH. The results demonstrated that there were changes in blood coagulation system following cold injury, blood coagulability was increased. These changes were closely related to the degree of frostbite. In addition, the degree of cold injury was aggravated by altitude acclimation and this may play an important role in the pathological process of dysfunction leading to necrosis of local frostbite tissue.

Topics: Acclimatization; Adaptation, Physiological; Animals; Blood Coagulation; Blood Coagulation Factors; Cold Temperature; Frostbite; Hypothermia, Induced; Hypoxia; Male; Oxygen; Prostaglandins F; Rats; Rats, Wistar; Thromboxane B2

We sought to determine whether a standardized "priming" event, namely a small dose of LPS, would alter physiological responses to a subsequent larger "challenge" dose of endotoxin. Accordingly, four groups of pigs (N = 5-6) were studied. One group received neither priming nor challenge doses of LPS. A second group were not primed but were infused with a challenge dose (250 micrograms/kg) of LPS. A third group were pretreated 18 h before being studied with a priming dose of LPS (20 micrograms/kg), but were not infused with a second dose of LPS. A fourth group received both priming and challenge doses of LPS. Priming with LPS exacerbated endotoxin-induced arterial hypoxemia, and decreased animal-to-animal variability in the degree of hypoxemia induced by a challenge dose of endotoxin. Priming blunted the early phase (30 min) and exacerbated the delayed phase (120-210 min) of LPS-induced pulmonary hypertension. Priming blunted LPS-induced release of prostacyclin and thromboxane A2. The use of a priming dose of LPS increases the severity and reproducibility of LPS-induced acute lung injury in swine.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Cardiac Output; Drug Administration Schedule; Endotoxins; Hypoxia; Lipopolysaccharides; Male; Oxygen; Partial Pressure; Premedication; Pulmonary Fibrosis; Shock, Septic; Swine; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha; Vascular Resistance

The effects of hypoxia on prostanoid production were studied in atria from normal, acute diabetic and insulin-treated diabetic rats. Diabetes was induced by intravenous administration of 65 mg/kg of streptozotocin, the rats were killed 5 days later. Hypoxia was performed by incubation of the atria during 60 min in nitrogen-equilibrated glucose free Krebs' solution followed by 15 min of reoxygenation. The prostanoids 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2), stable metabolites of prostacyclin and TXA2, respectively, as well as PGF2, were measured by reversed phase HPLC-UV. In control atria, the production of 6-keto PGF1 alpha was equivalent to that of PGE2, whereas TXB2 was released in a much smaller amount. In diabetic atria, 6-keto PGF1 alpha production was reduced by 65%, whereas TXB2 release was increased by 158% compared to the controls. When the normal atria were exposed to 60 min of hypoxia, the release of 6-keto PGF1 alpha increased by 142% compared to basal values and remained elevated after 15 min of reoxygenation whereas in diabetic and insulin-treated diabetic tissues the 6-keto PGF1 alpha production was not modified by the hypoxia-reoxygenation period. The release of TXB2 was increased after 60 min hypoxia in normal as well as in diabetic and insulin-treated diabetic tissues and remained elevated during the reoxygenation. The PGE2 output increased only after the onset of the reoxygenation in the three groups studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Diabetes Mellitus, Experimental; Dinoprostone; Female; Heart Atria; Hypoxia; In Vitro Techniques; Myocardial Reperfusion Injury; Myocardium; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2

In order to evaluate the effect of hypoxia on platelet activation, 53 pilots were chosen for this study. Thirty were selected as the hypoxic group, and the other 23 as a control group. The plasma concentration of thromboxane B2(TXB2), 6-keto-prostaglandin f1 alpha (6-keto-PGF1 alpha), beta-thrombo-globulin (BTG) and platelet factor 4 (PF4) were measured during altitude chamber tests. After staying at 5000 m for 15 min, the plasma level of TXB2, BTG and PF4 increased significantly over pre-test levels (p < 0.01), but 6-keto-PGF1 alpha had no distinct change (p > 0.05). These changes indicate that moderate acute hypoxia causes increases in platelet activation, but has less effects on the endothelial cells.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aerospace Medicine; beta-Thromboglobulin; Humans; Hypoxia; Male; Military Personnel; Platelet Activation; Platelet Factor 4; Thromboxane B2

Hippocampal slices of rats at postnatal day 7 were submitted to superfusion with Ca(2+)- and Mg(2+)-free, bicarbonate buffered ion balanced medium, and perfusate concentrations of eicosanoids: thromboxane B2 and 6-keto prostaglandin F1 alpha were determined by the radioimmunoassay. It was noted that the permanent presence of Ca2+ increased the basal eicosanoid level, and in these conditions modulation of eicosanoid production was lost, whereas temporary, a 20 min application of 1.3 mM Ca2+ did not influence significantly eicosanoid release. A 20 min application of the anoxic/aglycemic medium containing calcium did not change the content of eicosanoids in superfusates. A significant stimulation of the thromboxane B2 and 6-keto prostaglandin F1 alpha release was noted provided the application of the experimental medium was accompanied by a 10 min arrest of superfusion. This effect was inhibited by MK-801 and quinacrine, suggesting an involvement of NMDA receptors and phospholipase A2. We propose that a model of anoxic/aglycemic superfusion with a stop flow period allows retention of endogenous glutamate in the extracellular fluid, resembling a similar effect during in vivo ischemia, whereas during a continuous superfusion glutamate is immediately washed out. Consequently, an application of the anoxic/aglycemic medium accompanied by a temporary arrest of superfusion represents more adequate in vitro model of ischemia than a constant superfusion with this medium. In these conditions NMDA receptors mediate eicosanoid release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Brain Ischemia; Calcium; Culture Techniques; Dizocilpine Maleate; Eicosanoids; Hippocampus; Hypoxia; N-Methylaspartate; Quinacrine; Radioimmunoassay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Thromboxane B2

To determine the effect of humoral factors and their interaction on the development of acute hypoxic pulmonary pressor response (HPPR), we performed studies in 16 mongrel dogs. We measured plasma levels of noradrenaline (NE), angiotensin II (AII), prostaglandin F2 alpha (PGF2 alpha), 6-keto-prostaglandin F1 alpha (6KPGF1 alpha), thromboxane B2 (TXB2), leukotriene B4 (LTB4) and 5-hydroxytryptamine (5-HT) before, during and after HPPR. Multiple regression analysis showed that the changes of pulmonary arterial systolic pressure (PASP) and pulmonary arterial diastolic pressure (PADP) correlated well with those of plasma concentration of NE, PGF2 alpha and 6KPGF1 alpha, respectively (r were equal to 0.633 and 0.668, respectively, P < 0.01). The results of orthogonal experiment analysis with an injection of exogenous NE, PGF2 alpha and PGI alpha into main pulmonary artery of dogs showed that NE and the interaction of PGF2 alpha and PGI2 alpha increased PASP (P < 0.05) and PGI2 attenuated PASP (P < 0.01). The interaction of PGF2 alpha and PGI2 and of PGF2 alpha and NE increased PADP(P < 0.01) and PGI2 attenuated PADP (P < 0.01).

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Blood Pressure; Dinoprost; Dogs; Female; Hypertension, Pulmonary; Hypoxia; Male; Norepinephrine; Pressoreceptors; Pulmonary Artery; Thromboxane B2

Primary cultures of rat Kupffer cells liberated significant amounts of prostaglandin (PG) D2, PGE2, and thromboxane (measured as thromboxane B2) when exposed to reoxygenation after 4 h of hypoxia. After a delayed onset, prostanoids were released at high rates for at least 8 h and after that time 700 pmol PGD2, 280 pmol PGE2, and 200 pmol thromboxane per 10(6) cells had been liberated. Unlike prostanoid release, leukotriene B4 production in reoxygenated cell cultures was only twice as much as in aerobic controls. Superoxide dismutase and catalase had no effect on PGD2, PGE2, and thromboxane production, indicating that prostanoid formation was independent of reactive oxygen species generated extracellularly and of cell injury. On the other hand, diphenyliodonium, as well as amiloride, blocked hypoxia-reoxygenation-induced PGD2, PGE2, and thromboxane release. The elevated prostanoid synthesis was preceded by increases in intracellular pH (from 7.23 to 7.38) and in intracellular Ca2+ (from 55 nM to a maximum level of 807 nM). These observations suggest a participation of NADPH oxidase and a related Na(+)-H+ exchange in the enhanced prostanoid synthesis, probably through the induction of an increased intracellular Ca2+ concentration.

Topics: Amiloride; Animals; Anti-Infective Agents; Biphenyl Compounds; Calcimycin; Calcium; Carrier Proteins; Cell Survival; Cells, Cultured; Dinoprostone; Hydrogen-Ion Concentration; Hypoxia; Kupffer Cells; Leukotriene B4; Male; NADH, NADPH Oxidoreductases; NADPH Oxidases; Onium Compounds; Oxidation-Reduction; Oxygen; Prostaglandin D2; Rats; Rats, Wistar; Sodium-Hydrogen Exchangers; Tetradecanoylphorbol Acetate; Thromboxane B2

Polymorphonuclear leukocyte (PMN) sequestration within the pulmonary microvasculature is known to occur in association with ischemia/reoxygenation (I/R). This sequestration is dependent on eicosanoids and reactive oxygen species. PMN sequestration within the lungs suggests that pulmonary microvascular endothelial cells (MECs) may in part regulate the I/R response. Simulating I/R, we examined the effect of hypoxia/reoxygenation (H/R) on pulmonary MECs in vitro, with and without PMNs. Significant cellular injury, assessed by 51Cr release, occurred upon reoxygenation of MECs (P < .01). Addition of PMNs to the H/R-injured monolayers did not increase MEC injury. Reoxygenation of MECs also resulted in increased thromboxane (Tx) B2 production compared to controls (P < .01). Inhibition of Tx secretion by aspirin reduced H/R-induced PMN adhesion to MECs (P < .01). Furthermore, H/R-induced increases in PMN-MEC adhesion were prevented by allopurinol and superoxide dismutase (P < .01). These data suggest that the pulmonary response to H/R is mediated by MEC generation of reactive oxygen radical species and Tx, which promotes increased PMN adhesion.

Topics: Actins; Allopurinol; Animals; Cattle; Cell Adhesion; Cells, Cultured; Chromium Radioisotopes; Cytoskeleton; Dexamethasone; Eicosanoids; Endothelium, Vascular; Hypoxia; Leukotriene B4; Lung; Masoprocol; Microcirculation; Neutrophils; Radioimmunoassay; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Thromboxane B2; Xanthine Oxidase

Thrombocytosis and morphological changes in shape and size of circulating platelets are commonly found in splenectomized thalassemia patients. Functional abnormalities of the platelets are evidently related to their fragile nature. Spontaneous aggregation of platelets can easily occur following application of mild pressure either from a stirring magnetic bar or due to centrifugal force. Platelets are hyper-reactive to chemical stimulation and the release of platelet granule contents (eg ATP) together with other membranous lipid metabolites, thromboxane A2 and malondialdehyde is markedly enhanced. The lipid soluble antioxidant, vitamin E is depleted from various blood compartments. The findings suggest that circulating platelets in splenectomized thalassemia are continuously attacked by yet to be identified blood borne factor(s) and the defective platelets could play a pivotal role in the pathogenesis of hypoxemia.

Topics: beta-Thalassemia; Case-Control Studies; Hemoglobin E; Hemoglobinopathies; Humans; Hypoxia; Incidence; Malondialdehyde; Platelet Aggregation; Platelet Count; Postoperative Complications; Splenectomy; Thailand; Thromboxane B2; Vitamin E

Because alveolar hypoxia (HYP) triggers pulmonary mast cell degranulation with elaboration of vasoactive mediators such as leukotrienes, we investigated the effects of aerosolized cromolyn sodium (CS), a mast cell stabilizing agent, and U-60,257(U) (a leukotriene blocker) on the circulation, lung mechanics and thromboxane (TXB2) levels in 11 lambs during acute exposure to HYP. Studies were performed in awake, chronically instrumented animals, once after placebo (saline) and again after CS (100 mg; n = 5) or U (90 mg; n = 6). Pulmonary arterial pressure increased 42% during HYP after saline, and 32% and 19% after CS and U, respectively. Pulmonary vascular resistance did not change during HYP after CS or U. Systemic arterial pressure was unchanged after saline and CS but decreased after U; systemic vascular resistance dropped after both CS and U. No changes were seen in tidal volume, lung compliance or airway resistance during HYP after saline or either drug, but minute ventilation increased during HYP in all studies. TXB2 increased during HYP after saline in both studies and was not altered by CS. In contrast, after U, TXB2 decreased. Thus, U more effectively blunted the pulmonary vascular response to HYP than CS and resulted in mild systemic hypotension. The drop in TXB2 after U suggests leukotriene-induced thromboxane synthesis contributes to regulation of pulmonary, and possibly, systemic vasoactivity.

Topics: Animals; Blood Pressure; Cromolyn Sodium; Epoprostenol; Hypoxia; Lung; Pulmonary Circulation; Sheep; Thromboxane B2; Vasoconstriction

The effects of a beta-agonist (isoproterenol) and beta-antagonists (propranolol and pindolol) on hypoxic pulmonary vasoconstriction (HPV) and on changes in some chemical mediators were examined in 28 isolated blood-perfused dog lung lobes. Hypoxic challenge (4 min) was repeated twice, and each drug was administered at a bolus dose of 0.2 mg between the hypoxic periods. The first hypoxia increased pulmonary vascular resistance (PVR) by 33% or more in all groups. Both isoproterenol and pindolol inhibited the second HPV completely, but propranolol did not influence HPV. During normoxia, isoproterenol and pindolol significantly decreased PVR by 17.5 and 6.7% (P less than 0.01), respectively, but propranolol had no effect on PVR. In the control and propranolol groups, plasma levels of adenosine 3',5'-cyclic monophosphate (cAMP) significantly decreased during hypoxia, but those of prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 did not change. cAMP increased from 17.0 +/- 4.0 to 76.7 +/- 15.6 pmol/ml in the isoproterenol group (P less than 0.01), and prostaglandin E2 increased from 87.0 +/- 13.6 to 1,015.4 +/- 309.7 pg/ml in the pindolol group (P less than 0.05). The results suggest that the mechanism of HPV inhibition is different between isoproterenol and pindolol.

Topics: Animals; Cyclic AMP; Cyclooxygenase Inhibitors; Dogs; Hypoxia; Pindolol; Prostaglandins; Pulmonary Circulation; Thromboxane B2; Vasoconstriction

We investigated cellular mechanisms that may be involved in controlling cytosol calcium and pulmonary artery pressure during hypoxia and normoxia in isolated blood-perfused ferret lungs. Alveolar hypoxia in ferret lungs causes an active increase in pulmonary vascular resistance. Hypoxic pulmonary vasoconstriction directly correlates with extracellular calcium ([Ca2+]o), and the absence of [Ca2+]o in the perfusate markedly attenuates the hypoxemia-induced pulmonary vasoconstriction. Alveolar hypoxia does not potentiate the production of thromboxane B2 (TxB2) or 6-keto-PGF1 alpha. Vanadate, a widely used inhibitor of Ca2+ATPases, increases pulmonary arterial pressure (Ppa) in the presence or absence of [Ca2+]o and without affecting the production of TxB2 or 6-keto-PGF1 alpha. Vanadate and ouabain, an inhibitor of Na+/K+ATPase, produce synergistic increases in Ppa. Amiloride, an inhibitor of Na+/Ca2+ exchange, reverses the increase in Ppa caused by ouabain, but not the increase caused by vanadate. The additional effect produced by ouabain on Ppa after near maximal vanadate effect and the ability of amiloride to reverse the pulmonary vasoconstriction caused by ouabain, but not vanadate, suggests that vanadate does not inhibit Na+/K+ATPase in ferret lungs. In addition, cyclic GMP (cGMP), which has been reported to increase the activity of Ca2+ATPases in vascular smooth muscle, was able to reverse and prevent the effect of vanadate on Ppa, but not the effect of ouabain. Inhibition of Ca2+ATPases with vanadate in ferret lungs increases pulmonary vascular resistance during both normoxia and hypoxia. The Ca2+ entry mediated by alveolar hypoxia appears to overpower the ability of Ca2+ATPases and other membrane Ca2+ transport proteins to translocate [Ca2+]i.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcium; Calcium-Transporting ATPases; Cyclic AMP; Cyclic GMP; Ferrets; Hypoxia; Lung; Male; Pulmonary Artery; Thromboxane B2; Vanadates; Vasoconstriction

To evaluate the role of certain plasma biosubstances on the development of pulmonary hypertension and shock during severe hypoxia, hypercapnia and acidosis, plasma renin activity (PRA), angiotensin II (ATII), angiotensin converting enzyme (ACE), TXB2 and 6-Keto-PGF1 alpha (the stable metabolites of TXA2 and PGI2) were assayed in blood from pulmonary artery and aorta in seven pigs. Pulmonary arterial pressure (PAP) was monitored via Swan-Ganz catheter. During hypoxic and hypercapnic ventilation, PaO2 dropped to 4.7 kPa, PaCO2 rose to 21.1 kPa, pH dropped to 6.82, PAP increased from 2.43 +/- 0.06 to 4.46 +/- 0.45 kPa when acidotic shock developed (all P less than 0.05). Meanwhile ATII levels rose (all P less than 0.05). PRA significantly increased during acidotic shock as compared with normal ventilation (P less than 0.02). ACE dropped significantly (P less than 0.05), TXB2 and 6-keto-PGF1 alpha showed no significant change before and after hypoxic and hypercapnic ventilation.

Topics: 6-Ketoprostaglandin F1 alpha; Acidosis; Animals; Hypercapnia; Hypoxia; Male; Peptidyl-Dipeptidase A; Renin; Shock; Swine; Thromboxane B2

Pulmonary hypertension is a major source of morbidity and mortality in infants born with congenital diaphragmatic hernia (CDH). Increased pulmonary vascular resistance leads to right-to-left shunting, which is evident as decreases in the PaO2 measured in postductal arterial blood. Thromboxane A2 (TXA2), a vasoconstrictor, and prostacyclin (prostaglandin I2, PGI2), a vasodilator, have been studied as possible mediators of pulmonary hypertension in certain conditions of the newborn, including congenital diaphragmatic hernia (CDH). The goal of our study was to determine the association of TXA2 and PGI2 levels with hypoxemia in infants born with CDH. Eleven newborn infants with severe respiratory insufficiency (birth weight 2.0-4.1 kg; gestational age 32-42 weeks) were studied 0-5 days after surgical repair of CDH. Umbilical artery samples were collected for arterial blood gas determinations and radioimmunoassay of thromboxane B2 (TXB2) and 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolites of TXA2 and PGI2, respectively. Postductal arterial hypoxemia (reflected by a low a-A ratio, the ratio of oxygen tension in arterial blood to that in the alveolus) was associated with increases in TXB2 (r = -0.71, P = 0.004) and 6-keto-PGF1 (r = -0.65, P = 0.017). The a-A ratio also correlated inversely with TXB2/6-keto-PGF1 alpha (r = -0.50, P = 0.01), suggesting an increased influence of the vasoconstrictor TXA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Arteries; Carbon Dioxide; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hydrogen-Ion Concentration; Hypoxia; Infant, Newborn; Oxygen; Partial Pressure; Respiration; Thromboxane B2

In monkey coronary artery strips contracted with prostaglandin (PG) F2 alpha or K+, exchange of entire N2 for O2 in the gas aerating the bathing media produced a contraction. Endothelium denudation did not alter the response. Aspirin, indomethacin, and ONO 3708, a PG receptor antagonist, markedly inhibited the hypoxia-induced contraction, whereas superoxide dismutase and OKY 046, a thromboxane (Tx) A2 synthesis inhibitor, were ineffective. Diltiazem depressed the contraction. Hypoxia increased the release of PGE2 but not 6-keto-PGF1 alpha and TxB2. Contractions induced by hypoxia of human coronary artery strips were also independent of the endothelium but were suppressed by indomethacin and diltiazem. On the other hand, dog coronary artery contractions induced by hypoxia were attenuated by endothelium denudation but were not influenced by indomethacin. It may be concluded that the hypoxia-induced contraction of monkey and human epicardial coronary arteries is associated with vasoconstrictor PGs released from subendothelial tissues; however, TxA2 and superoxide anion are not involved. The dog coronary artery contraction appears to be elicited by substance(s), other than cyclooxygenase products, released from the endothelium.

Topics: Animals; Aspirin; Coronary Vessels; Dinoprost; Dogs; Endothelium, Vascular; Female; Humans; Hypoxia; In Vitro Techniques; Indomethacin; Isometric Contraction; Macaca; Male; Methacrylates; Muscle Relaxation; Muscle, Smooth, Vascular; Papaverine; Prostaglandins; Species Specificity; Superoxide Dismutase; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

In this study, we observed the effect of endotoxemia on hypoxic pulmonary vasoconstriction (HPV) in dogs and explored roles played by prostaglandins and leukotrienes in this process. 5 micrograms/kg BW of E. coli endotoxin induced transient rise in pulmonary arterial pressure and pulmonary vascular resistance (PVR). 30 min after injection of endotoxin when PVR tended to decline, pulmonary vasoconstriction response to alveolar hypoxia was lost, and the ratio of TXB2 to 6-keto-PGF1 alpha decreased significantly. HPV was enhanced at 60-100 min and then returned to the control level at 2 h after injection of endotoxin. At these periods the ratio of TXB2 to 6-keto-PGF1 alpha was the same as before use of endotoxin, whereas plasma concentration of leukotrienes was markedly increased. Indomethacin could prevent the early loss of HPV, but no effect on the late increment of HPV was found. Diethylcarbamazine, which blocked the production of leukotrienes after use of endotoxin, could inhibit late increment of HPV. We concluded that the early loss of HPV was related to the vasodilator prostacyclin, and the late increment of HPV was mainly brought about by leukotrienes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Endotoxins; Female; Hypertension, Pulmonary; Hypoxia; Leukotrienes; Male; Pulmonary Circulation; Thromboxane B2; Toxemia; Vascular Resistance; Vasoconstriction

The effect of hypoxia on renal prostanoid synthesis and renal function was studied. The kidneys of male Sprague-Dawley rats were cannulated and perfused in vitro with Krebs-Henseleit buffer with a pO2 of 460 (control) or 60 mm torr (hypoxia). The rate of perfusion was adjusted to maintain perfusion pressure at 100 mm Hg. The renal venous effluent was collected at 15, 30, 60, 120, 150, and 180 min and assayed for basal release of 6-keto-PGF1 alpha, PGE2, and thromboxane B2 by radioimmunoassay and inulin and sodium clearance. Prostanoid release was high at 15 min, decreased to a lower level up to 120 min, and then progressively increased after 150 min of perfusion. Hypoxia significantly decreased TxB2 release at 30, 60, 150, and at 180 min but not PGE2 or 6-keto-PGF1 alpha release. Hypoxia proportionally decreased both sodium and inulin clearances suggesting that the decrease in renal function was from decreased renal flow. The kidney responded to the altered renal function by increasing the ratio of vasodilator to vasoconstrictor prostanoids by inhibition of TxB2 release.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Hypoxia; Kidney; Kinetics; Male; Rats; Rats, Inbred Strains; Sodium; Thromboxane B2

In this study we examined the action of arachidonic acid in the isolated rat lung perfused with a cell- and protein-free physiological salt solution. When pulmonary vascular tone was elevated by hypoxia, bolus injection of a large dose of arachidonic acid (75 micrograms) caused transient vasoconstriction followed by vasodilation. When arachidonic acid (100 micrograms) was injected during normoxia and at base-line perfusion pressure (low vascular tone) or when vascular tone was elevated by KCl, arachidonic acid (50 micrograms) caused only vasoconstriction. Doses less than 7.5 micrograms caused vasodilation only when injected during hypoxic vasoconstriction and subsequent blunting of either angiotensin II- or hypoxia-induced pulmonary vasoconstriction. The higher doses of arachidonic acid (7.5 and 75 micrograms), but not the lower doses (7.5-750 ng), caused increases in effluent 6-ketoprostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 and F2 alpha. 6-Ketoprostaglandin F1 alpha was the major cyclooxygenase product. Meclofenamate (10(-5) M) blocked the increased metabolite synthesis over the entire dose range of arachidonic acid tested (7.5 ng-75 micrograms). Because vasodilation immediately after arachidonic acid was cyclooxygenase-independent, we investigated whether this effect was due to the unsaturated fatty acid properties of arachidonic acid and compared its action with that of oleic acid and docosahexaenoic acid. Because neither compound mimicked the vasodilation observed with arachidonic acid, we concluded that the cyclooxygenase-independent action of arachidonic acid could not be explained by unsaturated fatty acid properties per se. Because 1-aminobenzotriazole, a cytochrome P-450 inhibitor, partially inhibited the immediate arachidonic acid-induced pulmonary vasodilation, we concluded that cytochrome P-450-dependent metabolites can account for some of the cyclooxygenase-independent vasodilation of arachidonic acid.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Hypoxia; In Vitro Techniques; Male; Perfusion; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Rats; Rats, Inbred Strains; Thromboxane B2; Triazoles; Vasodilation

Several recent studies have suggested that peptidoleukotrienes are involved in or responsible for the pulmonary pressor response to hypoxia as well as the normally high pulmonary vascular resistance of fetal lambs. The present studies were carried out to test these hypotheses. Fetal lambs were prepared with indwelling vascular catheters and tracheal catheters for access to lung liquid. We measured lung liquid levels of leukotrienes C4 (LTC4) and D4 (LTD4) in control unanesthetized fetal lambs with blood gases and pH in the normal range. In the control series, LTC4 and LTD4 were either not detectable or their levels were close to the limit of resolution (LTC4, less than 80 pg/ml; LTD4, less than 50 pg/ml) of the techniques utilized. Leukotriene E4 was measured in a separate study by using pooled samples, and it was also found to be below the detection limit of that assay (10 pg/ml). In a second series of animals, a level of acute hypoxia was induced to decrease fetal arterial PO2 to 12 Torr for 20 min. After hypoxia, tracheal fluid levels of leukotrienes were again below detection limits of the assays used (LTC4, less than 80 pg/ml; LTD4, less than 142 pg/ml). In another study, methodology was altered to lower the detection limits of leukotrienes in lung fluid and to allow the measurement of total peptidoleukotriene concentrations. In this study, even when hypoxia was extended for up to 1 h, leukotriene levels were consistently below the limit of detection of the assay (less than 20 pg/ml for the sum of all leukotrienes).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Fluids; Female; Fetus; Hypoxia; Leukotrienes; Lung; Pregnancy; Prostaglandins; Pulmonary Circulation; Sheep; SRS-A; Thromboxane B2; Time Factors; Vascular Resistance

TXB2 and 6-keto-PGF1 alpha levels in arterial and venous plasma of Wistar and Hilltop rats during hypoxia were measured to investigate the roles of TXA2 and PGI2 in hypoxic pulmonary vasoconstriction (HPV) and responsiveness difference of pulmonary vessels to hypoxia between different strains of rats. The results showed that PGI2 might play an important role in maintaining the low resistance in pulmonary circulation of these two strains of rats. Increased TXA2 during hypoxia may partially mediate HPV in Wistar rats, while augmented PGI2 during hypoxia may modulate HPV in Wistar rats. This might be the important mechanism responsible for more intensive responsiveness of pulmonary vessels to hypoxia in Hilltop rats than in Wistar rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Hemodynamics; Hypoxia; Indomethacin; Male; Pulmonary Artery; Rats; Rats, Inbred Strains; Species Specificity; Thromboxane B2; Vasoconstriction

To verify the presence of the constitutional abnormality implicated in the pathogenesis of high-altitude pulmonary edema (HAPE), we evaluated the hemodynamic responses to hypoxia, hypobaria, and exercise in HAPE-susceptible subjects (HAPE-S). HAPE-S were five males with a history of HAPE. Five healthy volunteers who had repeated experiences of mountain climbing without any history of altitude-related problems served as controls. HAPE-S showed much greater increase in pulmonary vascular resistance index (PVRI) than the control subjects, resulting in a much higher level of pulmonary arterial pressure (Ppa), under both acute hypoxia of 15% O2 (Ppa = 29.0 +/- 2.8 vs. 17.8 +/- 0.3 Torr, P less than 0.05) and acute hypobaria of 515 Torr (32.3 +/- 2.8 vs. 19.1 +/- 0.8 Torr, P less than 0.05). Also, PVRI in HAPE-S exhibited a tendency to increase even during light exercise with supine bicycle ergometer (50 W), whereas PVRI in the control subjects significantly decreased, so that HAPE-S showed a greater increase in Ppa (delta Ppa = 16.0 +/- 1.5 vs. 4.9 +/- 1.1 Torr, P less than 0.001) and a greater decrease in arterial oxygen tension (17.8 +/- 4.7 vs. 5.6 +/- 1.7 Torr, P less than 0.05). We thus conclude that HAPE-S have a constitutional abnormality, which can be evaluated at low altitude, in the pulmonary circulatory responses to possible causative factors of HAPE such as hypoxia, hypobaria, and exercise.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Altitude Sickness; Atmospheric Pressure; Atrial Natriuretic Factor; Blood Gas Analysis; Disease Susceptibility; Hemodynamics; Humans; Hypoxia; Male; Physical Exertion; Pulmonary Edema; Thromboxane B2

The effect of hypoxia on isolated perfused rat mesenteric basal venous prostanoid output was studied. Male rat splanchnic vasculature was removed without (SV) or with its end organ (SV + SI) and perfused with Krebs' buffer with a pO2 of 460 or 60 mm torr. Basal splanchnic venous effluent was assayed for 6-keto-PGF1 alpha, TxB2 and PGE by radioimmunoassay at 30, 60, 120 and 180 min of perfusion. Basal output of SV 6-keto-PGF1 alpha was five and ten fold higher than for PGE and TxB2 respectively and comprised 36% or greater of SV + SI 6-keto-PGF1 alpha output. SV PGE and TxB2 output comprised less than 19 and 12% respectively of SV + SI output. Hypoxia decreased SV + SI PG output, 6-keto-PGF1 alpha being most affected. Hypoxia did not alter SV 6-keto-PGF1 alpha output indicating the SI as the anatomic location most influenced by hypoxia. The relative amounts of distribution of PGE or TxB2 output were not altered by hypoxia. These data suggest that there are two distinct areas of splanchnic prostanoid output, the SV and the SI. Decreased 6-keto-PGF1 alpha output might alter splanchnic blood flow at two levels, the splanchnic vasculature, and/or within the bowel wall.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Electrophoresis, Polyacrylamide Gel; Hypoxia; Male; Mesentery; Perfusion; Prostaglandins; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

This study investigated the role of prostaglandins (PGs) and leukotrieres (LTs) in hypoxic pulmonary vasoconstriction (HPV) and in cigarette smoking-induced changes in hemodynamics and HPV in Wistar rats. Selective LTD4-LTE4 receptor antagonist LY-171883 (LY) inhibited HPV by 71.8%, while cyclooxygenase inhibitor indomethacin (IND) augmented HPV. The results indicate that LTs mediate HPV in Wistar rats. Smoking increased the level of TXB2 over control by 143.6% in plasma and 69.2% in lung tissue, concomitantly, pulmonary and systemic vascular resistance (PVR and SVR) were increased by 38.7% and 46.7%, respectively. Both LY and IND prevented the smoking-induced increase of PVR and SVR. After smoking HPV increased twofold. The increase of HPV was abolished by LY, but not by IND. Our results suggest that smoking leads to pulmonary and systemic vasoconstriction partly mediated by TXA2 and LTs; smoking also leads to an augmentation of HPV, and LTs play an important role in it.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Hypoxia; Leukotrienes; Male; Prostaglandins; Pulmonary Artery; Rats; Rats, Inbred Strains; Smoking; Thromboxane B2; Vasoconstriction

Group B beta-hemolytic streptococcus (GBS) causes thromboxane (Tx)-associated pulmonary hypertension and hypoxemia in neonatal animals and human infants. The components of GBS that induce these features of sepsis are incompletely characterized. The capsular polysaccharide has been implicated based on the effects of GBS extracts. We used isogenic mutants of a parent GBS strain (COH 31 r/s) devoid of capsular polysaccharide or beta-hemolysin to determine if these components caused the acute features of GBS bacteremia. In neonatal piglets, we observed a similar increase in pulmonary vascular resistance (PVR, mm Hg/L/min) during a 1 h infusion at 5 x 10(8) colony-forming unit/kg/h of COH 31 r/s (n = 5, 11.6 +/- 1.4 to 67.1 +/- 17.9), an isogenic GBS mutant devoid of type III CP (n = 5, 12.5 +/- 1.4 to 56.9 +/- 5.0), and an isogenic GBS mutant devoid of beta-hemolysin (n = 4, 11.0 +/- 1.9 to 51.9 +/- 7.9). All three GBS strains caused increases in blood TxB2 levels, mild arterial hypoxemia, mild reduction in mixed venous PO2, and a 30-40% reduction in cardiac output after a 1 h infusion. The Tx-synthase inhibitor, dazmegrel, completely reversed pulmonary hypertension, and partially reversed arterial hypoxemia and TxB2 levels to baseline values for all GBS strains. In six additional piglets, infusion of polystyrene beads of similar size to GBS at a dose of 5 x 10(8) beads/kg/h caused no changes in gas exchange or blood TxB2 levels, but a mild increase in PVR (13.3 +/- 2.0 to 17.7 +/- 3.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Gas Analysis; Hemolysin Proteins; Hypertension, Pulmonary; Hypoxia; Polysaccharides, Bacterial; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2

Pretreatments of rats with the Carbochromene derivative AD6 (4 mg/kg i.p., 2 h before sacrifice) resulted in elevation of brain levels of 6-keto-PGF1 alpha in cerebral cortex under physiological conditions, had no effect on levels of TxB2 and 6-Keto-PGF1 alpha at 30 min of hypoxia (respiration of 5% O2 in N2) and prevented the accumulation of TxB2 occurring in brain at 5 min of recovery after hypoxia. In addition, the accumulation of LTC4 and B4 in brain slices incubated in the presence of the Ca++ ionophore A23187 and arachidonic acid, was reduced in samples obtained from pretreated rats. The drug, thus, had favourable effects on the 6-keto-PGF1 alpha/TxB2 ratio in normal conditions, as well as in conditions of altered oxygen supply. In addition it reduced the formation of compounds, the leukotrienes, which may exert pro-inflammatory activities on the cerebral microcirculation.

Topics: 6-Ketoprostaglandin F1 alpha; Anaerobiosis; Animals; Cerebral Cortex; Chromonar; Coumarins; Hypoxia; In Vitro Techniques; Kinetics; Leukotriene B4; Lipoxygenase; Male; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Topics: Adult; Altitude Sickness; Female; Humans; Hypoxia; Male; Middle Aged; Oxygen; Platelet Count; Pulmonary Circulation; Pulmonary Edema; Thromboxane B2

Potentiation of hypoxic pulmonary vasoconstriction by a low dose of almitrine bismesylate (1 microgram.kg-1.min-1) was evaluated in terms of blood chemical mediator concentrations. Time course changes in the blood concentrations of adrenaline, noradrenaline, serotonin, histamine, thromboxane TXB2 and 6-keto-PGF1 alpha were monitored after administration of almitrine bismesylate for 15 min at 1 microgram.kg-1.min-1) in hypoxic and normoxic beagles. The low almitrine dose significantly increased TXB2 levels in hypoxic beagles, but the levels remained virtually unchanged in the normoxic animals with almitrine bismesylate and in the hypoxic animals with solvent. TXB2 levels did not increase when the almitrine infusion was increased to 5 micrograms.kg-1.min-1 for 15 min in hypoxic conditions. These findings suggest that almitrine is involved in arachidonic acid metabolism at a low rate of infusion and that thromboxane release from hypoxic areas of the lung may cause local vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Almitrine; Animals; Blood Pressure; Catecholamines; Dogs; Histamine; Hypoxia; Piperazines; Pulmonary Circulation; Pulmonary Wedge Pressure; Serotonin; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasoconstriction

Pulmonary hypertension was generated in 11 newborn piglets, via either infusion of group B beta-hemolytic streptococci (n = 5) or induction of isocapnic hypoxia (n = 6), to study the contributions of thromboxane metabolite thromboxane B2 levels to different types of pulmonary hypertension. After 30 minutes of stable pulmonary hypertension, mean (+/- SD) pulmonary artery pressure increased similarly from 16 +/- 4 to 33 +/- 5 mm Hg (hypoxic), and from 14 +/- 2 to 34 +/- 6 mm Hg (septic). All other measured hemodynamic variables were similar. Despite these hemodynamic similarities, there were significant differences in thromboxane B2 levels. After 60 minutes of pulmonary hypertension, thromboxane B2 levels were 760 +/- 253 pg/mL (hypoxic), and 3103 +/- 1083 pg/mL (septic). These data demonstrate that, while thromboxane appears to be crucial in mediating septic pulmonary hypertension in the piglet, it is not associated with hypoxic pulmonary hypertension, implying that different types of pulmonary hypertension are probably mediated by different biochemical agents.

Topics: Animals; Hemodynamics; Humans; Hypoxia; Infant, Newborn; Oxygen Consumption; Persistent Fetal Circulation Syndrome; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2

To determine the role of eicosanoids in hypoxic pulmonary vasoconstriction, we studied 42 isolated, blood-perfused lamb lungs during normoxia and hypoxia. We used the lung micropuncture technique to measure microvascular pressures in 20- to 80-micron diameter arterioles and venules and estimated segmental vascular resistance. In separate experiments, lungs were untreated or treated with either indomethacin (a cyclooxygenase inhibitor), Dazmegrel (a thromboxane synthetase inhibitor), SQ 29548 (a thromboxane receptor blocker), FPL 57231 (a leukotriene receptor blocker), or U 60257 (a 5'lipoxygenase inhibitor). In control untreated lungs both pulmonary arteries and veins constricted during hypoxia. Addition of indomethacin, Dazmegrel, or SQ 29548 to the perfusate resulted in abolition of venous constriction during hypoxia but enhancement of arterial constriction. FPL 57231 or U 60257 resulted in complete abolition of the pulmonary hypoxic vasoconstrictor response. Our results indicate that during hypoxia, leukotrienes mediate arterial and venous constriction with thromboxane A2 being necessary for venous constriction. We conclude that the interaction between 5'lipoxygenase and cyclooxygenase products of arachidonic acid results in the characteristic pulmonary hypoxic vasoconstrictor response in isolated, perfused lamb lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Chromones; Epoprostenol; Hypoxia; Imidazoles; In Vitro Techniques; Indomethacin; Lipoxygenase; Lung; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Circulation; Receptors, Leukotriene; Receptors, Prostaglandin; Sheep; SRS-A; Thromboxane B2; Thromboxanes; Vasoconstriction

This study is to determine histamine, serotonin, TXA2 and PGI2 to be the cause of Hypoxic Pulmonary Vasoconstriction (HPV) at the same time of one lung ventilation and thoracotomy. Five patients who were to undergo upper-lobe resection of the right lung, were included in this study. All patients underwent same premedication and anesthetic method. Endotracheal intubation was done with a Univent tracheal tube. Gas analysis and determinations of the substances were done at six times in total. Respiratory Index (RI) began to increase immediately after the start of one lung ventilation. Post-thoracotomy RI further increased. After closing of the thorax, RI returned to the control values. Serotonin and histamine showed no change in any case throughout the experiment. TXB2 began to increase along with the start of one lung ventilation. The 15-min value was 167.2 +/- 85.8 pg/ml and 30-min value was 345.6 +/- 261.2 pg/ml, showing significant increase. The values of 6-keto PGF1 alpha were 22.6 +/- 2.9 pg/ml (15-min value), 89.6 +/- 52.3 pg/ml (30-min value), 290.8 +/- 120.1 pg/ml (post opening value) and 84.4 +/- 21.3 pg/ml (post-closing value). In our study, we concluded that neither serotonin nor histamine was the direct factor of HPV. TXA2 was the direct chemical mediator of HPV and PGI2 showed a negative feedback to the pulmonary vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthetics; Epoprostenol; Histamine; Humans; Hypoxia; Lung; Pulmonary Circulation; Respiration; Serotonin; Thoracic Surgery; Thromboxane A2; Thromboxane B2; Time Factors; Vasoconstriction

The influence of hypoxia on the spontaneous platelet aggregation (SPA) and thromboxane formation was studied. The analysis of aggregation curve was carried out according to Breddin. The hypoxia enhanced the aggregability from Q2norm = 2.46 +/- 0.40 (normoxia) to Q2hyp = 4.39 +/- 0.39 (hypoxia), n = 52, p less than 0.001. 10 samples of those showed no SPA under equilibration with air but the hypoxic stimulus provoked SPA (Q2norm = 0, Q2hyp = 1.19 +/- 60, n = 10, p less than 0.001). When the results were arranged according to the degree of the stimulation of SPA, two groups could be separated with low and high response to hypoxia. The hypoxia caused also an augmentation of the TXB2 level in comparison to normoxia. The stronger enhancement of the TXB2 formation during the incubation under hypoxic conditions was independent of the fact whether SPA took place or not. The present study suggests that hypoxic conditions alone may be a reason for a stimulated TXA2 formation of the platelets and that the enhanced TXA2 formation caused by hypoxia is possibly inducing or reinforcing the SPA.

Topics: Adult; Aged; Blood Platelets; Humans; Hydrogen-Ion Concentration; Hypoxia; Middle Aged; Oxygen; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Vascular Diseases

Although the mechanism underlying hypoxic pulmonary vasoconstriction remains undefined, various reports have suggested that mast cells and cell-derived mediators may be important in the production of this phenomenon. We investigated the effect of reducing oxygen tension on the release from human lung fragments of the mast cell-derived mediators histamine, prostaglandin (PG) D2 and peptide leukotrienes, as well as the release of the largely non-mast cell-derived mediators PGE2, PGF2 alpha, prostacyclin metabolite (6-keto-PGF1 alpha) and the thromboxane A2 metabolite (thromboxane B2). The effect of reducing oxygen tension on both basal mediator release and release triggered by goat antihuman immunoglobulin E was studied. Reducing pO2 of buffer in which lung fragments were placed from 161 to 54 mm Hg resulted in no spontaneous release of histamine, PGD2 or peptide leukotrienes. However, hypoxia had a marked effect on mediator release triggered by goat antihuman immunoglobulin E. Although net histamine release was relatively unaffected (control 13.9 +/- 2.7%, hypoxic 12.7 +/- 2.1%), hypoxic treatment resulted in an 89% inhibition of PGD2 release (control 47.7 +/- 17.4 ng/g of lung, hypoxic 5.26 +/- 1.91 ng/g of lung) and an 81% inhibition of peptide leukotriene release (control 22.5 +/- 7.6 ng/g of lung, hypoxic 4.37 +/- 2.4 ng/g of lung). Similar inhibition was seen for non-mast cell-derived mediators, including PGF2 alpha, prostacyclin metabolite and thromboxane B2, and probably for PGE2. We conclude that hypoxic treatment of human lung fragments in vitro results in no spontaneous release of preformed or newly formed mediators but that it markedly alters mediator release after goat antihuman immunoglobulin E triggering.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Histamine Release; Humans; Hypoxia; Immunoglobulin E; Leukotriene E4; Lung; Mast Cells; Oxygen; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; SRS-A; Thromboxane A2; Thromboxane B2

Exposure of cultured bovine pulmonary artery endothelial cells to varying levels of hypoxia (10% or 0% O2) for 4 hours resulted in a significant dose-dependent inhibition in endothelial prostacyclin synthesis (51% and 98%, at the 10% and 0% O2 levels respectively, p less than 0.05, compared to 21% O2 exposure values). Release of 3H-arachidonic acid from cellular pools was not altered by hypoxia. Some of the cells were incubated with arachidonic acid (20 microM for 5 min) or PGH2 (4 microM for 2 min) immediately after exposure. Endothelium exposed to 0% O2, but not to 10% O2, produced significantly less prostacyclin after addition of either arachidonic acid (25 +/- 5% of 21% O2 exposure values, n = 6, p less than 0.01) or PGH2 (31 +/- 3% of 21% O2 exposure values, n = 6, p less than 0.05). These results suggest that hypoxia inhibits cyclooxygenase at the 10% O2 level and both cyclooxygenase and prostacyclin synthetase enzymes at the 0% O2 exposure levels. Exposure of aortic endothelial cells resulted in a 44% inhibition of prostacyclin at the 0% exposure level. No significant alteration in prostacyclin production was found in pulmonary vascular smooth muscle cells exposed to hypoxia. These data suggest that the increased prostacyclin production reported in lungs exposed to hypoxia is not due to a direct effect of hypoxia on the main prostacyclin producing cells of the pulmonary circulation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Cattle; Cells, Cultured; Endothelium; Epoprostenol; Hypoxia; Muscle, Smooth; Oxygen; Pulmonary Artery; Thromboxane B2

Arachidonic acid is transiently accumulated in the brain as a result of a variety of pathological conditions. The synthesis and release of some of its metabolites, namely, prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) from cortical slices of mice were studied following exposure to 6 min of hypoxia (7% O2), 45 s of anoxia, and 5 min-4 h of reoxygenation following anoxia. Hypoxia induced a slight increase in the rate of TXB2 release and a slight decrease in the rate of PGE2 release, whereas 6-keto-PGF1 alpha was unaffected. Anoxia (45 s) followed by reoxygenation induced a transient increase in the release of PGE2 and of 6-keto-PGF1 alpha with a return to the normal rate at 30 min and 2 h of recovery, respectively. However, the rate of TXB2 synthesis and release reached its peak (twofold increase) after 1 h and remained significantly higher than the control rate even after 4 h of normal air breathing. Our results demonstrate that hypoxia and anoxia, even of short duration, selectively trigger the activity of thromboxane synthetase and that this elevated rate of synthesis and release persists long after normal oxygen supply is restored. We suggest that enhanced thromboxane synthesis, with normal prostacyclin levels, might have a role in the pathophysiology of ischemic cell damage.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebral Cortex; Dinoprostone; Hypoxia; Male; Mice; Prostaglandins; Prostaglandins E; Thromboxane B2

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aeromonas; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Cardiac Output; Epoprostenol; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Hypoxia; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Sepsis; Shock, Septic; Swine; Thromboxane A2; Thromboxane B2

Diethylcarbamazine (DEC) is an inhibitor of lipoxygenase, with protective effects in several experimental models of anaphylaxis and lung dysfunction. The hypothesis of this study was that DEC would alter the pulmonary response to endotoxin infusion, especially the prolonged pulmonary hypertension, leukopenia, hypoxemia, and high flow of protein-rich lung lymph. We prepared sheep for chronic measurements of hemodynamics and collection of lung lymph. In paired studies we gave six sheep endotoxin (0.5 micrograms/kg iv) either with or without DEC. DEC was given (80-100 mg/kg iv) over 30 min followed by a continuous infusion at 1 mg X kg-1 X min-1. Endotoxin was given after the loading infusion of DEC, and variables were monitored for 4 h. The response to endotoxin was characterized by pulmonary hypertension, leukopenia, hypoxemia, and elevations of thromboxane B2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha). Lymph flow and protein content reflected hemodynamic and permeability changes in the pulmonary circulation. DEC did not significantly modify the response to endotoxin by any measured variable, including pulmonary arterial and left atrial pressures, cardiac output, lymph flow and protein content, alveolar-to-arterial PO2 difference, blood leukocyte count, and lymph thromboxane B2 and 6-keto-PGF1 alpha. We could not find evidence of release of leukotriene C4/D4 by radioimmunoassay in lung lymph after endotoxin infusion with or without DEC treatment. We conclude that lipoxygenase products of arachidonic acid may not be a major component of the pulmonary vascular response to endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Diethylcarbamazine; Endotoxins; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Leukopenia; Lung; Lymph; Pulmonary Circulation; Sheep; SRS-A; Thromboxane B2

Infusion of plasma containing zymosan-activated complement into sheep produces leukopenia, pulmonary leukostasis, pulmonary hypertension, hypoxia and increased plasma levels of thromboxane. We investigated the effects of the calcium channel blocking agent verapamil in this system using conscious sheep. Verapamil in 5 mg and 10 mg doses was administered by intravenous infusion prior to an infusion of autologous plasma containing zymosan-activated complement. Pretreatment with verapamil inhibited thromboxane synthesis, the rise in pulmonary artery pressure and the hypoxia without affecting the transient leukopenia. These effects are similar to those previously demonstrated with nonsteroidal antinflammatory drugs, suggesting that verapamil is acting at one or more early steps of the arachidonic acid cascade in addition to its influence on the calcium-sensitive protein interactions involved in smooth muscle function.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Complement Activation; Female; Hypertension, Pulmonary; Hypoxia; Neutropenia; Sheep; Thromboxane B2; Verapamil; Zymosan

Acid aspiration may recruit a generalized inflammatory reaction that can potentiate the local injury. After surgical isolation of bronchi in a group of 15 dogs, 1 milliliter per kilogram of 0.37 normal hydrochloric acid was instilled into either side. After five minutes, platelet and white blood cell counts fell to 10,000 and 1,000 per cubic millimeter (p less than 0.05). Platelet aggregates were noted in blood smears. 111Indium-platelet activity doubled over both the aspirated and nonaspirated lung (p less than 0.05). Physiologic dead space rose from 18 to 67 per cent and to 46 per cent in the aspirated and nonaspirated lung (p less than 0.05). Physiologic shunt increased from 12 to 47 per cent and to 43 per cent (p less than 0.05) on the two sides. Plasma thromboxane B2 levels at 30 minutes rose from 0.28 to 0.93 nanograms per milliliter (p less than 0.05). Edema fluid from the aspirated lung had thromboxane B2 values of 2.87 nanograms per milliliter, indicating pulmonary synthesis. Within five minutes of aspiration, systemic effects were prominent; mean arterial pressure fell from 114 to 46 milliliters of mercury (p less than 0.05), and the cardiac index fell 24 per cent from 106 to 81 milliliters per kilogram per minute (p less than 0.05) along with an 18 per cent decrease in contractility of a rat papillary muscle bathed in plasma from the aspirated dog. Mean pulmonary arterial pressure rose from 12 to 18 millimeters of mercury (p less than 0.05). Despite fluid infusion at 36 milliliters per kilogram per hour to keep wedge pressure constant at 5.5 millimeters of mercury, and sampling of one-third the blood volume, hemoglobin concentration rose 0.9 grams per cent (p less than 0.05) indicating increased microvascular permeability. At autopsy, the aspirated and nonaspirated lung were indistinguishable with congestion, interstitial hemorrhage, and white blood cell infiltrates. Systemic organs showed vascular congestion and edema. These data demonstrate that local aspiration leads to generalized inflammatory sequelae with cardiopulmonary failure.

Topics: Animals; Blood Gas Analysis; Dogs; Female; Hemodynamics; Hydrochloric Acid; Hypoxia; Leukocyte Count; Lung; Lung Volume Measurements; Male; Platelet Count; Pneumonia, Aspiration; Respiratory Function Tests; Thromboxane B2

In dogs with acute lobar atelectasis, meclofenamate administration decreases shunt fraction uniformly and moderately without abolishing the wide variation of strength of hypoxic vasoconstriction and resultant variability of shunt fraction (J. Appl. Physiol. 54: 284-289, 1983). To further assess the role of prostanoids, we measured prostanoid metabolites as well as shunt fraction and pressor response to alveolar hypoxia. In six intact anesthetized dogs with acute left lower lobe atelectasis, shunt fraction during normoxia was measured with SF6. Levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 in arterial, mixed venous, and left lower lobe venous blood were measured with the double antibody radioimmunoassay technique. Ten percent O2 was administered to assess pressor response. Twenty-one percent O2 was restarted, meclofenamate was administered, and measurements were repeated 30 min later. Atelectasis did not elevate levels of prostanoid metabolites. 6-Keto-PGF1 alpha averaged 88 +/- 65 pg/ml prior to atelectasis and 81 +/- 73 pg/ml after atelectasis (F = 0.7, P = NS). Likewise, thromboxane B2 values were normal. No transpulmonary concentration differences were found. 6-Keto-PGF1 alpha did not correlate with shunt values, which ranged from 14 to 35% (mean 21%). Meclofenamate effectively blocked cyclooxygenase, as demonstrated by decreases in prostanoid metabolite levels. It seems likely that in dogs with acute atelectasis prostacyclin localized in the pulmonary vasculature decreases strength of hypoxic vasoconstriction modestly and uniformly without raising blood levels of prostacyclin metabolite.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Hemodynamics; Hypoxia; Meclofenamic Acid; Prostaglandins; Pulmonary Atelectasis; Thromboxane B2; Vasoconstriction

Pretreatment with estradiol (20 mg IM) attenuated vasoreactivity to decreases in inspired PIO2, lowered baseline resistance measured under conditions of maximal vasodilation (PIO2 = 0 mm Hg), and appeared to increase prostaglandin release in isolated, blood-perfused lungs of juvenile female sheep. Indomethacin (40 micrograms/ml) inhibited prostaglandin release and restored hypoxic vasoreactivity in estrogen-treated lungs, but did not alter the estrogen-induced decrease in baseline resistance. These results suggest that estradiol enhanced the production of prostaglandins which secondarily attenuated hypoxic vasoreactivity. The estradiol-induced decrease in baseline resistance, however, must have been mediated by some other mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Estradiol; Female; Hypoxia; Lung Diseases; Muscle, Smooth, Vascular; Oxygen; Respiration; Sheep; Thromboxane B2; Vasoconstriction

In order to investigate the possibility that high-frequency oscillatory ventilation (HFO) might preferentially stimulate intrapulmonary prostacyclin (PGI2) synthesis thereby decreasing pulmonary vascular smooth muscle tone, we determined pulmonary prostacyclin and thromboxane production in neonatal piglets ventilated by conventional means and by HFO (8 Hz). There was no detectable release of prostacyclin or thromboxane into blood passing through the lungs (i.e., pulmonary arterial concentrations were greater than aortic concentrations) during ventilation by conventional means or during HFO. Furthermore, there were no differences between the two modes of ventilation in cardiac output, systemic or pulmonary vascular resistance, or pulmonary vascular response to hypoxia/hypercapnia. We conclude that HFO does not stimulate pulmonary prostacyclin production and does not affect pulmonary vascular resistance or the pulmonary vasoconstriction associated with alveolar hypoxia/hypercapnia when compared to conventional ventilation in anesthetized newborn piglets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Epoprostenol; Hypercapnia; Hypoxia; Lung; Pulmonary Ventilation; Respiration; Respiration, Artificial; Swine; Thromboxane A2; Thromboxane B2; Thromboxanes

Our purpose was to determine whether peripheral soft tissues produce and release prostanoids in response to local sepsis, and whether this mediator release can produce pulmonary dysfunction. Escherichia coli endotoxin (2 micrograms/kg in 100 mL of saline) was injected below the hide of the flank in seven unanesthetized sheep. In three additional sheep, ibuprofen (12.5 mg/kg of body weight) was injected with the endotoxin. Thromboxane B2 and 6-keto-PGF1 alpha (prostacyclin) levels were measured in tissue lymph draining the flank, lung lymph, pulmonary artery (Ppa), and aortic plasma. One hour after endotoxin administration, mean PaO2 decreased from 90 to 74 mm Hg and Ppa increased from 22 to 35 mm Hg. Lung lymph flow (QL) increased only 50% with QL being protein poor. No increase in lung or peripheral soft-tissue vascular permeability was noted. Tissue lymph (TxB2) increased from 220 +/- 114 to greater than 10,000 pg/mL with levels in Ppa plasma increasing from 300 +/- 128 to 595 +/- 124 pg/mL and aortic plasma from 270 +/- 141 to 410 +/- 104 pg/mL. Lung lymph TxB2 paralleled aortic values. Peak levels of 6-keto-PGF1 alpha in systemic lymph exceeded 2,000 pg/mL while levels in lung lymph remained relatively constant. The pulmonary injury and the increase in TxB2 was prevented by ibuprofen. We conclude that the response of soft tissue to local endotoxin is to release thromboxane in quantities sufficient to raise plasma levels and to produce hypoxia and pulmonary hypertension. The lung dysfunction is not produced by an increase in lung water or vascular permeability.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Hypertension, Pulmonary; Hypoxia; Ibuprofen; Lung; Lung Diseases; Lymph; Lymphatic System; Muscles; Sheep; Thromboxane B2

Hypoxemia during hemodialysis may result from several differing processes. We initially studied patients undergoing standard acetate hemodialysis. At 15 minutes of dialysis, leukopenia (primarily neutropenia), a decline of platelet count, and hypoxemia occurred, but without a significant change in mean minute ventilation. Complement activation (V/A ratios of C5a greater than 1.0) persisted throughout dialysis. Leukocyte count returned to baseline by one hour. To separate the effects of solute and/or gas fluxes from those of blood-membrane interaction we studied changes in Po2, WBC, C5a, TxB2, and PGI2 during a period of blood membrane interaction without dialysis, and during subsequent acetate dialysis. Patients were studied with both polyacrylonitrile (PAN) and cuprophan membranes containing different priming solutions during membrane contact alone. Despite leukopenia and complement activation, hypoxemia failed to occur during membrane contact alone. At 15 minutes of subsequent acetate dialysis, significant hypoxemia occurred with both membranes. However, the degree of hypoxemia was twice as great with a cuprophan membrane primed with acetate (18.6 +/- 3.3 mm Hg) compared with air or bicarbonate (9.1 +/- 1.4 and 7.0 +/- 2.0 mm Hg, respectively), or compared with PAN (8 +/- 2.8 mm Hg). Changes in thromboxane B2, PGI2, and C5a did not correlate with changes in Po2. We conclude that there are two major components to dialysis related hypoxemia. One is membrane independent, and may relate to the metabolic effects of acetate or to dialyzer CO2 loss. The remaining portion is membrane dependent, occurring with cuprophan, but not with PAN, and is conditioned by an acetate dependent interaction between blood and membrane.

Topics: Adolescent; Adult; Carbon Dioxide; Epoprostenol; Female; Humans; Hypoxia; Leukocyte Count; Male; Membranes, Artificial; Middle Aged; Oxygen; Platelet Count; Renal Dialysis; Respiration; Thromboxane B2; Time Factors

We studied the effects of a burn injury on the response of the lung to endotoxin. Seventeen unanesthetized sheep with lung lymph fistulas were studied. Eight were given Escherichia coli endotoxin (1.5 micrograms/kg) alone and nine were given the same dose 72 hours after a 25% total body surface burn injury. At this time after burn, all physiologic parameters were at baseline levels. A characteristic two-phase lung injury was seen after administration of endotoxin with an initial hypertension phase, characterized by pulmonary artery hypertension, and a second or permeability phase, characterized by an increase in protein-rich lymph flow. all eight animals that underwent only endotoxin administration survived, whereas four of the nine burned animals died during the permeability phase in pulmonary edema. Major physiologic differences between the groups were noted during the permeability phase, including a more severe hypoxia, pulmonary hypertension, and increased postburn lymph flow. Major biochemical changes included significant increases in lymph thromboxane, thromboxane B2, and beta-glucuronidase activity in the burn group. We conclude that the lung is more sensitive to endotoxin after burn, probably as a result of an increased release of products of arachidonic acid metabolism and products of leukocyte activation caused by the body burn.

Topics: Animals; Burns; Endotoxins; Escherichia coli Infections; Fistula; Glucuronidase; Hypertension, Pulmonary; Hypoxia; Lung Diseases; Lymph; Sheep; Thromboxane B2; Thromboxanes

We have investigated the possibility that pulmonary biosynthesis of prostacyclin and thromboxane A2 (TXA2) may be affected by variations in PO2. Fresh lung homogenated from 8 dogs were incubated for 1 hour at 37 degrees C in Krebs-Ringer solution, at high (492 mmHg) or low (53 mmHg) PO2. After incubation, the stable metabolites of prostacyclin (6-keto-PGF1) and of TXA2 (TXB2) were measured by radioimmunoassay. The basal ("pre-incubation") levels of these metabolites, measured in tubes in which biosynthesis was arrested by the addition of indomethacin (10 g/ml), were 0.76 +/- 0.15 and 0.76 +/- 0.11 ng/mg wet wt. for 6-keto-PGF1 alpha, in high and low PO2, respectively, and 0.97 +/- 0.09 and 0.82 +/- 0.15 x 10(-1) ng/mg wet wt. for TXB2, in high and low PO2 respectively. Synthesis during incubation in other tubes was estimated by subtracting basal values from those measured at the end of incubation. More 6-keto-PGF1 alpha was formed in homogenates exposed to low PO2 (3.01 +/- 0.45) than in those exposed kept at high PO2 (1.89 +/- 0.37, p less than 0.001), but equal amounts of TXB2 were bound under both conditions. These results suggest that hypoxia may stimulate pulmonary prostacyclin synthesis; a pulmonary vasodilator, prostacyclin may help modulate hypoxic vasoconstriction in the lung.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Epoprostenol; Hypoxia; In Vitro Techniques; Indomethacin; Lung; Prostaglandins; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Histamine; Hypoxia; Pulmonary Embolism; Serotonin; Thromboxane B2; Thromboxanes

Topics: Animals; Brain; Brain Ischemia; Cerebral Cortex; Convulsants; Fatty Acids, Essential; Gerbillinae; Hypoxia; Probenecid; Prostaglandins; Prostaglandins F; Rats; Seizures; Thromboxane B2

Topics: Animals; Arachidonic Acids; Biological Transport; Epoprostenol; Humans; Hydroxyprostaglandin Dehydrogenases; Hypoxia; Linolenic Acids; Lung; Lung Diseases; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2; Thromboxane B2; Vasomotor System