thromboxane-b2 and Hypertension--Pulmonary

Interleukin (IL)-2 therapy leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of the chemoattractant, immunomodulator, and permeability-promoting agent leukotriene (LT) B4 in this setting. Sheep with chronic lung lymph fistulae were given IL-2, 10(5) U/kg as an IV bolus (n = 6). Within 2 hours this led to a significant increase in LTB4 levels in both plasma and lung lymph. The mean pulmonary artery pressure (MPAP) rose while the pulmonary artery wedge pressure was unchanged. Arterial oxygen tension (PaO2) fell. Lung lymph flow (QL) was tripled (P less than 0.05) at 3 hours, coinciding with an increase in the lymph/plasma (L/P) protein ratio (P less than 0.05) resulting in an increase in the lymph protein clearance (P less than 0.05), data documenting increased microvascular permeability to protein. Mild leukopenia and thrombocytopenia (P less than 0.05) occurred. Body temperature rose and shaking chills were common. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC; n = 6) reduced baseline plasma LTB4 levels and prevented the IL-2-induced increases in LTB4 in plasma and lung lymph (P less than 0.05). In contrast to IL-2 treatment alone, DEC blunted the increase in MPAP and prevented the rises in QL (P less than 0.05), L/P protein ratio (P less than 0.05), and lymph protein clearance (P less than 0.05). DEC also prevented the IL-2-induced leukopenia, the fall in platelet count, and the rise in body temperature (P less than 0.05, respectively). Infusion of IL-2 excipient control (n = 5) did not affect plasma or lymph LTB4 levels but there were mild increases in MPAP (P less than 0.05). The QL also rose but this occurred while the L/P protein ratio fell (P less than 0.05). Body temperature rose moderately. The PaO2, leukocyte, and platelet counts were unaffected. These data indicate that IL-2 administration leads to pulmonary dysfunction manifest by pulmonary hypertension and increased vascular permeability, events associated with LTB4 synthesis and prevented by DEC. Leukotriene B4 appears therefore to mediate the IL-2-induced lung injury.

Topics: Animals; Blood Pressure; Body Temperature; Capillary Permeability; Diethylcarbamazine; Female; Hypertension, Pulmonary; Interleukin-2; Leukocyte Count; Leukotriene B4; Lung; Lymph; Oxygen; Platelet Count; Pulmonary Artery; Thromboxane B2

To study the effect of tetramethylpyrazine (TMP) on the vascular endothelial cell (VEC) related humoral factors, including endothelin (ET), factor VIII related antigen (i.e. von Willebrand factor, vWF) and thromboxane A2(TXA2) in patients of congenital heart disease with pulmonary hypertension (CHD-PH) during cardiopulmonary bypass (CPB), and explore the clinical physiopathologic significance of them.. Thirty non-cyanotic patients of CHD-PH were randomly divided into the control group and the treated group. TMP was given to the treated group by intravenous dripping 3 mg/kg after anesthesia induction and adding 1 mg/kg in oxygenator during CPB. Blood samples were collected from radial artery at the time points of after anesthesia induction, 15 min after beginning CPB, 5 min after opening aorta, 20 min, 6 hrs and 24 hrs after stopping CPB, to determine the plasma contents of ET and vWF, as well as TXB2, the stable metabolite of TXA2. The pulmonary vascular reactivity 6 hrs (6h-PVR) after CPB and the mechanical ventilatory support time (VST) after operation were calculated.. Levels of ET, vWF and TXB2 increased obviously during CPB, but the degree of increasing in the treated group was lower than that in the control group (P < 0.05), and the 6h-PVR and VST in the former were also lower than those in the latter respectively.. TMP could obviously reduce the production of ET, vWF and TXB2 during CPB and relieve the pulmonary vascular reactivity after operation, indicating that TMP could reduce the injury of CPB on VEC, and is benefit to enhance the efficacy of treatment.

Topics: Adolescent; Adult; Calcium Channel Blockers; Cardiopulmonary Bypass; Child; Child, Preschool; Endothelins; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pyrazines; Thromboxane B2; von Willebrand Factor

To study protective effects of tetramethylpyrazine (TMP) on the imbalance of TXA2/PGI2 during cardiopulmomary bypass (CPB) in congenital heart disease (CHD) with pulmonary hypertension (PH) patients.. Thirty patients suffered from non-cyanotic CHD-PH were randomly divided into control group (n = 15) and treatment group (n = 15). 3 mg/kg of TMP was dripped intravenously after anesthesia and 1 mg/kg of TMP was infused into oxygenator after CPB individually. Blood samples were collected and TXA2 as well as PGI2 were measured after anesthesia induction, 15 min during CPB, 5 min after release of the aortic cross-clamp, and 20 min, 6 hrs and 24 hrs after CPB.. There was significant difference between treatment group and control group except before operation and 24 hrs after CPB.. The imbalance of TXA2 and PGI2 in patients with CHD-PH during CPB could correct by TMP.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Cardiopulmonary Bypass; Child; Child, Preschool; Female; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Male; Pyrazines; Thromboxane B2; Vasodilator Agents

Prostacyclin (PGI2) is a bioactive substance produced by vascular endothelial cells, which exerts powerful vasodilative and anti-platelet actions. Patients with pulmonary hypertension have an imbalance between vasodilative PGI2 and vasoconstrictive thromboxane B2 (TXB2). Treatment with vasodilative agents is essential for such patients. Continuous intravenous infusion of PGI2 is an effective treatment of primary pulmonary hypertension in terms of exercise capacity and survival rate. We tested a new stable PGI2 analogue, beraprost sodium (Procyclin, Dornar) suitable for oral administration, in patients with primary and secondary pulmonary hypertension. A short-term study of cardiac catheterization in four patients with primary pulmonary hypertension showed a 15 +/- 12% reduction in mean pulmonary artery pressure in three of the four patients, and a 24 +/- 22% decrease in pulmonary vascular resistance in all four patients. Cardiac index increased by 27 +/- 14% in three of the four patients. Among three patients with secondary pulmonary hypertension, there was a 7% reduction in pulmonary artery pressure in one patient, and a 24 +/- 14% decrease in pulmonary vascular resistance in all three patients. In a long-term study (23 +/- 11 months), NYHA functional class improved from 3.0 +/- 0.7 to 2.4 +/- 0.5 in two of the five patients with primary pulmonary hypertension. Although the radiographic cardiothoracic ratio was not significantly improved, cardiac index increased by 78 +/- 60% in four of the five patients. Only two patients, one with primary and one with secondary pulmonary hypertension, died during the long-term follow-up period. Plasma TXB2/6-keto prostaglandin F1 alpha ratio decreased from 8.1 +/- 8.7 to 1.5 +/- 0.4. The optimal dose remains uncertain, but the initial dosage of 40-60 micrograms/day given in three to four doses for adult patients is considered to be acceptable. Side effects such as flushing face, headache, vomiting, and nausea were mild and resolved when the dose was reduced. Oral PGI2, beraprost, appears to be an effective and possibly adequate substitute for intravenous vasodilators in pulmonary hypertension for both short- and long-term management.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infant; Male; Middle Aged; Platelet Aggregation Inhibitors; Pulmonary Circulation; Pulmonary Wedge Pressure; Thromboxane B2; Time Factors; Vascular Resistance; Vasodilator Agents

The effect of the rate of intravenous infusion of protamine on the acute hemodynamic and pulmonary effects of heparin neutralization was investigated in six adult sheep surgically instrumented for chronic studies. Bovine lung heparin at a dose of 200 IU/kg was injected intravenously over 10 sec, 5 min before the start of protamine administration. On separate experimental days, each sheep received protamine at the same dose of 2 mg/kg, but it was infused over four different time periods: 3 s, 30 s, 300 s, or 30 min. At an additional session, protamine was administered over 3 s without prior heparinization to assess the effect of protamine alone. The sequence of the sessions was randomized and performed blindly. Injecting protamine in unheparinized sheep produced no change in any of the measured variables. In contrast, when protamine was injected over 3 s in heparinized sheep, it induced a transient and significant (P less than 0.001) pulmonary hypertension (from 17.2 +/- 1.5 to 45.6 +/- 2.4 mmHg at 1 min) with an increased pulmonary (five-fold) and systemic (2.5-fold) vascular resistance; a decrease of cardiac output (from 3.85 +/- 0.43 to 1.93 +/- 0.29 l/min) without change in left atrial pressure (from 5.3 +/- 1.3 to 6.0 +/- 1.7 mmHg; P = NS); a significant (P less than 0.001) increase of plasma thromboxane B2 (TxB2) concentrations (from 349 +/- 131 to 974 +/- 218 pg/ml); leukopenia (76 +/- 4% of baseline white blood cell counts); and hypoxemia (PaO2 decreased from 81 +/- 3 to 63 +/- 4 mmHg at 2 min). Administering the same amount of protamine after heparin at a slower infusion rate significantly attenuated and delayed all components of the adverse response to protamine. This attenuation occurred in an infusion rate-dependent fashion, so that when protamine was infused over 30 min, no significant changes in any of the measured variables were noted. The time course of plasma heparin concentrations following protamine indicated that chemical heparin was completely neutralized over the time period of protamine infusion. These results demonstrate that the rate of generation of heparin-protamine complexes (as detected by changes of plasma concentrations of chemical heparin) during iv protamine infusion started 5 min after heparin administration is a factor involved in the generation of sufficient mediators required to initiate a characteristic physiologic response in sheep, including systemic and pulmonary vasoconstriction, TxB2 generation, and leukopenia. In

Topics: Animals; Double-Blind Method; Hemodynamics; Heparin Antagonists; Hypertension, Pulmonary; Infusions, Intravenous; Protamines; Randomized Controlled Trials as Topic; Sheep; Stimulation, Chemical; Thromboxane B2; Time Factors

Transjugular intrahepatic portosystemic shunt (TIPSS) cause haemodynamic changes in patients with cirrhosis, yet little is known about long-term cardiopulmonary outcomes.. To evaluate the long-term cardiopulmonary outcome after TIPSS.. We evaluated cardiopulmonary parameters including echocardiography during long-term follow-up after TIPSS. Results at 1-5 years after TIPSS were compared to those of cirrhotic controls. Pulmonary hypertension (PH) diagnoses rates were included. Endothelin 1, thromboxane B2 and serotonin were measured.. We found significant differences 1-5 years after TIPSS compared to pre-implantation values: median left atrial diameter (LAD) increased from 37 mm [interquartile range (IQR): 33-43] to 40 mm (IQR: 37-47, P = 0.001), left ventricular end-diastolic diameter (LV-EDD) increased from 45 mm (range: 41-49) to 48 mm (IQR: 45-52, P < 0.001), pulmonary artery systolic pressure (PASP) increased from 25 mmHg (IQR: 22-33) to 30 mmHg (IQR: 25-36, P = 0.038). Comparing results 1-5 years post-implantation to the comparison cohort revealed significantly higher (P < 0.05) LAD, LV-EDD and PASP values in TIPSS patients. PH prevalence was higher in the shunt group (4.43%) compared to controls (0.91%, P = 0.150). Thromboxane B2 levels correlated with PASP in the TIPSS cohort (P = 0.033). There was no transhepatic gradient observed for the vasoactive substances analysed.. TIPSS placement is accompanied by long-term cardiovascular changes, including cardiac volume overload, and is associated with an increased rate of pulmonary hypertension. The need for regular cardiac follow-up after TIPSS requires further evaluation.

Topics: Adult; Cardiac Volume; Endothelin-1; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Portasystemic Shunt, Transjugular Intrahepatic; Serotonin; Thromboxane B2

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

Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.. We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration.. Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor.

Topics: Animals; Blood Pressure; Epoprostenol; Hepatocyte Growth Factor; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Pyridines; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase

Patients with Down syndrome (DS) and a left-to-right shunt often develop early severe pulmonary hypertension (PH) and pulmonary vascular obstructive disease (PVOD); the pathophysiological mechanisms underlying the development of these complications are yet to be determined. To investigate the mechanisms, we evaluated the biosynthesis of thromboxane (TX) A(2) and prostacyclin (PGI(2)) in four groups of infants, cross-classified as shown below, by measuring the urinary excretion levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha): DS infants with a left-to-right shunt and PH (D-PH, n = 18), DS infants without congenital heart defect (D-C, n = 8), non-DS infants with a left-to-right shunt and PH (ND-PH, n = 12), and non-DS infants without congenital heart defect (ND-C, n = 22). The urinary excretion ratios of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) in the D-PH, D-C, ND-PH, and ND-C groups were 7.69, 4.71, 2.10, and 2.27, respectively. The ratio of 11-dehydro-TXB(2) to 2,3-dinor-6-keto-PGF(1alpha) was higher in the presence of DS (P < 0.001), independently of the presence of PH (P = 0.297). The predominant biosynthesis of TXA(2) over PGI(2), leading to vasoconstriction, was observed in DS infants, irrespective of the presence/absence of PH. This imbalance in the biosynthesis of vasoactive eicosanoids may account for the rapid progression of PVOD in DS infants with a left-to-right shunt.

Topics: 6-Ketoprostaglandin F1 alpha; Child, Preschool; Cross-Sectional Studies; Down Syndrome; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung Diseases, Obstructive; Male; Prognosis; Pulmonary Heart Disease; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Alterations in pulmonary blood flow are often associated with the initiation and progression of pulmonary vascular disease. However, the cellular mechanisms involved in mediating flow effects in the pulmonary circulation remain unclear. Depending on the disease condition, flow may be extremely low or high. We therefore examined effects of pathologically low and high flow on endothelial production of factors capable of affecting pulmonary vascular tone and structure as well as on potential underlying mechanisms.. Flow effects on pulmonary endothelial release of NO, PGF(1a), ET-1 and TxB(2), on expression of total and phosphorylated eNOS as well as Akt, and on VEGF were examined. Additionally, in a coculture system, effects of flow-exposed endothelial cells on smooth muscle (SM) proliferation and contractile protein were studied.. Compared to physiological flow, pathologically high and low flow attenuated endothelial release of NO and PGF(1a), and enhanced release of ET-1. Physiological flow activated the Akt/eNOS pathway, while pathological flow depressed it. Pathologically high flow altered VE-cadherin expression. Pathologically high flow on the endothelium upregulated alpha-SM-actin and SM-MHC without affecting SM proliferation.. Physiological flow leads to production of mediators which favor vasodilation. Pathological flow alters the balance of mediator production which favors vasoconstriction.

Topics: Actins; Animals; Animals, Newborn; Antigens, CD; Cadherins; Cattle; Cell Proliferation; Cells, Cultured; Coculture Techniques; Endothelial Cells; Endothelial Growth Factors; Endothelin-1; Hypertension, Pulmonary; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Myosin Heavy Chains; Nitric Oxide; Nitric Oxide Synthase Type III; Phosphorylation; Prostaglandins F; Proto-Oncogene Proteins c-akt; Pulmonary Artery; Pulsatile Flow; Stress, Mechanical; Thromboxane B2; Vascular Endothelial Growth Factor A; Vasoconstrictor Agents; Vasodilator Agents

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

Pulmonary hypertension (PHT) has been reported to be high among end-stage renal disease (ESRD) patients. This study evaluated PHT in ESRD patients and the role of arteriovenous fistula (AVF), thromboxane B(2) (TXB(2)) and pro-BNP in this complication.. 45 ESRD patients on regular hemodialysis (HD) (group 1) and 31 ESRD patients on conservative treatment (group 2) underwent clinical and biochemical testing. Pulmonary artery pressure (PAP) was evaluated using Doppler echocardiography. Cardiac assessment by echocardiography and AVF flow measurement by Doppler ultrasound were done. Levels of TXB(2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in plasma were determined.. PHT was found in 44.4% in group 1 and in 32.3% in group 2. Comparing the two groups shows a significant difference with regard to PAP, proBNP, and TXB(2). Patients with PHT have a significantly higher AVF blood flow, proBNP, and TXB(2). In patients with PHT, 76.7% have left ventricular diastolic dysfunction (LVDD). PAP correlates with AVF flow, proBNP, and TXB(2).. Results show a high prevalence of PHT among patients with ESRD on chronic HD or on conservative treatment. PHT in such patients is related to AVF flow, TXB(2) and NT-proBNP level and LVDD. AVF flow is an important correctable cause of PHT.

Topics: Adult; Aged; Arteriovenous Fistula; Blood Pressure; Echocardiography, Doppler; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Radioimmunoassay; Thromboxane B2

Topics: Disease Progression; Electrocardiography; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Male; Middle Aged; Thromboxane A2; Thromboxane B2; Thromboxanes

The balance between prostacyclin and thromboxane plays an important role in the regulation of pulmonary vascular tone. Recently, we developed ONO-1301, a novel, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.. We investigated whether modulation of prostacyclin/thromboxane balance by ONO-1301 ameliorates monocrotaline-induced pulmonary hypertension in rats.. After subcutaneous injection of monocrotaline or vehicle, rats were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle twice per day for 3 wk.. There was significant development of pulmonary hypertension 3 wk after monocrotaline injection. Treatment with ONO-1301 significantly attenuated the increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in monocrotaline rats. Furthermore, ONO-1301 significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in monocrotaline rats. The half-life of plasma ONO-1301 concentration after a single subcutaneous administration was approximately 5.6 h. A single administration of ONO-1301 increased plasma cyclic adenosine 3', 5'-monophosphate level, which lasted at least up to 8 h. Treatment with ONO-1301 significantly decreased plasma 11-dehydro-thromboxane B2, a metabolite of thromboxane, in monocrotaline rats. Finally, Kaplan-Meier survival curves demonstrated that repeated administration of ONO-1301 improved survival rate in monocrotaline rats compared with vehicle administration (80 vs. 30% in 6-wk survival).. Subcutaneous administration of a novel prostacyclin agonist (ONO-1301) markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. The beneficial effects of ONO-1301 may occur through its long-lasting stimulation of cyclic adenosine 3', 5'-monophosphate and inhibition of thromboxane synthase.

Topics: Animals; Blood Pressure; Epoprostenol; Heart Rate; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Monocrotaline; Pyridines; Rats; Rats, Wistar; Thromboxane B2; Thromboxane-A Synthase

This study aimed to study the role of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. Similar results were obtained with inhaled NO (3 ppm). Plasma TXB2 levels were markedly elevated during the pulmonary hypertension, and this was abolished in indomethacin-treated dogs. Our study shows that interaction of heparin-protamine in anesthetized dogs lead to TXA2- and ET-1-mediated pulmonary hypertension. Drugs that interfere with the synthesis of these mediators as well as inhaled NO may be of beneficial value to control this disorder.

Topics: Administration, Inhalation; Animals; Dogs; Endothelin-1; Female; Heparin Antagonists; Hypertension, Pulmonary; Male; Nitric Oxide; Protamines; Thromboxane A2; 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

Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O(2) for 14 days, a model for human chronic neonatal lung injury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A(2) receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A(2) receptor contributed to O(2)-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A(2) receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O(2) or air exposure. L670596, but not DFU, prevented 60% O(2)-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O(2)-exposed animals. We conclude that TX A(2) receptor activation, though not by TX A(2), caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A(2) receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blotting, Western; Carbazoles; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprost; Endothelin-1; F2-Isoprostanes; Furans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Muscle, Smooth, Vascular; Oxygen; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rats; Receptors, Thromboxane; Thromboxane B2; Up-Regulation; Vasoconstrictor Agents

To investigate the mechanism of perioperative lung injury in patients of ventricular septal defect (VSD) with severe pulmonary hypertension.. The thromboxane B(2) (TXB(2)), 6-keto-prostagladin F(1 alpha) (6-keto-PGF(1 alpha)), malonyldiadehyde (MDA), interleukin-6 (IL-6), and IL-8, and blood pressure, pulmonary arterial pressure (PAP) and total pulmonary pressure (TPR) in thirty-one patients of VSD, 16 cases without pulmonary hypertension and 15 cases with severe pulmonary hypertension, were examined after anesthesia (AA), over extracorporeal circulation (OEC), and 1 hour (PEC1), 6 hours (PEC6), 24 hours (PEC24), 48 hours (PEC48), and 72 hours (PEC72) post extracorporeal circulation. The respiratory index (RI) and ratio of 6-keto-PGF(1alpha) and TXB(2) (P/T) were calculated. Before and after extracorporeal circulation, pulmonary tissues were taken to be examined by light microscopy and electron microscopy.. In the cases with severe pulmonary hypertension the P/T was 0.81 +/- 0.26 after anesthesia, then decreased 0.65 +/- 0.28 over extracorporeal circulation, and reached its lowest value (0.51 +/- 0.32) 1 hour post extracorporeal circulation. MDA was 2.4 micromol/L +/- 0.6 micromol/L after anesthesia, then increased, was 7.0 micromol/L +/- 1.7 micromol/L OEC, and reached its peak value (7.3 micromol/L +/- 0.9 micromol/L) PEC1. IL-6 was 0.27 ng/L +/- 0.12 ng/L after anesthesia, then increased, and reached its peak value (0.50 ng/L +/- 0.19 ng/L) PEC1. IL-8 was 7.5 ng/L +/- 1.5 ng/L after anesthesia, then increased, was 152 ng/L +/- 50 ng/L PEC1, and reached its peak (183 ng/L +/- 63 ng/L) PEC6. TXB(2) was 251 ng/L +/- 44 ng/L after anesthesia, then increased, and reached its peak (967 ng/L +/- 145 ng/L) at PEC1. The PAP was 72.1 +/- 18.8 mm Hg after anesthesia, 55 mm Hg +/- 15.3 mm Hg OPC, and 7.4 +/- 2.1 at PEC1, then decreased, and was 53 mm Hg +/- 15 mm Hg at PEC72. The total pulmonary resistance (TPR) was 10.6 +/- 2.9 mm Hg x min(-1) x L(-1) after anesthesia, then increased, and reached its peak (15.0 +/- 3.9 mm Hg x min(-1) x L(-1) at PEC6. Respiratory index (RI) was 0.88 +/- 0.23, then increased, and reached its peak (2.35 +/- 0.72) at PEC6. TXB(2) and RI were positively correlated with pulmonary vascular resistance (gamma = 0.283, P < 0.05; gamma = 0.403, P < 0.05). RI was positively correlated with MDA (gamma = 0.403, P < 0.05). Morphologic studies revealed discontinuities in the endothelial cell lining of pulmonary capillaries, infiltration of inflammatory cells, plugging of pulmonary capillaries with neutrophils, and intraalveolar hemorrhage.. During the perioperative period, the pulmonary damage, which leads to pulmonary hypertensive crisis, is more severe among the cases of VSD with severe pulmonary hypertension than among the case without pulmonary hypertension.

Topics: Adolescent; Blood Pressure; Child; Extracorporeal Circulation; Female; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Interleukin-6; Interleukin-8; Lung Diseases; Lung Injury; Male; Malondialdehyde; Postoperative Complications; Pulmonary Artery; Thromboxane B2; Time Factors

This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock.. Experimental.. Laboratory.. Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion.. Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups.. Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Antihypertensive Agents; Bacteremia; Epoprostenol; Gram-Negative Bacterial Infections; Hemodynamics; Hypertension, Pulmonary; Leukotriene B4; Lung Diseases; Matched-Pair Analysis; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; SRS-A; Swine; Thromboxane B2

A comparative analysis of the content of the soluble form of cell adhesion protein P-selectin in the blood plasma of patients with acute myocardial infarction (AMI), massive atherosclerosis (MA) and primary pulmonary hypertension (PPH), investigation of the relationship between plasma content of P-selectin and known markers of platelets and endothelial cells activation, preliminary assessment of the prognostic value of P-selectin determination.. This study included 16 patients with AMI, 20 patients with MA, 21 patients with PPH and 18 healthy donors. The follow-up was 1-5 years. End-points in the group of patients with AMI were recurrent acute coronary syndrome and coronary artery by-pass operation, in the group with MA--thrombotic complications (acute coronary syndrome, ischemic stroke) and in the group with PPH--death. P-selectin was measured by ELISA and platelet factor 4 (PF4), thromboxane B2 (TXB2), endothelin-I and stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by means of commercial ELISA kits.. Mean level of P-selectin in blood plasma of patients with AMI (1 day) (361 +/- 18 ng/ml), MA (410 +/- 31 ng/ml) and PPH (627 +/- 83 ng/ml) was increased in comparison with the group of healthy donors (269 +/- 12 ng/ml) (everywhere p < 0.001). In AMI, P-selectin was increased on day 1 only, on days 2, 3 and 10-14 of the disease the level of P-selectin was significantly lower than on day 1 and did not differ from the control level in the group of donors. In patients with MA a significant correlation was detected between plasma content of P-selectin and platelet activation marker PF4 (r = 0.606, P = 0.007) and in patients with PPH between the content of P-selectin and another platelet activation marker TXB2 (r = 0.622, p = 0.013). However, no correlation was found in PPH patients between the content of P-selectin and markers of endothelial activation and/or damage (endothelin-1 and 6-keto-PGF1 alpha). Difference in the concentration of P-selectin in patients with or without end-points during the follow-up period was detected in patients with AMI (353 +/- 14 ng/ml and 451 +/- 24 ng/ml, p = 0.009) and PPH (477 +/- 58 ng/ml and 927 +/- 184 ng/ml, p = 0.017) but not with MA (426 +/- 37 ng/ml and 361 +/- 24 ng/ml, p = 0.295).. The level of P-selectin in plasma was increased in patients with acute thrombosis (AMI, 1 day) as well as in patients without clinical signs of thrombosis but with a massive injury of the vasculature (MA and PPH). The increase of P-selectin was, presumably, caused by its secretion from activated platelets since its concentration in plasma correlated with platelet concentration but not endothelial activation markers. Preliminary data indicate that blood plasma soluble P-selectin may be considered as a potential prognostic marker in AMI and PPH.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; Biomarkers; Blood Coagulation; Blood Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Factor 4; Prognosis; Solubility; Thromboxane B2

The purpose of this study was to investigate whether the effect of milrinone on platelet aggregation was related to the selectivity of vasodilation vasculature in a swine model with PH.. To induce pulmonary hypertension, we injected two sets of acid-washed glass beads in 15 swine, which were divided into two groups (those receiving milrinone or not) and compared with each other.. The induction of pulmonary hypertension decreased the platelet count and increased the plasma levels of thromboxane B2 and 6-keto-prostaglandin F1alpha.. A locally high concentration of prostaglandin I2, at least in part, may produce selectivity of vasodilation in the pulmonary vasculature.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Biological Availability; Blood Gas Analysis; Hemodynamics; Hypertension, Pulmonary; Male; Milrinone; Platelet Aggregation; Platelet Aggregation Inhibitors; Structure-Activity Relationship; Swine; Thromboxane B2; Vasodilation

To examine whether a thromboxane receptor antagonist, NT-126, or a thromboxane synthase inhibitor, OKY-046, prevents circulatory changes caused by protamine reversal of heparin and to evaluate the significance of thromboxane generation in the phenomena.. Prospective, randomized, controlled, animal study.. A university research laboratory.. Twenty-four adult mongrel dogs.. According to the pretreatments, the animals were divided into 3 groups (n = 8 in each): (1) control (normal saline); (2) NT-126, 0.01 mg/kg; and (3) OKY-046, 1 mg/kg. Under general anesthesia, all animals were anticoagulated with intravenous heparin, 200 IU/kg, 5 minutes before the pretreatment. Five minutes after the pretreatment, protamine sulfate, 2 mg/kg, was administered intravenously over 10 seconds. Hemodynamic variables were recorded repeatedly until 60 minutes after the protamine. Plasma thromboxane B2 level was determined at baseline and 10 minutes after protamine injection.. The average values of mean arterial blood pressure and mean pulmonary artery pressure among the 3 groups in each period and values in each group over the study period were not significantly different. There was weak correlation between maximum percent increases in systolic pulmonary artery pressure or maximum percent decreases in systolic arterial blood pressure for 5 minutes after the protamine versus percent increases in plasma thromboxane B2 level.. Neither NT-126 nor OKY-046 appears to be effective in preventing protamine-induced circulatory changes in this dog model, suggesting that thromboxane generation alone is not responsible for the phenomena.

Topics: Animals; Anticoagulants; Blood Pressure; Bridged Bicyclo Compounds; Dogs; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Hemodynamics; Heparin; Heparin Antagonists; Hypertension, Pulmonary; Methacrylates; Protamines; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

We tested the effect of interferon-alpha on lung function to examine whether interferon-alpha causes some pathophysiological change in the lung. We prepared awake sheep with chronic lung lymph fistula, and measured the pulmonary hemodynamics, lung fluid balance and concentrations of prostanoid products. At 1 h after intravenous interferon-alpha administration (18 x 10(6) I.U.), pulmonary arterial pressure and pulmonary vascular resistance were significantly increased compared to the baseline values. The levels of thromboxane B2 in both plasma and lung lymph were increased concomitant with early elevation on pulmonary arterial pressure. In addition, OKY-046 [sodium-3[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid] (10 mg kg(-1)), a selective thromboxane synthase inhibitor, significantly prevented the interferon-alpha-induced pulmonary hypertension and thromboxane B2 production. While no evidence of increased pulmonary vascular leakage was observed. These findings suggest that a single infusion of interferon-alpha stimulates a thromboxane cascade and causes transient pulmonary hypertension. However, interferon-alpha itself or increased thromboxane A2 might not affect the pulmonary vascular permeability in sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Antiviral Agents; Body Temperature; Capillary Permeability; Enzyme Inhibitors; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Interferon-alpha; Lung; Methacrylates; Sheep; Thromboxane B2; Thromboxane-A Synthase

To evaluate the hemodynamic effects of inhaled nitric oxide (NO) during a venous air infusion (VAI) in dogs. We also addressed the question of whether NO therapy changes thromboxane (Tx) A(2) release and nitrate/nitrite production during a VAI.. Prospective trial.. University laboratory.. Anesthetized mongrel dogs received a VAI (0.2 ml x kg(-1)x min(-1)) after the measurement of baseline hemodynamics. Control dogs (n = 8) received no further treatment. After 30 min of VAI, NO 3 ppm inhalation was initiated (n = 7) for 30 min, followed by 30 min without NO inhalation, and then a final 30 min of NO 40 ppm treatment. Hemodynamic variables were registered and arterial and mixed venous blood samples were drawn for gas analysis and for the determinations of serum TxB(2) (by enzyme-linked immunosorbent assay) and nitrate/nitrite (by high-performance liquid chromatography) levels.. The cardiac index increased 24 % and the pulmonary vascular resistance index decreased 30 % during both periods of NO inhalation. Arterial oxygen tension and arterial oxygen saturation were slightly lower after NO therapy. Nitrate/nitrite concentrations were unaltered in the control group and there were no differences between the arterial and mixed venous serum nitrate/nitrite levels. Nitrite concentrations remained below 1 microM in both groups of animals, but the nitrate concentration increased after inhalation of 40 ppm NO. Serum TxB(2) increased after 60 min of VAI in the control group, but there was no increase in NO-treated animals (all p < 0.05). Nitrate/nitrite concentrations were unaltered after VAI in dogs. NO therapy attenuated TxA(2) release and improved hemodynamics, but not blood oxygenation, in dogs with a VAI. There were no differences between the responses to 3 ppm and 40 ppm NO.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Embolism, Air; Female; Hemodynamics; Hypertension, Pulmonary; Male; Nitrates; Nitric Oxide; Nitrites; Prospective Studies; Thromboxane A2; Thromboxane B2; Vasodilator Agents; Veins

Plasma thromboxane B2 (TXB2), leukotriene B4 (LTB4), and endothelin-1 (ET-1) levels increase on cardiopulmonary bypass (CPB). Elevated levels of TXB2 and ET-1 have been correlated with postoperative pulmonary hypertension in infants undergoing repair of congenital heart defects. LTB4 is a potent chemotactic cytokine whose levels correlate with leukocyte-mediated injury. Modified ultrafiltration (MUF) has been associated with improved hemodynamics and pulmonary function, in addition to its beneficial effects on fluid balance and blood conservation. Recent investigations have suggested that removal of cytokines may be the cause of the improved cardiopulmonary function seen with MUF.. Plasma TXB2, ET-1, and LTB4 levels were measured in 34 infants undergoing CPB: 22 underwent MUF (group 1), and 12 did not (group 2). Samples were obtained at various time points. All patients underwent conventional ultrafiltration during the rewarming phase of cardiopulmonary bypass.. In group 1, mean end-CPB TXB2 level was 101.2 pg/mL versus 46.9 pg/mL post-MUF (p < 0.05). The mean TXB2 level 1 hour post-CPB (54.1 pg/mL) was not significantly different from the post-MUF level. In group 2, the mean end-CPB TXB2 level was 123.6 pg/mL versus 53.2 pg/mL 1 hour post-CPB. Hence, TXB2 levels decreased by similar amounts and to similar levels by 1 hour post-CPB in both groups. ET-1 levels increased after CPB and were unaffected by MUF: 1.45, 1.80, 2.55 pg/mL at end-CPB, post-MUF, and 1 hour post-CPB, respectively, in group 1; and 1.51, and 2.73 pg/mL at end-CPB and 1 hour post-CPB in group 2. LTB4 levels post-MUF were 119% of pre-MUF values, and were similar at 1 hour post-CPB in both groups.. Despite reduction in TXB2 by MUF, values were similar and approached baseline 1 hour post-CPB in both groups. LTB4 levels increased slightly with MUF. ET-1 levels increased during and post-CPB and were unaffected by MUF. MUF does not appear to have a significant effect on post-CPB levels of TXB2, ET-1, and LTB4. Therefore, the improved hemodynamics observed with MUF do not appear to be related to removal of these cytokines.

Topics: Cardiopulmonary Bypass; Endothelin-1; Female; Heart Defects, Congenital; Hemofiltration; Humans; Hypertension, Pulmonary; Infant; Leukotriene B4; Male; Postoperative Complications; Risk Factors; Thromboxane B2; Treatment Outcome

BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. A possible role for endothelin in endotoxin-induced pulmonary hypertension in sheep was investigated by studying animals given intravenous endotoxin with and without pretreatment with BMS182874. BMS182874 administration alone caused a reduction in pulmonary artery pressure (P[PA]) and systemic arterial pressure (P[SA]). Endotoxin alone caused an acute, nearly threefold increase in P(PA) which was followed, from 2-5 h after endotoxin, by a sustained but less severe increase in P(PA). These changes were accompanied by a threefold increase in lung lymph flow and dramatic increases in plasma and lung lymph thromboxane B2 concentrations. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in P(PA) and completely blocked the late sustained pulmonary hypertension (p < 0.05), while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level. We theorize that BMS182874 attenuates the early endotoxin-induced pulmonary hypertension by counteracting the effects of thromboxane, since previous studies demonstrated that the early acute rise in P(PA) is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin.

Topics: Animals; Antihypertensive Agents; Dansyl Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelins; Endotoxemia; Female; Hypertension, Pulmonary; Lymph; Male; Premedication; Pulmonary Wedge Pressure; Sheep; Thromboxane B2

Abnormal biosynthesis of thromboxane and prostacyclin has been implicated in patients with primary pulmonary hypertension and secondary pulmonary hypertension associated with congenital heart disease, and could be involved in the pathogenesis of pulmonary vascular disease. The chronic effects of an oral prostacyclin analogue, beraprost sodium, on thromboxane and prostacyclin biosynthesis and on pulmonary circulation were investigated in 15 children with pulmonary hypertension. The plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured, as was the urinary excretion of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, which are stable metabolites of thromboxane A2 and prostacyclin, respectively. In patients with pulmonary hypertension, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were greater than in healthy controls: 210 +/- 49 versus 28 +/- 4 pg/mL (P < 0.05) and 32.6 +/- 8.9 versus 5.7 +/- 1.8 (P < 0.01), respectively. After 3 months of administration of beraprost, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were reduced significantly: 210 +/- 49 to 98 +/- 26 pg/mL (P < 0.01) and 32.6 +/- 8.9 to 18.0 +/- 6.7 (P < 0.05), respectively. In contrast, the plasma concentrations of 6-keto-prostaglandin F1 alpha in patients were slightly but not significantly higher than in controls, and did not change significantly after administration of beraprost. The concentrations of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in urine correlated significantly with thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively, in plasma. Beraprost improved the imbalance of thromboxane and prostacyclin biosynthesis and has a potential efficacy for preventing the progressive development of pathological changes in pulmonary vasculature.

Topics: Child; Child, Preschool; Epoprostenol; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Platelet Aggregation Inhibitors; Prostaglandins F; Thromboxane A2; Thromboxane B2; Vasodilator Agents

Plasma thromboxane B2 (TXB2)-a stable metabolite of thromboxane A2 (TXA2)-conventional hemodynamic parameters, mean pulmonary input energy (input energy), and mean pulmonary output energy (output energy) were measured to assess platelet activation in 21 patients with pulmonary hypertension and a ventricular septal defect (VSD). The patients were divided into 2 groups: group A (normal range) and group B (high level). TXB2 levels were measured by radioimmunoassay. There was no relationship between plasma TXB2 concentrations and conventional hemodynamic parameters except the pulmonary-to-systemic pressure ratio. Output-to-input energy ratio was correlated logarithmically with the plasma TXB2 concentration. We concluded that patients with output/input energy ratio >0.15 had a high TXB2 concentration and activated platelets in pulmonary capillaries.

Topics: Blood Pressure; Child, Preschool; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Radioimmunoassay; Thromboxane B2

A porcine model of endotoxemic shock was used to test the hypothesis that endothelins (ET) mediate the sustained increases in portal and pulmonary vascular resistances. Anesthetized pigs (n = 18) were instrumented and pretreated with 1) saline as a control; 2) indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed ET-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic parameters and plasma levels of ET-1 and thromboxane B2 were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products combine to increase portal venous resistance; 3) ET independently reduces cardiac output and attenuates or negates global systemic arterial vasodilation (presumptively mediated by nitric oxide) and exhibits regional differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of the same beds in endotoxemic shock (N. Brienza, T. Ayuse, J. P. Revelly, C. P. O'Donnell, and J. L. Robotham, J. Appl. Physiol. 78: 784-792, 1995), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in microvascular and/or venous beds in multiple organs. The overall results suggest that a dynamic balance exists between NO and ET regulating arterial and microvascular and/or venous vasomotor activity during the evolution of endotoxemic shock.

Topics: Analysis of Variance; Animals; Bosentan; Cyclooxygenase Inhibitors; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endotoxemia; Hemodynamics; Hypertension, Portal; Hypertension, Pulmonary; Indomethacin; Liver Circulation; Portal System; Pulmonary Artery; Pulmonary Circulation; Regional Blood Flow; Shock, Septic; Sulfonamides; Swine; Thromboxane B2; Vascular Resistance

To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion.. Randomized, controlled trial.. Animal laboratory.. Twenty seven domestic pigs, weighing 24 to 31 kg.. All pigs were anesthetized and mechanically ventilated during the experiment. Eighteen pigs were subjected to an intracaval infusion of 10% allogeneic bone marrow suspension at a dose of 100 mg/kg over 5 mins. Nine pigs received only bone marrow suspension (fat embolism group). Nine pigs were given an intravenous bolus of aspirin (300 mg) 1 hr before the bone marrow suspension infusion. After the induction of fat embolism, intravenous aspirin was administered at a dose of 150 mg/hr for 2 hrs (aspirin-treated group). Nine pigs were infused with saline (control group).. In the fat embolism group, cardiac index decreased within 30 mins, while mean arterial pressure remained unchanged. Central venous pressure and pulmonary artery occlusion pressure remained relatively stable over time in the animals with fat embolism. Mean pulmonary arterial pressure and pulmonary vascular resistance increased immediately after the bone marrow suspension infusion from 23 +/- 0.8 (SEM) to 34 +/- 1.3 mm Hg and from 305 +/- 28 to 585 +/- 45 dyne x sec/cm5, respectively; these variables remained increased throughout the study period. Simultaneously, pulmonary shunt in the fat embolism group increased persistently from the baseline of 12.3 +/- 2.8%, and reached its maximum of 26.1 +/- 4.8% at the end of the experiment. Instant and gradual decreases in PaO2 (from 95 +/- 4 to 67 +/- 5 torr [12.6 +/- 0.5 to 8.9 +/- 0.7 kPa]), hemoglobin oxygen saturation (from 97.2 +/- 0.4 to 91.8 +/- 1.8%), and oxygen delivery (from 16.3 +/- 1.0 to 12.6 +/- 0.4 mL/min/kg) were observed in the fat embolism group. In the bone marrow suspension-infused animals, urine 2,3-dinor-6-ketoprostaglandin F1alpha excretion increased transiently from 451 +/- 63 up to 1466 +/- 499 pg/micromol creatinine, while urine 11-dehydrothromboxane B2 excretion increased transiently from 385 +/- 36 up to 2307 +/- 685 pg/micromol creatinine. In the aspirin-treated animals, urinary excretion of these prostanoid metabolites was reduced by 81% and 88%, respectively. The changes in mean pulmonary arterial pressure and PaO2 were ameliorated, and the alterations in pulmonary shunt and SaO2 were abolished in the animals with aspirin treatment.. Pulmonary hypertension, increased pulmonary vascular tone, and increased pulmonary shunt are hallmarks of the present fat embolism model. These hemodynamic responses may, at least partly, be related to the changed balance between prostacyclin and thromboxane A2 production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Cyclooxygenase Inhibitors; Embolism, Fat; Epoprostenol; Evaluation Studies as Topic; Hemodynamics; Hypertension, Pulmonary; Lung Diseases; Random Allocation; Swine; Thromboxane A2; Thromboxane B2

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

Chronic administration of prostacyclin (PGI2) improves hemodynamics in patients with primary pulmonary hypertension, but abrupt cessation of infusion can cause severe dyspnea of unknown etiology. We hypothesized that the discontinuation of PGI2 results in platelet activation, thromboxane A2 production, and increased pulmonary vascular tone. To test this, six sheep with indwelling catheters were monitored during infusion of PGI2 and after its cessation. Infusion of PGI2 caused a reduction in mean systemic arterial pressure (MAP) and systemic (SVR) and pulmonary vascular resistances (PVR), a rise in cardiac output (CO), and no change in pulmonary arterial or pulmonary capillary wedge pressure (PCWP). After discontinuation of PGI2, MAP and SVR rebounded to 30 and 67% above baseline, respectively, and PVR rose 26%. CO was depressed 23% within 10 min, and PCWP nearly doubled after stoppage of the drug. Concurrent treatment with a cyclooxygenase inhibitor did not attenuate these responses. 11-Dehydro-thromboxane B2 levels were not elevated during infusion or after cessation of PGI2. We conclude that the abrupt cessation of PGI2 infusion leads to systemic and pulmonary hypertension and transient cardiac dysfunction not mediated by cyclooxygenase metabolites of arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Hypertension; Hypertension, Pulmonary; Infusions, Intravenous; Platelet Activation; Platelet Aggregation Inhibitors; Pulmonary Circulation; Sheep; Substance Withdrawal Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasodilation

Protamine reversal of heparin-induced anticoagulation causes thromboxane release followed by pulmonary vasoconstriction in sheep and pigs. The aim of this study was to determine whether heparin-protamine (H-P) complexes are causative agents of thromboxane release followed by pulmonary hypertension associated with protamine reversal of heparin.. We separated H-P complexes and non-heparin-protamine (non-H-P) complexes from heparinized defibrinated human plasma neutralized with protamine by chromatography and studied the changes in hemodynamics, airway pressure, and thromboxane B2 concentration after injection of H-P complexes or non-H-P complexes into seven goats. In addition, we studied whether these pulmonary responses were blocked in goats pretreated with cyclooxgenase inhibitor (Indomethacin, n = 5) or thromboxane synthetase inhibitor (OKY-046, n = 5).. A very small dose of H-P complexes increased pulmonary arterial and peak airway pressures and was followed by thromboxane B2 release (from 12 [5.5-23] to 28 [16-44] mmHg, from 9.0 [7.5-15] to 12 [8-19] cmH2O, and from 0.85 [0.34-3.2] to 16.4 [1.4-39.3] ng.ml-1, respectively). On the other hand, animals that received non-H-P complexes showed no significant changes. Indomethacin totally blocked and OKY-046 partially blocked the increases in pulmonary arterial pressure and thromboxane B2 concentration.. H-P complexes play a major role in pulmonary hypertension after protamine reversal of heparin, and thromboxane A2 is a main mediator of the pulmonary hypertensive response to H-P complexes in goats.

Topics: Animals; Anticoagulants; Female; Goats; Heparin; Heparin Antagonists; Hypertension, Pulmonary; Indomethacin; Male; Methacrylates; Protamines; Pulmonary Artery; Thromboxane B2

The impact of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) on experimental pulmonary hypertension was investigated. The model of buffer-perfused rabbit lungs was stimulated by infusion of Escherichia coli hemolysin (HlyA), which is known to provoke sustained thromboxane (Tx)-mediated pulmonary hypertension. Release of di- and trienoic Tx into the recirculating perfusate was quantified by a post-high-performance liquid chromatography enzyme-linked immunosorbent assay technique. HlyA at 0.08 hemolytic unit/ml caused a sustained rise in pulmonary arterial pressure (PAP; maximum increase 14 +/- 2 mmHg) accompanied by progressive TxB2 liberation (maximum perfusate concn 33 +/- 4 pg/ml, baseline < 2 pg/ml). Between 5 and 30 nM, AA provoked a transient monophasic rise in PAP (maximum pressor response 1.5-15 mmHg) and concomitant TxB2 release (peak concn 2-30 pg/ml). Simultaneous administration of HlyA and AA exhibited additive effects with regard to mediator release and pressor responses. EPA at 200-2,000 nM caused a transient rise in PAP similar to that provoked by 5-30 nM AA (maximum pressor response 3-18 mmHg). This was accompanied by liberation of TxB2 (peak concn 16 +/- 5 and 28 +/- 4 pg/ml after 1,000 and 2,000 nM EPA) and TxB3 (peak concn 9 +/- 4 and 30 +/- 3 pg/ml). Combined application of HlyA and EPA resulted in approximate addition of the TxB2 release reaction to each single compound, and TxB3 liberation more than doubled (maximum concn 59 +/- 12 pg/ml). The pressor responses to HlyA-EPA (200-2,000 nM) did not, however, surpass those to HlyA-AA (5-30 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Escherichia coli; Female; Hemolysin Proteins; Hypertension, Pulmonary; Male; Potassium; Pulmonary Artery; Pulmonary Wedge Pressure; Rabbits; Thromboxane B2; Thromboxanes

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Masoprocol; Pentoxifylline; Sepsis; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Toxemia; Tumor Necrosis Factor-alpha

Reversal of heparin anticoagulation by intravenous protamine sulfate consistently produces acute pulmonary vasoconstriction mediated by the release of thromboxane in the awake lamb. Recently, recombinant platelet factor 4 (rPF4) has been cloned, expressed in Escherichia coli, and infused to reverse heparin anticoagulation in the rat, without producing adverse hemodynamic or pulmonary morphologic effects. The authors sought to learn whether intravenous administration of PF4 is devoid of side effects in the pulmonary circulation of lambs.. The authors evaluated the hemodynamic response and plasma release rates of thromboxane during intravenous challenges with heparin-rPF4 (n = 2), rPF-free carrier (n = 5), rPF4 (n = 5), rPF4 after indomethacin (n = 5), protamine (n = 5) and heparin-protamine (n = 5) in 17 awake, hemodynamically monitored lambs. Each lamb underwent up to three random challenges with a 2-h recovery period between each challenge.. In two lambs, systemic anticoagulation with heparin followed by reversal of anticoagulation with an intravenous bolus of rPF4 (4 mg/kg) led to acute pulmonary vasoconstriction and hypertension with the release of thromboxane (peak pulmonary artery pressure [Ppa] 40 and 33 mmHg and peak plasma thromboxane B2 50 and 30 ng/ml, respectively). Intravenous administration of rPF4 (1.5 mg/kg) alone increased the Ppa from 17.2 +/- 0.7 mmHg (mean +/- SEM) at baseline to 31.2 +/- 2 mmHg at 1 min (n = 5, P < 0.05). This was associated with an increase of plasma thromboxane B2 from 0.06 +/- 0.02 to 3.96 +/- 1.21 ng/ml. Acute pulmonary vasoconstriction lasted approximately 5 min and was completely prevented by pre-treatment with oral indomethacin (10 mg/kg). Intravenous bolus administration of rPF4 carrier (n = 5) or protamine (2 mg/kg) alone (n = 5) did not induce pulmonary hypertension or the release of thromboxane. In five lambs, intravenous heparin (200 U/kg) followed by protamine (2 mg/kg) consistently produced acute pulmonary vasoconstriction and hypertension.. Intravenous injection of human rPF4 into the awake lamb produces acute pulmonary vasoconstriction and hypertension associated with thromboxane release into circulating blood. The effects of rPF4 on the pulmonary vasculature should be evaluated in primates before rPF4 is substituted for protamine in reversing heparin anticoagulation in humans.

Topics: Animals; Hemodynamics; Heparin Antagonists; Hypertension, Pulmonary; Injections, Intravenous; Platelet Factor 4; Protamines; Sheep; Thromboxane B2

Little is known about the role of circulating platelets in PMA-induced lung injury in vivo. We investigated the effects of platelet depletion (PD) on the injury using seven unanesthetized sheep with lung lymph fistulas and eight other sheep for morphological study. PD diminished a decrease in the lymph to plasma concentration ratio (L/P) after 1 microgram/kg PMA treatment (n = 4) and caused more increases in lung lymph flow, L/P and lung lymph clearance after 5 micrograms/kg PMA treatment (n = 3) than in control sheep. The high dose was lethal to platelet-depleted sheep. However, PD had no effects on pulmonary hemodynamics. Morphologically, alveolar hemorrhages and exudate, and bleb formation of type I epithelial cells were more prominent in the platelet-depleted sheep than in the control sheep. We conclude that circulating platelets have protective effects against PMA-induced lung injury but have little involvement in PMA-induced pulmonary hypertension.

Topics: Animals; Blood Platelets; Blood Proteins; Capillary Permeability; Hemodynamics; Hypertension, Pulmonary; Immune Sera; Leukocyte Count; Lung; Lymph; Male; Microscopy, Electron; Pulmonary Alveoli; Sheep; Tetradecanoylphorbol Acetate; Thromboxane B2; Vacuoles

It has been reported that an injection of anti-sheep platelet serum (AsPS) induces transient pulmonary hypertension in sheep, but the mechanism by which this occurs has not been well explained. To examine the hypothesis that pulmonary intravascular macrophages (PIMs) are involved in this phenomenon, we investigated the morphological features of PIMs from sheep that received three different kinds of AsPS injections. The pulmonary arterial pressure response was examined not only in sheep that have many PIMs in the lung and had received AsPS, but also in rats that reportedly have few PIMs and had received an injection of anti-rat platelet serum. The pulmonary arterial pressure responses of the two species were quite different in quality and quantity. In sheep whose pressure response was definitely positive in association with production of thromboxane in the pulmonary circulation, PIMs were found by fluorescent microscopy and electron microscopy to phagocytize aggregated platelets that bound AsPS. These results suggest that PIMs significantly contribute to AsPS-induced transient pulmonary hypertension in sheep.

Topics: Animals; Blood Platelets; Hypertension, Pulmonary; Leukocyte Count; Lung; Macrophages, Alveolar; Male; Microscopy, Electron; Microscopy, Fluorescence; Platelet Count; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Sheep; Thromboxane B2; Vascular Resistance

The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bacteremia; Blood Gas Analysis; Endotoxins; Escherichia coli Infections; Esterases; Glycine; Hypertension, Pulmonary; Leukocytes; Lung Diseases; Lymph; Neutrophils; Pulmonary Circulation; Sheep; Sulfonamides; Thromboxane B2

Because some patients with Streptococcus pneumoniae bacteremia may present with shock, we reasoned that this organism may produce substances that cause shock. To test this hypothesis, type III pneumococcus supernatant, suspended in 10 ml of sterile water, was infused over 1 min in 8 adult anesthetized sheep. Normal saline was used as a control and had no effect on any of the hemodynamic parameters. Infusion of supernatant resulted in a precipitous fall in cardiac output from a control value of 4.25 +/- 0.54 to 2.80 +/- 0.43 (SE) l/min, a fall in mean systemic arterial pressure from 70 +/- 4 to 49 +/- 8 mmHg, and an increase in the mean pulmonary arterial pressure from 13 +/- 2 to 23 +/- 4 mmHg within 1 min after the infusion was completed. The peak hemodynamic effects were observed at approximately 3 min and returned to normal within 10 min after the infusion was completed. The thromboxane B2 level increased from a control value of 10 +/- 5 to 156 +/- 43 pg/ml at 3 min after the infusion was completed and decreased to 63 +/- 34 pg/ml at 20 min. A second identical dose of pneumococcal supernatant, repeated within 2 h of the first dose, had no effect on hemodynamic variables. Pretreatment with indomethacin, 5 mg/kg body wt, completely blocked the hemodynamic effects of pneumococcal supernatant (n = 3 sheep). Thus, we conclude that S. pneumoniae supernatant contains substances that cause septic shock syndrome through the synthesis of arachidonic acid metabolites and that a sublethal dose of the supernatant causes rapid tachyphylaxis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cardiac Output; Hypertension, Pulmonary; Hypotension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Pneumococcal Infections; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sheep; Shock, Septic; Streptococcus pneumoniae; Thromboxane A2; Thromboxane B2

We investigated the plasma concentration of thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2), to assess platelet activation in 78 patients who had pulmonary hypertension associated with congenital heart disease (PH group) and 16 patients with almost normal hemodynamics (control group).. The PH group was divided into two subgroups: pulmonary vascular resistance (Rp) < or = 10 U/m2 (Rp < or = 10 group) and > 10 U/m2 (Rp > 10 group). In addition, the Rp < or = 10 group was divided on the basis of clinical symptoms into groups with dyspnea (dyspnea[+] group) and without dyspnea (dyspnea[-] group). Plasma TXB2 levels were measured by radioimmunoassay. Plasma TXB2 levels in the three groups (control, Rp < or = 10, and Rp > 10) were significantly different (P < .005); the TXB2 levels in the Rp < or = 10 group were significantly higher than the others. Among the Rp < or = 10 patients, the plasma TXB2 levels were significantly higher in the dyspnea(+) group than in the dyspnea(-) group (P < .0001). In addition, the pulmonary-to-systemic flow ratio and pulmonary blood flow divided by body surface area were significantly higher in the dyspnea(+) group than in the dyspnea(-) group (P < .02 and P < .002, respectively).. These findings suggest that platelet activation led to increased TXA2 release in patients with pulmonary hypertension, especially those with dyspnea and Rp < or = 10. TXA2 release from platelets probably caused constriction of the pulmonary arterioles and the bronchi, thus worsening pulmonary hypertension and dyspnea in these patients. In the patients with high Rp values, it was considered that the number of pulmonary arterioles where platelets could be activated had been reduced.

Topics: Adolescent; Adult; Child; Child, Preschool; Dyspnea; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Osmolar Concentration; Platelet Activation; Pulmonary Circulation; Reference Values; Thromboxane B2

To clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus.. Prospective, randomized controlled trial.. Twelve chronically instrumented and six age-matched uninstrumented newborn piglets.. Six animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling.. Hemodynamic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 +/- 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 +/- 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 +/- 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 +/- 312 to 752 +/- 372 pg/mL, 638 +/- 201 to 1462 +/- 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 +/- 160 to 705 +/- 187 pg/mL).. We conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production.

Topics: Analysis of Variance; Animals; Animals, Newborn; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Lung; Prospective Studies; Pulmonary Artery; Random Allocation; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

The effect of complement activation on the pulmonary vascular system and on right ventricular function was studied in sheep (n = 12) by injection of cobra venom factor. Animals were instrumented for measurement of pulmonary flow, mean pulmonary artery pressure, right ventricular stroke work, arterial blood gases, and systemic vascular resistance. Blood was sampled from the left atrium and pulmonary artery to measure thromboxane B2, the metabolite of thromboxane A2, by radioimmunoassay. After baseline measurements, animals were randomly assigned to receive a selective thromboxane receptor antagonist SQ30741 as a 10 mg/kg bolus with an infusion of 10 mg/kg per hour or else to receive vehicle. Cobra venom factor was then injected (30 U/kg) in all animals, and data were recorded at 15, 30, 60, 90, and 120 minutes. In control animals there was a 2.4-fold increase in mean pulmonary artery pressure and a 76% increase in right ventricular stroke work at 15 minutes from baseline (p < 0.05); these values remained elevated for 30 minutes and returned to baseline by 1 hour with no change in systemic vascular resistance. Arterial oxygenation decreased by 124% at 15 minutes and remained depressed through the experiment, but in treated animals oxygen tension remained unchanged from baseline. Thromboxane B2 increased 95% from baseline in the control group and 1.5 fold in treated animals and followed a similar time course as the functional measurements (p < 0.05). A pulmonary vascular thromboxane B2 gradient of approximately 1000 pg/ml was measured at 15 and 30 minutes in both control and treated groups. (p < 0.05) We conclude that after complement activation in this model pulmonary hypertension and decreased oxygen tension are mediated by thromboxane release from the pulmonary vascular bed. This increased afterload causes a stress on the right ventricle as demonstrated by the increased right ventricular stroke work. Selective thromboxane receptor antagonism may be a beneficial therapy for pulmonary hypertension in patients after cardiopulmonary bypass.

Topics: Animals; Cardiopulmonary Bypass; Complement Activation; Elapid Venoms; Hypertension, Pulmonary; Oxygen; Pulmonary Wedge Pressure; Sheep; Thromboxane A2; Thromboxane B2; Time Factors; Vascular Resistance; Ventricular Function, Right

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

Pulmonary hypertension is an uncommon complication of portal hypertension seen in cirrhotic as well as noncirrhotic patients. We report a 10-year-old girl who presented with extrahepatic portal hypertension and pulmonary hypertension in the absence of intrinsic liver disease. Further investigations revealed high serum concentrations of prostaglandin F2 alpha, thromboxane B2 in the inferior vena cava, and angiotensin I in the inferior vena cava and right ventricle. The increased levels of these vasoconstrictive substances strongly suggest that the possible mechanism for the pulmonary hypertension in such patients with extrahepatic portal hypertension include shunting of vasoactive agents from the splanchnic circulation to the pulmonary vascular bed.

Topics: Angiotensin I; Angiotensin II; Child; Dinoprost; Fatal Outcome; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Thromboxane B2

The pathogenesis of pulmonary vascular disease in children with congenital heart disease is incompletely understood. Thromboxane (TX) A2 and prostacyclin (PGI2) have opposing effects on platelet aggregation and pulmonary vascular smooth muscle. An imbalance in their biosynthesis could contribute to the progressive increase in pulmonary vascular resistance seen in older untreated patients with pulmonary hypertensive congenital heart disease and the thrombotic complications they may develop.. We investigated TXA2 and PGI2 biosynthesis in 15 young children (0.2 to 2.25 years old) with congenital heart disease with increased pulmonary blood flow and potentially reversible pulmonary vascular disease by measuring urinary excretion of 2,3-dinor-TXB2 and 2,3-dinor-6-oxoprostaglandin (PG) F1 alpha and compared the findings with those in 16 healthy children (0.5 to 2.8 years old). 2,3-Dinor-TXB2 excretion was greater in the patients than in control subjects (1253 +/- 161 versus 592 +/- 122 ng/g creatinine; P < .001). Excretion of 2,3-dinor-6-oxo-PGF1 alpha was 452 +/- 54 compared with 589 +/- 95 ng/g creatinine in control subjects. In 5 patients who underwent successful cardiac surgery > or = 1 year later excretion of 2,3-dinor-TXB2 decreased from 1100 +/- 298 to 609 +/- 131 ng/g creatinine (P < .05), a value comparable to those in 5 healthy children of similar age (749 +/- 226 ng/g creatinine). We also compared 15 patients (11 to 23 years old) with advanced irreversible pulmonary vascular disease with 19 healthy control subjects (10 to 23 years old). The ratio of TX to PGI2 metabolite excretion was greater in the patients than in control subjects (3.5 +/- 0.6 versus 2.0 +/- 0.3; P < .05).. There is increased 2,3-dinor-TXB2 excretion in children with congenital heart disease and a high pulmonary blood flow that may reflect an imbalance in biosynthesis of TXA2 and PGI2 in the pulmonary vascular bed. The imbalance may contribute to the progressive development of increased pulmonary vascular resistance and persists in older patients whose heart defects are uncorrected.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aging; Cardiac Surgical Procedures; Child; Child, Preschool; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Postoperative Period; Pulmonary Heart Disease; Reference Values; Thromboxane A2; Thromboxane B2

Intravenous infusion of group B Streptococcus (GBS) into neonatal animals produces pulmonary hypertension, ventilation/perfusion (VA/Q) mismatch, and an increase in serum levels of thromboxane B2 (TxB2) and tumor necrosis factor (TNF) alpha. The vasodilator amrinone (amr) is a cGMP-inhibited phosphodiesterase inhibitor and is reported to inhibit thromboxane A2 and TNF production. We hypothesized that infusion of amr would cause pulmonary vasodilation and reduce serum TxB2 and TNF levels in piglets with late phase GBS-induced pulmonary hypertension. The effect of amr on gas exchange was also determined. A continuous infusion of GBS was administered for 5 hr to 4 groups of anesthetized, mechanically ventilated neonatal piglets. An amr bolus of 8 mg/kg was given at 4 hr followed by a 1 hr continuous infusion of either 10 or 20 micrograms/kg/min of amr (amr 10 and amr 20, respectively). Control piglets received a bolus and 1 hr infusion of amr carrier. The infusion of amr, but not of carrier reversed late phase GBS-induced pulmonary hypertension. Piglets infused with amr 20 showed transient selective pulmonary vasodilation, based on a reduced ratio of pulmonary to systemic vascular resistance (PVR/SVR ratio) value at 30 min but not at 1 hr, compared to pre-amr treatment values. The PVR/SVR ratio values for amr 10 and control group did not change after treatment with either amr or carrier. Treatment with amr 10 or 20 did not decrease serum TxB2 or TNF levels or increase VA/Q mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amrinone; Animals; Animals, Newborn; Blood Pressure; Dose-Response Relationship, Drug; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Gas Exchange; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance; Ventilation-Perfusion Ratio

One of the main causes of pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is considered to be hypoxic pulmonary vasoconstriction, which may partly be mediated by angiotensin II. Ten patients with COPD were administered with captopril (25mg sublingually). Hemodynamics blood gases renin activity inducing angiotensin II and angiotension converting enzyme (ACE) and TXB2/6-ketone-PGF1 alpha were studied through Swan-Ganz catheter before and after administration of the drug. Captopril reduced mean pulmonary artery pressure and pulmonary vascular resistance by 22% and 30% respectively. Levels of ACE angiotension II and TXB2/6-ketone-PGF1 alpha were reduced. There was no significant change in blood gases. Heart rate and systemic arterial pressure did not change significantly. These results suggest that captopril is of value in reducing pulmonary artery pressure and pulmonary vascular resistance.

Topics: Angiotensin II; Captopril; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Peptidyl-Dipeptidase A; Thromboxane B2

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Bacterial Capsules; Disease Models, Animal; Drug Evaluation, Preclinical; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Polysaccharides, Bacterial; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

We tested the hypothesis that pulmonary hypertension and thromboxane A2 release after heparin neutralization by protamine are mediated by oxygen free radicals. Forty-five pigs in five groups were studied during general anesthesia. Group I animals received 250 IU heparin followed by 100 mg protamine after 15 min. Group II and group III animals received dimethyl sulfoxide (DMSO) and dimethylthiourea (DMTU) 30 min before heparin infusion. Group IV animals were given superoxide dismutase (SOD) 5 min before protamine. Group V served for testing the pulmonary vascular reactivity in DMTU-treated animals to a thromboxane A2 analogue (U-46619). Generation of oxygen free radicals by polymorphonuclear granulocytes (PMNs) was measured in vitro by chemiluminescence. Severe pulmonary hypertension and thromboxane A2 release after protamine were not prevented by either DMSO or SOD. DMTU reduced pulmonary vasoconstriction to U-46619 and protamine but not to TxA2 release, indicating that DMTU had unspecific vascular effects in group III. Heparin-protamine released no oxygen free radicals from isolated PMNs. The results indicate that oxygen free radicals do not have a key role in mediating pulmonary vasoconstriction after protamine neutralization of heparin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Dimethyl Sulfoxide; Female; Free Radical Scavengers; Hemodynamics; Heparin; Heparin Antagonists; Hypertension, Pulmonary; Leukocyte Count; Leukocytes; Male; Neutrophils; Prostaglandin Endoperoxides, Synthetic; Protamines; Reactive Oxygen Species; Superoxide Dismutase; Swine; Thiourea; Thromboxane B2; Vasoconstrictor Agents

The lung appears to be one of the dominant sites of bacterial clearance from the blood of infant piglets. Part of the lung bacterial clearance involves activation of an oxygen radical bactericidal mechanism that may be central to induction of acute pulmonary hypertension. The present study determined whether this bactericidal activity was intrinsic to resident lung cells. Isolated piglet lung preparations perfused with blood-free salt solution were used to delineate the amount of group B streptococci (GBS) extracted and killed upon transit through pulmonary vasculature. Approximately 45% of infused GBS was deposited in the lung during a single pulmonary transit, whereas nearly 40% of the organisms sequestered in the lung were killed within a 30-min period. Pretreatment with dimethylthiourea, a scavenger of hydroxyl radical that inhibits GBS-induced pulmonary hypertension, attenuated both bacterial uptake and killing to similar extents. Along with its deposition in the lung, GBS also induced concentration-dependent increases in total pulmonary resistance, which were related principally to increases in upstream arterial resistance. Lung weight also increased in a concentration-dependent manner. Both the increase in total pulmonary resistance and lung weight were temporally related to elevation in perfusion medium content of the stable thromboxane degradation product, thromboxane B2. Pretreatment with indomethacin, a prostaglandin H synthase inhibitor, or sodium(E)-3[4-(1-imidazolyl-methyl)phenyl]-2-propenoic acid a thromboxane synthase inhibitor, reduced GBS-induced pulmonary hypertension and edema. These results suggest that, in isolated piglet lungs, GBS evokes an intrinsic bactericidal response residing within lung cells, probably pulmonary intravascular macrophages, which may be responsible for the initiation of pulmonary hemodynamic changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Blood Bactericidal Activity; Hypertension, Pulmonary; In Vitro Techniques; Lung; Pulmonary Circulation; Reactive Oxygen Species; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea; Thromboxane B2; Vascular Resistance

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

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Body Temperature; Escherichia coli; Female; Hypertension, Pulmonary; Immunoglobulin M; Leukocyte Count; Leukopenia; Lipid A; Lipopolysaccharides; Male; Pulmonary Circulation; Serratia marcescens; Sheep; Thromboxane B2; Vascular Resistance; Vasoconstriction

Tumor necrosis factor alpha (TNF) is a mediator of acute lung injury after endotoxemia, but the precise mechanism of TNF-induced lung injury remains unclear. To clarify the role of oxygen radicals, especially superoxide anion, in TNF-induced lung injury, we examined the effects of recombinant human superoxide dismutase (rhSOD; 4,200 U/mg) on lung physiological and biochemical changes after TNF infusion in awake sheep (n = 17). We prepared chronically instrumented sheep for lung lymph collection and hemodynamic monitoring. Recombinant human TNF (3.5 micrograms/kg iv) induced a biphasic response in awake sheep. Pulmonary hypertension peaked within 15 min of initiation of TNF and remained elevated for 3 h, followed by increased lung vascular permeability. rhSOD attenuated the pulmonary hypertension in both early and late phases but caused no change in the timing or magnitude of lung fluid balance changes during the late phase. Thromboxane A2 (thromboxane B2) and prostacyclin (6-ketoprostaglandin F1 alpha) metabolite levels in plasma and lymph increased after the TNF infusion, and rhSOD attenuated these changes. The intravenous infusion of rhSOD resulted in the appearance of significant levels of SOD activity in both plasma and lung lymph before and after TNF infusion. These findings suggest that superoxide anion may be implicated in the pathogenesis of the pulmonary hypertension induced by TNF in sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Humans; Hypertension, Pulmonary; Lung; Lung Injury; Pulmonary Circulation; Recombinant Proteins; Sheep; Superoxide Dismutase; Superoxides; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha

We hypothesized that 5-lipoxygenase and cyclooxygenase products might be mediators of cardiopulmonary and systemic vascular effects induced by a 4 h continuous infusion of platelet-activating factor (PAF, 10 ng/kg/min) in anesthetized pigs. Indomethacin (cyclooxygenase inhibitor) potentiated and CGS 8515 (5-lipoxygenase inhibitor) attenuated PAF-induced increases in total peripheral resistance (TPR) from 2.5 to 4 h. However, the 5-lipoxygenase inhibitor failed to modify pulmonary vasoconstriction and hypertension caused by PAF. Except for a delay in onset (approximately 44 s) and rate of development of pulmonary hypertension during the initial 10 min of PAF infusion, the pulmonary hemodynamic changes were also not attenuated by indomethacin. On the other hand, at 4 h, the PAF-induced pulmonary hypertension and systemic vasoconstriction were completely or partially reversed, respectively, by WEB 2086 (PAF receptor antagonist). The PAF-induced increases in plasma thromboxane B2 (TXB2) were blocked by indomethacin but not by CGS 8515, and at 4 h the 5-lipoxygenase inhibitor potentiated the levels of TXB2 in pigs treated with PAF. The plasma concentrations of 6-keto-PGF1 alpha and leukotriene B4 (LTB4) were not modified by PAF or CGS 8515 + PAF. We conclude that PAF-induced increases in TPR (2.5-4 h) are potentiated by indomethacin and are dependent on 5-lipoxygenase products other than LTB4. Although the early pulmonary vascular response (< 10 min) to PAF is dependent on cyclooxygenase products, the sustained response (after 10 min) cannot be explained by either 5-lipoxygenase or cyclooxygenase products but may be mediated directly by PAF receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Blood; Calcimycin; Chromatography, High Pressure Liquid; Cyclooxygenase Inhibitors; Hemodynamics; Hypertension, Pulmonary; In Vitro Techniques; Indomethacin; Infusions, Intra-Arterial; Leukotriene B4; Lipoxygenase Inhibitors; Naphthoquinones; ortho-Aminobenzoates; Platelet Activating Factor; Swine; Thromboxane B2; Triazoles

We examined the effects of continuous intravenous infusion of nitroglycerin (NTG) on lung dysfunction induced by endotoxemia in awake sheep chronically instrumented with lung lymph fistula. We measured the responses of hemodynamics, lung lymph balance, and thromboxane (Tx)B2 and 6-keto-prostaglandin (PG) F1 alpha levels in plasma and lung lymph to endotoxin administration (1 microgram/kg, intravenously [IV], over 30 min) with and without continuous infusion of NTG (1 microgram/kg/min). Continuous infusion of NTG alone (n = 5) over 5 hr did not significantly alter systemic, pulmonary hemodynamics, and/or lung lymph fluid filtration. Infusion of endotoxin alone (n = 7) caused remarkable increases in pulmonary artery pressure (Ppa) and lung lymph flow (Qlym) in the early phase. Continuous infusion of NTG (n = 6) significantly prevented the early increases in Ppa and Qlym after endotoxin. The increased values of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph after endotoxemia showed the same increases in groups with and without NTG. These findings suggest that the reduction of pulmonary artery pressure induced by NTG decreased the filtration of fluid into the lungs associated with endotoxemia in sheep, and that the mechanism of vasodilating action of NTG is not due to modifications of constrictive-dilated cyclo-oxygenase products of arachidonate, such as TxA2 and PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Consciousness; Endotoxins; Hypertension, Pulmonary; Infusions, Intravenous; Lung; Lymph; Lymphatic System; Nitroglycerin; Pulmonary Circulation; Sheep; Thromboxane B2; Time Factors

Exposure of isolated perfused rabbit lungs (IPL) to ischemia-reperfusion causes a transient increase in pulmonary arterial (PA) pressure at the onset of reperfusion. Because thromboxane A2 (TxA2) is a potent vasoconstrictor, we hypothesized that it may contribute to the ischemia-reperfusion-induced pressor response. To evaluate this hypothesis, we exposed IPL perfused with a cell-free solution to 40 min of warm ischemia followed by reperfusion and measured perfusate immunoreactive thromboxane B2 (iTxB2) and 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha). We observed that ischemia-reperfusion IPL compared with controls had an increase in PA pressure (40.2 +/- 4.8 vs. 9.3 +/- 0.3 mmHg, P < 0.05), lung edema (29.3 +/- 6.3 vs. -0.2 +/- 0.2 g, P < 0.05), iTxB2 perfusate levels (155 +/- 22 vs. < 50 pg/ml, P < 0.05), and i6-keto-PGF1 alpha (436 +/- 33 vs. 61 +/- 16 pg/ml, P < 0.05). In ischemia-reperfusion IPL, infusion of SQ 29548 (10(-6) M), a specific TxA2/prostaglandin H2 receptor antagonist, attenuated the PA pressor response and the degree of edema. We conclude that pulmonary hypertension associated with ischemia-reperfusion results in part from pulmonary release of TxA2. Furthermore, TxA2 directly through membrane effects or indirectly through hydrostatic mechanisms increases the severity of ischemia-reperfusion-induced lung edema.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; In Vitro Techniques; Ischemia; Lung; Organ Size; Pulmonary Circulation; Pulmonary Edema; Rabbits; Radioimmunoassay; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Thromboxane B2; Thromboxanes; Vasoconstriction

Transfusion of small quantities of heterologous blood may cause severe pulmonary hypertensive response in certain species. To determine the responsible component in the donor blood and the main mediator, we studied the responses of goats to small quantities of rabbit blood components and observed the effects of several pharmacologic agents on these responses. In anesthetized goats, a bolus injection of 0.004 ml/kg rabbit blood caused the pulmonary arterial pressure to increase from 25.3 +/- 2.8 to 57.1 +/- 11.6 cm H2O within 45 to 90 s, and the aortic thromboxane concentration rose from 44 +/- 38 to 238 +/- 104 pg/ml. Pulmonary vascular resistance increased more than 4-fold, whereas systemic vascular resistance increased moderately (50%). The erythrocyte stroma, mainly cell membranes, caused similar responses; other blood components were all ineffective. By blocking the production of thromboxane, indomethacin and U63557A (thromboxane synthetase inhibitor) abolished nearly all of the hemodynamic responses to rabbit blood. Isoproterenol also largely attenuated the responses to rabbit blood by blocking thromboxane production without interfering with the responses to the thromboxane mimic U46619. Nitrendipine (calcium-channel blocker) equally attenuated rabbit blood and U46619-induced hemodynamic responses but did not block thromboxane production. Chlorpheniramine (H1-receptor antagonist) partially blocked the hemodynamic responses to rabbit blood without affecting thromboxane production or U46619-induced responses. We conclude that the erythrocyte membrane is the responsible component in the donor blood and thromboxane is the predominant mediator. The main action of isoproterenol is to reduce thromboxane production and histamine participates by possible interaction with cyclooxygenase products.

Topics: Animals; Blood Physiological Phenomena; Chlorpheniramine; Female; Goats; Hemodynamics; Hypertension, Pulmonary; Indomethacin; Isoproterenol; Male; Nitrendipine; Prostaglandin Endoperoxides, Synthetic; Rabbits; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Thromboxane B2

Topics: Animals; Complement Activation; Heparin Antagonists; Humans; Hypertension, Pulmonary; Macrophage Activation; Macrophages; Protamines; Thromboxane B2

Exposing rabbits for 1 h to 100% O2 at 4 atm barometric pressure markedly increases the concentration of thromboxane B2 in alveolar lavage fluid [1,809 +/- 92 vs. 99 +/- 24 (SE) pg/ml, P less than 0.001], pulmonary arterial pressure (110 +/- 17 vs. 10 +/- 1 mmHg, P less than 0.001), lung weight gain (14.6 +/- 3.7 vs. 0.6 +/- 0.4 g/20 min, P less than 0.01), and transfer rates for aerosolized 99mTc-labeled diethylenetriamine pentaacetate (500 mol wt; 40 +/- 14 vs. 3 +/- 1 x 10(-3)/min, P less than 0.01) and fluorescein isothiocyanate-labeled dextran (7,000 mol wt; 10 +/- 3 vs. 1 +/- 1 x 10(-4)/min, P less than 0.01). Pretreatment with the antioxidant butylated hydroxyanisole (BHA) entirely prevents the pulmonary hypertension and lung injury. In addition, BHA blocks the increase in alveolar thromboxane B2 caused by hyperbaric O2 (10 and 45 pg/ml lavage fluid, n = 2). Combined therapy with polyethylene glycol- (PEG) conjugated superoxide dismutase (SOD) and PEG-catalase also completely eliminates the pulmonary hypertension, pulmonary edema, and increase in transfer rate for the aerosolized compounds. In contrast, combined treatment with unconjugated SOD and catalase does not reduce the pulmonary damage. Because of the striking increase in pulmonary arterial pressure to greater than 100 mmHg, we tested the hypothesis that thromboxane causes the hypertension and thus contributes to the lung injury. Indomethacin and UK 37,248-01 (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid hydrochloride, an inhibitor of thromboxane synthase, completely eliminate the pulmonary hypertension and edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bronchoalveolar Lavage Fluid; Butylated Hydroxyanisole; Hyperbaric Oxygenation; Hypertension, Pulmonary; Imidazoles; In Vitro Techniques; Indomethacin; Lung; Lung Injury; Male; Pulmonary Edema; Rabbits; Superoxide Dismutase; Thromboxane B2; Thromboxane-A Synthase

Pulmonary air embolism causes physical obstruction of microvasculature and leads to permeability changes, release of mediators, and injury to lung tissue. In this study we employed an isolated perfused rat lung model to investigate the primary and secondary effects produced by infusion of air into the pulmonary artery. Infusion of various doses of air (0.10-0.25 ml) over a 1-min period produced a dose-dependent increase in pulmonary arterial pressure and lung weight gain. In contrast, when a constant air dose was administered over various periods of time (0.25 ml over 0.5-8.0 min), the pulmonary arterial pressure rose to the same extent regardless of the infusion rate, whereas the lung weight gain increased proportionately with the rate of infusion. Total vascular resistance rose from 1.41 +/- 0.04 to 5.04 +/- 0.09 mmHg.ml-1.min in rats given 0.25 ml air over 1 min (n = 14, P less than 0.001), with greater than or equal to 90% of this increase occurring in the arterial segments. Both thromboxane B2 and endothelin concentrations also increased in the perfusate, suggesting their involvement in this increased resistance. Furthermore the pulmonary filtration coefficient increased from 0.21 +/- 0.05 to 1.28 +/- 0.26 g.min-1.cmH2O-1.100 g (n = 8, P less than 0.001), and the protein concentration in lung lavage fluid also rose, indicating lung injury. Leukocyte counts in the perfusate were unaffected by embolization, but chemiluminescent activity was increased, indicating a possible role for activated leukocytes in lung injury induced by air emboli.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Embolism, Air; Endothelins; Free Radicals; Hypertension, Pulmonary; In Vitro Techniques; Leukocytes; Lung; Lung Injury; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Inbred Strains; Thromboxane B2

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium.. We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls.. The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls.. An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Radioimmunoassay; Thromboxane A2; Thromboxane B2

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

We have found that the goat is extraordinarily sensitive to very small quantities of rabbit or rat blood. As little as 0.004 ml/kg induces transient pulmonary hypertension [maximal rise in pulmonary arterial pressure 32 +/- 10 (SD) cmH2O] in goats. We hypothesized that this reaction may be related to the presence of the resident population of intravascular macrophages that reside in the pulmonary capillaries of goats. If that is so, then rabbits or rats, which have few or no intravascular macrophages, should not be reactive to foreign blood. We compared pulmonary hemodynamics and changes in blood thromboxane B2 concentrations among goats, rabbits, and rats in response to graded doses of foreign blood. The pulmonary reaction to foreign blood was much greater in goats than in rabbits or rats, even though we injected up to 10- or 60-fold larger amounts into the latter species. In goats the pulmonary vascular pressure response to rabbit blood was dose dependent in goats and correlated well with changes in systemic arterial thromboxane B2 concentrations [change in pulmonary arterial pressure = 0.07 (thromboxane B2) + 8.3, r = 0.79]. We also tested the prostaglandin H2 endoperoxide analogue (U-46619) and found that the goats are somewhat more reactive than rabbits. We conclude that the pulmonary hemodynamic reaction to foreign blood is consistent with the concept that the foreign erythrocytes are reacting with the pulmonary intravascular macrophages in goats. The lower reactivity of the rabbit pulmonary circulation to thromboxane may also have a role.

Topics: Animals; Blood Pressure; Female; Goats; Hemodynamics; Hypertension, Pulmonary; Male; Pulmonary Circulation; Rabbits; Rats; Thromboxane B2; Transfusion Reaction; Transplantation, Heterologous

We examined 3 infants with persistent pulmonary hypertension. They also showed signs of heart failure. The signs of cardiac dysfunction noted in the acute phase were resolved after treatment with catecholamines and vasodilators. Contrary to the general concept that transient myocardial dysfunction is secondarily caused by persistent pulmonary hypertension, left myocardial dysfunction accompanied pulmonary hypertension and was followed by right myocardial dysfunction. High blood concentration of thromboxane B2 was reported in 2 neonates with persistent pulmonary hypertension. We considered thromboxane A2 as a possible cause of coronary spasm, resulting in myocardial ischemia.

Topics: Catecholamines; Coronary Disease; Coronary Vasospasm; Echocardiography; Humans; Hypertension, Pulmonary; Infant, Newborn; Thromboxane B2; Vasodilator Agents

Escherichia coli hemolysin, a transmembrane pore-forming exotoxin, is considered an important virulence factor. In the present study, the possible significance of hemolysin production was investigated in a model of septic lung failure through infusion of viable bacteria in isolated rabbit lungs; 10(4) to 10(7) E. coli/ml perfusate caused a dose- and time-dependent appearance of hemolysin, accompanied by release of potassium, thromboxane A2, and PGI2 into the perfusate. Concomitantly, marked pulmonary hypertension developed. Inhibitor studies suggested that the pressor response was predominantly mediated by pulmonary thromboxane generation. Administration of hemolysin-forming E. coli additionally caused a protracted, dose-dependent increase in the lung capillary filtration coefficient, followed by severe edema formation. The permeability increase was independent of lung prostanoid generation. An E. coli strain that releases an inactive form of hemolysin completely failed to provoke the described biophysical and biochemical responses. Preapplication of 2 x 10(8) human granulocytes was without effect in the present experimental model. We conclude that the hemolysin produced by low numbers of E. coli organisms can provoke thromboxane-mediated pulmonary hypertension and severe vascular leakage. E. coli hemolysin and, possibly, other related cytolysins may thus contribute directly to the pathogenesis of acute respiratory failure under conditions of sepsis or pneumonia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Pressure; Capillary Permeability; Epoprostenol; Escherichia coli; Female; Hemolysin Proteins; Hypertension, Pulmonary; In Vitro Techniques; L-Lactate Dehydrogenase; Lung; Male; Neutrophils; Perfusion; Potassium; Pulmonary Artery; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Respiratory Insufficiency; Sulfonamides; Thromboxane B2; Thromboxanes

We measured the pulmonary arterial pressure and the level of Thromboxane A2 (TXA2), and Prostacyclin (PGI2) in 30 stable COPD patients and the level of TXA2 and PGI2 in 10 normal subjects so as to investigate the changes of TXA2 and PGI2 in COPD patients with pulmonary hypertension. The results showed that the level of TXA2 increased significantly in COPD patients with dominant and latent pulmonary hypertension when compared with that in normal subjects (P less than 0.001, less than 0.01), and the level of TXA2 in COPD patients with dominant pulmonary hypertension was also higher than that in COPD patients with latent pulmonary hypertension (P less than 0.02), but there was no difference in the level of PGI2 among normal subjects and COPD patients with or without pulmonary hypertension. This indicates that TXA2 plays an important role in causing pulmonary hypertension in COPD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Thromboxane B2

Interleukin-2 therapy leads to respiratory dysfunction caused by increased vascular permeability. This study examines the role of oxygen-derived free radicals (OFR). Sheep (n = 6) with chronic lung lymph fistulae were given interleukin-2, 10(5) units/kg, as an intravenous bolus. The mean pulmonary artery pressure rose from 13 to 23 mm Hg (p less than 0.05) at 1 hour and remained elevated for 4 hours, although the pulmonary artery wedge pressure was unchanged at 4 mm Hg. Arterial oxygen tension fell from 88 to 77 mm Hg (p less than 0.05). Lung lymph flow rose from 2.2 to 6.4 ml/30 min (p less than 0.05) at 3 hours. This rise coincided with an increase in the lymph/plasma protein ratio from 0.67 to 0.77 (p less than 0.05) and lymph protein clearance from 1.5 to 4.4 ml/30 min (p less than 0.05), indicating increased lung microvascular permeability. Interleukin-2 led to transient increases in plasma thromboxane B2 from 168 to 388 pg/ml (p less than 0.05) and lung lymph thromboxane B2 from 235 to 694 pg/ml (p less than 0.05). The leukocyte count fell from 8156 to 4375/mm3 (p less than 0.05) primarily caused by a 78% drop in lymphocyte count. Platelet count declined from 292 to 184 X 10(3)/mm3 (p less than 0.05). Pretreatment with the hydroxyl radical scavenger dimethylthiourea, 1 gm/kg, intravenously, (n = 6) prevented the interleukin-2-induced increase in mean pulmonary artery pressure, lung lymph flow, lymph/plasma protein ration, lymph protein clearance, and thromboxane B2 levels in plasma and lung lymph. The arterial oxygen tension decreased from 85 to 80 mm Hg (p less than 0.05). The leukocyte count declined from 7854 to 6229/mm3 (p less than 0.05), but this was not as low nor as prolonged as the interleukin-2 group. Further, the decrease in platelet count was prevented (p less than 0.05). Interleukin-2 incubated with sheep or human leukocytes led to a dose-dependent increase in intracellular hydrogen peroxide production by neutrophils as measured by flow cytometry of dichlorofluorescein oxidation. These data indicate that interleukin-2 stimulates OFR generation and that OFR moderate the interleukin-2-induced increased lung permeability.

Topics: Animals; Blood Pressure; Female; Free Radical Scavengers; Free Radicals; Hydrogen Peroxide; Hypertension, Pulmonary; Interleukin-2; Leukopenia; Lung; Lymph; Oxygen; Platelet Count; Pulmonary Artery; Recombinant Proteins; Sheep; Thiourea; Thromboxane B2

Bilateral cemented arthroplasty (BCA) in anaesthetized mongrel dogs produces particulate fat and marrow embolism of the lung. Methylprednisolone sodium succinate (MPSS) has been advocated for post-traumatic fat embolism to prevent acute lung injury. We used the BCA procedure to produce acute fat and marrow embolism, and tested the efficacy of MPSS (30 mg.kg-1) in preventing physiological and pathological markers of acute lung injury. Dogs (n = 6) pre-treated with MPSS demonstrated similar acute increases in pulmonary artery pressure (PAP) within one minute of BCA (17.8 +/- 7.3 mmHg) as the untreated (control n = 7) dogs (18.6 +/- 12.6). Pulmonary vascular resistance (PVR) increased to the same degree in both groups (455 +/- 323 and 319 +/- 137 dyne.sec.cm-5) and PaO2 decreased by 18.3 +/- 6.4 mmHg in the control group as opposed to 12.4 +/- 7.7 mmHg in the MPSS group within five minutes of BCA. Circulating arterial and mixed venous plasma concentrations of thromboxane B2 (TxB2) increased within one minute of BCA in both groups with no increase in the transpulmonary gradient. Arterial plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) increased (0.91 +/- 0.29 ng.ml-1 and 0.87 +/- 0.43 ng.ml-1) in both groups one minute after BCA. Mixed venous 6-keto PGF1 alpha plasma concentration also increased, but a significant transpulmonary 6-keto PGF1 alpha gradient was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bone Cements; Bone Marrow; Dogs; Embolism, Fat; Femur; Hip Prosthesis; Hypertension, Pulmonary; Lung; Methylprednisolone; Oxygen; Pulmonary Artery; Pulmonary Embolism; Thromboxane B2; Time Factors; Vascular Resistance

The effects of adenosine (ADO) on pulmonary vascular resistance (PVR) distribution, vascular compliance (C), and permeability were determined in normal and PMA-injured isolated rabbit lungs perfused with a 1:1 mixture of 6% albumin in Krebs-Henseleit buffer and autologous blood. ADO or vehicle was continuously infused into the reservoir at 1,4, or 5 mumol/min after a 1-mumol bolus of ADO or vehicle. The capillary filtration coefficient (Kf) and arterial, venous, and double occlusion pressures were measured at baseline and 30 min after phorbol myristate acetate (PMA; 4 x 10(-8) M) or vehicle. Perfusate differential and total leukocyte counts as well as adenine nucleotides, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TxB2) concentrations were determined at each measurement period. ADO was recovered as hypoxanthine and inosine in the perfusate. ADO alone did not alter PVR, C, Kf, or TxB2 but reduced 6-keto-PGF1 alpha levels. PMA induced an increase in Kf (0.024 +/- 0.002 to 0.040 +/- 0.006 g.cmH2O-1.min-1, P less than 0.05) that was completely blocked by 4 or 5 mumol/min ADO. PVR increased by 63 +/- 11% after PMA, primarily in the arteries and arterial and venous microvessels. The postcapillary resistance increase was blunted by 4 mumol/min ADO; 5 mumol/min ADO prevented the PVR increase in all segments. ADO did not affect the initial adherence of neutrophils in the lung or the PMA-induced 87 +/- 2% decrease in circulating leukocytes (greater than 98% lymphocytes) or threefold increase in TxB2 levels. These results suggest that protection by ADO is not mediated by the altering of cyclooxygenase products or by leukocyte adherence.

Topics: 6-Ketoprostaglandin F1 alpha; Adenine Nucleotides; Adenosine; Animals; Capillary Permeability; Filtration; Hypertension, Pulmonary; In Vitro Techniques; Leukocyte Adherence Inhibition Test; Leukocyte Count; Lung Compliance; Lung Diseases; Male; Perfusion; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Rabbits; Tetradecanoylphorbol Acetate; Thromboxane B2; Vascular Resistance

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprost; Extracorporeal Membrane Oxygenation; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Prostaglandins; Thromboxane B2

Both thromboxane A2 and oxygen-derived free radicals appear to play central roles in group B streptococcus (GBS)-induced pulmonary hypertension in piglets. This study tested the hypothesis that GBS promotes oxygen radical-dependent thromboxane accumulation and pulmonary hypertension in infant piglets. Piglets 4-12 d old were anesthetized and prepared for assessment of pulmonary arterial pressure and arterial blood gases. In control animals, GBS (10(8) organisms/kg/min for 15 min) increased mean pulmonary artery pressure by 30 +/- 1.5 torr and reduced arterial PO2 by 100 +/- 20 torr. Thromboxane A2, radioimmunoassayed in venous blood as thromboxane B2, increased by 2452 +/- 800 pg/mL. A second group of piglets was treated with dimethylthiourea (DMTU: 750 mg/kg), a putative oxygen radical scavenger. In these animals, GBS increased pulmonary arterial pressure by only 7 +/- 1 torr and reduced arterial PO2 by a modest 10 +/- 8 torr. Importantly, thromboxane B2 content in venous blood failed to increase above control levels in DMTU-treated animals. The protective effects of DMTU in GBS-treated piglets could not be ascribed to inhibition of cyclooxygenase or thromboxane synthase because the oxygen radical scavenger failed to attenuate increases in pulmonary arterial pressure and venous thromboxane B2 content or reductions in arterial PO2 caused by i.v. infusions of arachidonic acid. DMTU also did not ameliorate pulmonary hypertension evoked by the thromboxane mimetic U44069, thereby suggesting that the scavenger did not act as an end-organ antagonist of thromboxane receptors. These observations suggest that GBS promotes accumulation of thromboxane A2 and attendant pulmonary hypertension through an oxygen radical-dependent mechanism.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Free Radicals; Hypertension, Pulmonary; Oxygen; Streptococcal Infections; Streptococcus agalactiae; Swine; Thiourea; Thromboxane B2

Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Chromones; Cyclooxygenase Inhibitors; Diethylcarbamazine; Dogs; Foreign-Body Reaction; Granuloma, Foreign-Body; Hemodynamics; Hypertension, Pulmonary; Indomethacin; Lipoxygenase; Lipoxygenase Inhibitors; Lung; Lung Diseases; Pentazocine; Prostaglandin-Endoperoxide Synthases; Thromboxane B2; Vascular Resistance

The neutralisation of heparin by protamine can cause life-threatening pulmonary hypertension. We studied this reaction in animal experimental models (sheep and rat) to determine the cellular mechanisms of the pulmonary vasoconstriction. The heparin-protamine reaction (H-P) with pulmonary hypertension (peak of mean pulmonary artery pressure = 57.3 +/- 2.2 mmHg), decreased cardiac output (-20%), leukopenia (-30%) and plasma release of high concentrations of thromboxane B2 (6.03 +/- 0.03 ng/ml) was constantly observed in sheep. The reaction was identical in sheep with induced thrombocytopenia by administration of antiplatelet antibodies. On the other hand, the neutralisation of heparin by protamine in rats did not cause thromboxane release or pulmonary vasoconstriction although the leukopenia was identical to that observed in sheep. Therefore, the platelets and white blood cells did not seem to cause the pulmonary vasoconstriction induced by the H-P complexes. The inter-species difference observed suggests that pulmonary intravascular macrophages may be responsible for the liberation of eicosanoids and acute pulmonary vasoconstriction occurring during the neutralisation of heparin by protamine.

Topics: Animals; Disease Models, Animal; Heparin Antagonists; Hypertension, Pulmonary; Leukocyte Count; Macrophages; Protamines; Pulmonary Artery; Pulmonary Wedge Pressure; Rats; Rats, Inbred Strains; Sheep; Thromboxane B2; Vasoconstriction

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Topics: Animals; Animals, Newborn; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Oxygen; Partial Pressure; Pulmonary Circulation; Sepsis; Streptococcal Infections; Swine; Thiourea; Thromboxane B2

GBS (Group B Hemolytic Streptococci) cause pulmonary hypertension with associated neutropenia. We investigated whether there is a correlation between the neutropenia of sepsis and GBS-induced pulmonary vasoconstriction, through study of the effects of inhibiting pulmonary vasoconstriction on the neutropenia of GBS in newborn piglets. Fifteen piglets were infused with GBS. After one hour, animals were given either a thromboxane inhibitor (DAZ), a combined cyclooxygenase/lipoxygenase inhibitor, BW755C, or placebo. With GBS infusion, WBC and PMN counts dropped steadily, from similar baselines, to 2250 +/- 570, 3300 +/- 500 and 5400 +/- 1100 cells/mm3 respectively (p less than 0.05; DAZ and BW vs. placebo). PMN's dropped similarly to 710 +/- 320, 2390 + 1240 and 3130 +/- 1050 cells/mm3 respectively (p less than 0.05; DAZ vs. BW and placebo). The drop in WBC's predominantly resulted from proportional decreases in PMN's (DAZ: r = 0.98; BW: r = 0.88; placebo r = 0.93). Compared to GBS alone, DAZ reduced pulmonary vasoconstriction, but exacerbated the granulocytopenia. BW755C similarly reduced pulmonary hypertension: however, it ameliorated the exacerbation of GBS induced neutropenia described above. These data imply that there is no direct correlation between GBS induced granulocytopenia and pulmonary hypertension.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Animals, Newborn; Blood Pressure; Cyclooxygenase Inhibitors; Hypertension, Pulmonary; Imidazoles; Leukocyte Count; Lipoxygenase Inhibitors; Neutropenia; Neutrophils; Pulmonary Artery; Streptococcus agalactiae; Swine; Thromboxane B2; Vasoconstriction

Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model, we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWH) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels, a threefold increase of pulmonary vascular resistance and pulmonary artery pressure, and a 25% decrease of PaO2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However, with polybrene (1 mg/kg) reversal of LMWH (1 mg/kg), we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6 +/- 3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9 +/- 4.2 mm Hg after protamine reversal of unfractionated heparin, p less than 0.005 groups differ), hypoxemia (PaO2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine, p less than 0.05), nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2 +/- 0.1 at 1 minute after polybrene compared with 3.7 +/- 1.7 ng/ml at 1 minute after protamine, p less than 0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LMWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p less than 0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction.

Topics: Animals; Consciousness; Heparin Antagonists; Heparin, Low-Molecular-Weight; Hexadimethrine Bromide; Hypertension, Pulmonary; Protamines; Sheep; Thromboxane B2

A 30-year-old male was admitted because of dyspnea, which had started three years before the admission. Chest roentgenogram showed prominence of the proximal pulmonary arteries and diminished vascularity of the peripheral pulmonary arteries. Electrocardiogram showed right axis deviation and right ventricular hypertrophy. Right heart catheterization revealed a markedly elevated pulmonary arterial pressure and pulmonary vascular resistance with normal capillary wedge pressure. Oximetry showed no evidence of intracardiac shunt. Perfusion lung scan revealed nonsegmental, patchy defects in both lungs. Pulmonary arteriography showed no evidence of pulmonary thromboembolism. From the above findings, primary pulmonary hypertension was diagnosed. Nifedipine, ISDN, prazosin, and captopril were administered to evaluate the short term-effect of he vasodilators. Nifedipine was found to be the most effective. The venous thromboxane B2 level was high. After oxygen therapy, venous thromboxane B2 level fell within the normal range following improvement of arterial oxygenation and decrease in venous FDP level. Hemodynamic changes induced by ice-water hand immersion showed marked increase in the mean pulmonary arterial pressure and total pulmonary arterial resistance. These results suggested that chemical mediators such as thromboxane, and pulmonary arterial vasospasm were involved in the pathogenesis.

Topics: Adult; Cold Temperature; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Nifedipine; Oxygen Inhalation Therapy; Thromboxane B2

Thromboxane (Tx) has been suggested to mediate the pulmonary hypertension of phorbol myristate acetate- (PMA) induced acute lung injury. To test this hypothesis, the relationship between Tx and pulmonary arterial pressure was evaluated in a model of acute lung injury induced with PMA in pentobarbital sodium-anesthetized male mongrel dogs. Sixty minutes after administration of PMA (20 micrograms/kg iv, n = 10), TxB2 increased 10-fold from control in both systemic and pulmonary arterial blood and 8-fold in bronchoalveolar lavage (BAL) fluid. Concomitantly, pulmonary arterial pressure (Ppa) increased from 14.5 +/- 1.0 to 36.2 +/- 3.5 mmHg, and pulmonary vascular resistance (PVR) increased from 5.1 +/- 0.4 to 25.9 +/- 2.9 mmHg.l-1.min. Inhibition of Tx synthase with OKY-046 (10 mg/kg iv, n = 6) prevented the PMA-induced increase in Tx concentrations in blood and BAL fluid but did not prevent or attenuate the increase in Ppa. OKY-046 pretreatment did, however, attenuate but not prevent the increase in PVR 60 min after PMA administration. Pretreatment with the TxA2/prostaglandin H2 receptor antagonist ONO-3708 (10 micrograms.kg-1.min-1 iv, n = 7) prevented the pressor response to bolus injections of 1-10 micrograms U-46619, a Tx receptor agonist, but did not prevent or attenuate the PMA-induced increase in Ppa. ONO-3708 also attenuated but did not prevent the increase in PVR. These results suggest that Tx does not mediate the PMA-induced pulmonary hypertension but may augment the increases in PVR in this model of acute lung injury.

Topics: Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Dogs; Hypertension, Pulmonary; Lung; Lung Injury; Male; Methacrylates; Pulmonary Artery; Tetradecanoylphorbol Acetate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Vascular Resistance

The infusion of Group B beta hemolytic streptococci (GBS) in newborn animals generates a dual phase pulmonary hypertensive response. The initial, acute phase responds to cyclooxygenase or thromboxane inhibition, and appears to be thromboxane mediated. The second phase is characterized by a more moderate rise in pulmonary vascular resistance, accompanied by an increase in microvascular permeability. It has been speculated that this phase may be leukotriene mediated. In an attempt to clarify this, we have studied and compared the effects of the thromboxane synthetase inhibitor, Dazmegrel (DAZ), and the combined cyclooxygenase/lipoxygenase inhibitor, BW755C, on the cardiopulmonary hemodynamics of the secondary phase of GBS induced pulmonary hypertension in newborn piglets. Ten piglets were infused with GBS, and all animals developed a significant increase in pulmonary artery pressure (to 39 +/- 5 and 36 +/- 5 mmHg for DAZ and BW755C animals respectively). After one hour of GBS, either DAZ or BW755C was administered. Data were collected for another two hours following drug administration. GBS infusion was continued throughout. Both DAZ and BW755C were associated with transient, acute reductions in pulmonary artery pressure (to 22 +/- 5 and 22 +/- 8 mmHg, respectively). However, after 60 minutes, PAP again began to rise in both groups (PAP 30 +/- 5 and 30 +/- 11 mmHg respectively by 240 minutes). There were no differences between the groups at any time. These data do not support a significant role for lipoxygenase products in mediating the secondary phase of septic pulmonary hypertension.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cyclooxygenase Inhibitors; Heart Rate; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Lipoxygenase Inhibitors; Pyrazoles; Swine; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Neonatal calves exposed to chronic hypobaric hypoxia develop severe pulmonary hypertension associated with altered vascular reactivity, cellular proliferation, and increased elastin and collagen production. We hypothesized that prostaglandin (PG) production would be decreased in the pulmonary arterial vessel wall of these calves. Further, because of the possibility that the hemodynamic stresses of hypoxic pulmonary hypertension might change along the longitudinal axis of the pulmonary circulation, we measured prostaglandin synthetic capability in tissues isolated from proximal pulmonary artery, distal pulmonary artery, and pulmonary vein. We found that PGI2 production was decreased in both proximal and distal pulmonary artery rings isolated from pulmonary hypertensive calves compared to controls. PGI2 production was greater in distal than in proximal lobar pulmonary artery. In contrast, pulmonary veins from hypertensive calves, which are protected from the hemodynamic stress of pulmonary arterial hypertension, did not demonstrate altered PGI2 production compared to controls. PGE2 production was also decreased in proximal hypertensive pulmonary arterial rings as compared to controls. To determine if this decrease in vessel wall production of prostaglandins was due to changes in cellular prostaglandin production, we studied prostaglandin production by the three major cell types comprising hypertensive and control arteries. Endothelial cells cultured from hypertensive main pulmonary artery produced less PGI2 than did those from control artery, and there appeared to be a shift from PGI2 production to PGE2 production in endothelial cells isolated from hypertensive artery. Explanted advential fibroblasts from hypertensive artery produced less PGE2 than did controls. Smooth muscle cell PGI2 production did not differ between cells isolated from hypertensive and control arteries in these brief 30-min incubations. We conclude that there is a relative deficit in PGI2 and PGE2 production in the pulmonary arteries of calves with hypoxia-induced pulmonary hypertension and speculate that this contributes to altered vascular tone and vessel remodeling.

Topics: Animals; Animals, Newborn; Calcimycin; Cattle; Cells, Cultured; Dinoprostone; Endothelium, Vascular; Epoprostenol; Fibroblasts; Hemodynamics; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Pulmonary Artery; Pulmonary Veins; Thromboxane B2

Endogenous formation of thromboxane A2 and prostacyclin were evaluated in seven neonatates with persistent pulmonary hypertension by serial gas chromatographic mass spectrometric determination of their urinary metabolites dinor-thromboxane B2 and dinor-6-keto-prostaglandin F1 alpha, respectively. The patients were studied until their hypertension had resolved on clinical criteria. Urinary excretion of dinor-thromboxane B2 and dinor-6-keto-prostaglandin F1 alpha was increased when the persistent pulmonary hypertension was associated with group B streptococcal (n = 2) and pneumococcal (n = 1) sepsis. Based on urinary metabolite excretion, endogenous formation of thromboxane A2 and prostacyclin did not consistently differ from normal neonates in four patients with non-septic persistent pulmonary hypertension (hyaline membrane disease (n = 2), asphyxia, and meconium aspiration). These data suggest that thromboxane A2 is not a universal mediator of persistent pulmonary hypertension. It may, however, have a role in the pathophysiology of early onset group B streptococcal disease, and persistent pulmonary hypertension of other infectious aetiology. If these findings are confirmed by further studies, thromboxane synthetase inhibition or receptor antagonism may offer a potential therapeutic approach in neonates with persistent pulmonary hypertension associated with sepsis.

Topics: 6-Ketoprostaglandin F1 alpha; Bacterial Infections; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Thromboxane A2; Thromboxane B2

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

Lipid infusions can interfere with oxygenation and cause pulmonary hypertension. We studied the effects of iv lipid infusions on pulmonary hemodynamics and oxygen transport to investigate whether the vasoconstrictor, thromboxane (Tx), mediates resulting changes. Newborn piglets were instrumented to observe cardiopulmonary hemodynamics, blood gases, and oxygen contents. Oxygen delivery (DO2), oxygen consumption, and extraction ratios were calculated. All piglets received continuous 1-g/kg.h iv lipid infusions. After one hour, and as the lipid infusion continued, six piglets were given placebo (PL) and six others were given the Tx antagonist SQ 29548 (SQ). Pulmonary vasoconstriction occurred in both groups after one hour of lipid infusion (pulmonary artery pressure [PAP] 28 +/- 6 mm Hg in the PL piglets and to 31 +/- 13 mm Hg in the SQ piglets. After intervention, PAP remained elevated only in the PL group (32 +/- 2 vs. 23 +/- 8 mm Hg) (p less than .02). PaO2 and DO2 fell significantly with iv lipid and improved after intervention in SQ animals only (p less than .02). TxB2 increased in all animals with iv lipid (276 +/- 295 to 1481 +/- 716 in PL; 228 +/- 110 to 1402 +/- 580 in SQ), and fell with intervention in the SQ animals only (2632 +/- 1236 vs. 964 +/- 305, respectively; p less than .02). In conclusion, interference with DO2 associated with pulmonary hypertension and increased TxB2 occurred with iv lipid infusion in piglets. Tx antagonism ameliorated these changes.

Topics: Animals; Animals, Newborn; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fat Emulsions, Intravenous; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Lung; Oxygen Consumption; Pulmonary Artery; Swine; Thromboxane B2; Thromboxanes; Vascular Resistance; Vasodilation

Rapid protamine reversal of heparin anticoagulation in awake sheep caused, after 1 min, a approximately 15-fold increase of arterial plasma thromboxane B2 (TxB2) levels, a 4-fold rise of pulmonary vascular resistance (PVR), a 2-fold rise of pulmonary arterial pressure, and after 3 min, a 2-fold rise of ovine arterial plasma complement C3a levels (P less than 0.05). Infusion of nafamstat mesilate (FUT-175), a protease and complement pathway inhibitor, before protamine reduced these increases by approximately 60-90% (P less than 0.05). FUT-175 did not modify heparin + protamine-induced leukopenia, suggesting that FUT-175 incompletely blocked C5a production. We also learned that infusing protamine first and heparin 5 min later did not increase either plasma C3a or TxB2 levels or PVR while the activated clotting time increased only minimally. Thus, in awake sheep, the sequence of heparin and protamine infusion influences complement activation and pulmonary vasoconstriction. FUT-175 pretreatment reduces thromboxane release and pulmonary vasoconstriction probably by limiting complement activation.

Topics: Animals; Benzamidines; Blood Pressure; Complement C3a; Complement Inactivator Proteins; Drug Interactions; Guanidines; Hemodynamics; Heparin; Hypertension, Pulmonary; Lung; Protamines; Protease Inhibitors; Pulmonary Artery; Sheep; Thromboxane B2; Vascular Resistance

The prevalence of pulmonary hypertension among patients with portal hypertension, especially following a shunt operation, is significantly higher than that of primary pulmonary hypertension, suggesting the hypothesis that large portasystemic shunt plays a major role in development of pulmonary hypertension. To support this hypothesis, I studied experimentally the hemodynamic changes and the pathological findings in lung in 97 rats killed between one and 24 months after portasystemic shunt operations. The right ventricular systolic pressure (RVSP) and the right ventricular wall thickness were significantly high in the 82 rats raised over 3 months after the operations. In these rats the pathological findings in the lung revealed a thickness of pulmonary arterioles with medial hypertrophy, concentric intimal proliferation, and plexiform lesions. The values of endotoxin in central venous blood were significantly high and related with RVSP and shunt ratio. In pulmonary venous blood, thromboxane B2 increased and 6-keto PGF1a decreased. In conclusion, some of the rats developed pulmonary hypertension fter receiving a portasystemic shunt operation. It is suspected that endotoxin passing through the shunt plays a role in the development of pulmonary hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterioles; Blood Pressure; Collateral Circulation; Endotoxins; Hypertension, Portal; Hypertension, Pulmonary; Lung; Male; Portasystemic Shunt, Surgical; Pulmonary Circulation; Rats; Rats, Inbred Strains; Thromboxane B2

Intravenous injection of the complement activator, cobra venom factor (CVF), produces acute lung injury that is neutrophil-dependent and oxygen radical mediated. Using the ex vivo model of lung perfusion, the current studies were designed to measure the appearance of eicosanoids in relation to the development of pulmonary arterial hypertension and vascular permeability. Inhibitors of the cyclooxygenase and lipoxygenase pathways were also employed to assess the possible role of eicosanoids in these two functional responses. Ten minutes after infusion of CVF, when the pulmonary hypertensive changes were maximal, no increases in eicosanoids could be detected in whole lung lavage fluid (TXB2, 6-keto-PGF1 alpha, LTB4, LTC4) or plasma (TXB2, 6-keto-PGF1 alpha) and the inhibitors failed to affect the pressor response. In contrast, lung injury as defined by increased vascular permeability was temporally associated with the appearance in whole lung lavage fluid of TXB2, LTB4 and LTC4, the presence of which was blocked by the relevant inhibitors. Lung injury was attenuated by both cyclooxygenase and lipoxygenase inhibitors. This effect was not peculiar to the isolated lung model since cyclooxygenase (ibuprofen, indomethacin) and lipoxygenase (nafazatrom, U66,855) inhibitors also attenuated the CVF-induced increased vascular permeability in intact rats. These data suggest that in the model system employed eicosanoid production is linked to increases in lung vascular permeability but not to pulmonary artery hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Chromatography, High Pressure Liquid; Complement Activation; Cyclooxygenase Inhibitors; Elapid Venoms; Hypertension, Pulmonary; Indomethacin; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Naphthols; Organ Culture Techniques; Rats; SRS-A; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Serotonin; Thromboxane B2

13 newborn piglets with group-B-beta-hemolytic-streptococci (GBS)-induced pulmonary hypertension were assigned to receive either placebo (group 1) or Dazmegrel, a thromboxane synthetase inhibitor (group 2). All piglets with pulmonary hypertension had increased thromboxane B2 (TxB2) and 6-keto PGF1 alpha levels. With continued GBS infusion, the placebo group demonstrated a continued elevation of pulmonary artery pressure (PAP) and of TxB2. The Dazmegrel piglets, however, despite continued GBS infusion, demonstrated a selective decrease in PAP associated with a significant decrease in TxB2 levels and stability of systemic pressure and cardiac output. These data demonstrate that thromboxane synthetase inhibition is effective therapeutically in selectively reducing PAP.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Epoprostenol; Hypertension, Pulmonary; Imidazoles; Radioimmunoassay; Streptococcal Infections; Swine; Thromboxane B2; Thromboxane-A Synthase

Thromboxane-associated pulmonary hypertension occurs in animals during intravenous infusion of group B streptococcus (GBS), a gram-positive neonatal pathogen. We postulated that other gram-positive neonatal pathogens, such as Streptococcus fecalis (ENT) and Staphylococcus epidermidis (S. epi) would also induce increased thromboxane synthesis and pulmonary hypertension when infused into piglets. We observed similar hemodynamic and gas exchange abnormalities during stepwise increases in the dose of GBS, Ent, and S. epi (n = 3, 4, and 4 piglets receiving each bacteria, respectively). Pulmonary vascular resistance increased significantly in the absence of acidosis or reduced arterial or mixed venous pO2 at a dose of 2.5 x 10(8) cfu/kg/h for Ent and S. epi. In 14 additional piglets, pulmonary vascular resistance increased markedly after 60 min of intravenous infusion of 4 +/- 1 x 10(8) cfu/kg/h for each organism (p less than 0.05, GBS: 11.7 +/- 1.8 to 75.6 +/- 18.4 mm Hg/liter/min, Ent: 12.7 +/- 1.7 to 64.9 +/- 10.6 mm Hg/liter/min, S. epi: 10.5 +/- 0.8 to 56.9 +/- 6.0 mm Hg/liter/min), and blood thromboxane B2 levels increased (p less than 0.05, GBS: 30 +/- 10 to 1830 +/- 330 pg/ml, Ent: 20 +/- 7 to 1110 +/- 300 pg/ml, S. epi: 31 +/- 9 to 1260 +/- 350 pg/ml). This dose of each bacteria caused a similar degree of mild arterial hypoxemia (57-66 mm Hg). The thromboxane synthetase inhibitor, dazmegrel, completely reversed pulmonary hypertension, reduced TxB2 levels to near baseline values, and partially reversed arterial hypoxemia despite ongoing bacterial infusion. We conclude that thromboxane-associated pulmonary hypertension occurs in piglets during infusion of different gram-positive neonatal pathogens.

Topics: Animals; Animals, Newborn; Enterococcus faecalis; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Sepsis; Staphylococcal Infections; Staphylococcus epidermidis; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

Monocrotaline pyrrole (MCTP) causes pulmonary vascular injury and pulmonary hypertension in rats. Although the mechanism by which MCTP causes pulmonary hypertension is unknown, vasoconstriction may play a role. Thromboxane (Tx) A2 is a vasoconstrictor released from platelets and other blood cells. Following treatment with MCTP in vivo, the release of stable metabolites of TxA2 and prostacyclin [TxB2 and 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha), respectively] was determined in isolated lungs perfused with blood. Early in the development of pulmonary hypertension, the concentrations of TxB2 and 6-keto-PGF1 alpha in the effluent plasma of lungs from treated rats were not different from control rats. When pulmonary hypertension was well established, the concentration of TxB2 was higher in the effluent plasma of lungs from MCTP-treated rats, although the concentration of 6-keto-PGF1 alpha was not affected by treatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Pyrrolizidine Alkaloids; Rats; Thromboxane B2

Lower torso ischemia and reperfusion has been shown to stimulate the generation of thromboxane (Tx)A2, leading to transient pulmonary hypertension and later to polymorphonuclear leukocyte accumulations in the lungs. This study investigated whether hind limb ischemia leads to increased pulmonary microvascular permeability. Anesthetized sheep (n = 6) previously prepared with a lung lymph fistula underwent 2 hr of tourniquet ischemia of both lower limbs. One minute following tourniquet release mean pulmonary arterial pressure (MPAP) rose from 14 +/- 1 to 36 +/- 4 mm Hg (p less than 0.05) and returned to baseline within 30 min. The pulmonary arterial wedge pressure of 4 +/- 1 mm Hg was unchanged. Plasma TxB2 levels rose from 211 +/- 21 to 304 +/- 52 pg/ml (p less than 0.05) 10 min after tourniquet release and were back to baseline at 30 min. Lymph flow (QL) rose from 4.3 +/- 0.6 ml/30 min to 8.3 +/- 1.8 ml/30 min (p less than 0.05); the lymph/plasma (L/P) protein ratio rose slightly but not significantly. In three sheep, inflation of a left atrial balloon increased left atrial pressure from 3 to 16 mm Hg. MPAP rose from 14 to 24 mm Hg. There was an increase in QL from 3.6 to 17 ml/30 min; the L/P protein ratio declined from 0.63 to 0.41. These results indicate that reperfusion following 2 hr of bilateral hind limb ischemia results in increased pulmonary microvascular permeability.

Topics: Animals; Capillary Permeability; Hypertension, Pulmonary; Ischemia; Leg; Lung; Neutrophils; Regional Blood Flow; Sheep; Thromboxane B2

Pulmonary hypertension with an elevated pulmonary vascular resistance was observed during the immediate recovery period in patients who underwent mitral valve surgery. In eight such patients, intravenous infusion of CGS-13080, imidazo(1,5-a)pyridine-5-hexanoic acid (a thromboxane synthetase inhibitor), at a dose range of 0.08-0.1 mg/kg/hr, effectively reduced pulmonary hypertension (from a mean pulmonary arterial pressure of 36 +/- 2 to 31 +/- 2 torr) and pulmonary vascular resistance (from 339 +/- 38 to 238 +/- 37 dynes.sec.cm-5) within 30 minutes and remained reduced for the entire infusion period (48 hours in five patients and 18 hours in three patients). Mean arterial pressure or systemic vascular resistance were not significantly affected by the drug infusion. Serum thromboxane B2 levels (a stable metabolic product of thromboxane A2) were significantly reduced after administration of the compound, with the maximum effect of greater than 90% reduction. All patients tolerated the drug infusion without significant side effects.

Topics: 6-Ketoprostaglandin F1 alpha; Cardiopulmonary Bypass; Heart Valve Prosthesis; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Mitral Valve; Postoperative Complications; Pulmonary Circulation; Pyridines; Thromboxane B2; Thromboxane-A Synthase; Vascular Resistance

In patients with pre-existing pulmonary hypertension, severe pulmonary vasoconstriction has been observed following protamine administration. Thromboxane A2, a potent vasoconstrictor, is capable of producing increases in pulmonary vascular resistance, and animal studies suggest that heparin-protamine complexes stimulate thromboxane A2 synthesis. This study assessed the effect of protamine administration on hemodynamics and on plasma thromboxane A2 and its biologic antagonist, prostacyclin, by serial measurement of the stable metabolites, thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Ten adults with pulmonary artery hypertension undergoing elective mitral valve replacement were studied. After termination of cardiopulmonary bypass, baseline hemodynamic measurements were obtained and arterial blood for prostanoid analysis was sampled. Hemodynamic and prostanoid measurements were obtained 5, 10, 15, and 30 minutes after the protamine infusion began. Prostanoid levels were performed by double antibody radio-immunoassay. No significant hemodynamic changes occurred and no significant changes in prostanoid levels were observed. It is concluded that in patients with pulmonary hypertension, heparin-protamine complexes do not consistently raise circulating thromboxane levels, and the relationships among prostanoids, pulmonary hypertension, and systemic hypotension are still not clear.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Blood Pressure; Cardiac Output; Epoprostenol; Female; Heart Rate; Heparin; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Protamines; Thromboxane A2; Thromboxane B2; Vascular Resistance; Vasoconstriction

Monocrotaline pyrrole (MCTP) causes pulmonary endothelial cell injury and pulmonary hypertension in rats. Damage to endothelial cells in culture has been associated with altered prostacyclin (PGI2) production; therefore, it was of interest to determine if MCTP affected pulmonary PGI2 production. Release of the stable metabolites of PGI2 and thromboxane A2, 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TxB2), respectively, was examined in isolated, buffer-perfused lungs from MCTP-treated rats at times when elevated pulmonary arterial pressure is first observed (day 7) and when the pulmonary hypertensive state has existed for some time (day 14), 6-keto PGF1 alpha release was not affected by MCTP treatment 7 or 14 days after a single intravenous injection of MCTP. TxB2 release was also unaffected at day 7, however 14 days after treatment TxB2 release was greater in lungs from MCTP-treated rats compared to controls. The concentration of both 6-keto PGF1 alpha and TxB2 increased when arachidonic acid was infused into lungs from control or treated rats. These data indicate that MCTP treatment increases the release of TxB2 from isolated lungs at a time when pulmonary hypertension is well-established, but not during early development of pulmonary hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Body Weight; Hydrostatic Pressure; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Organ Size; Perfusion; Pyrrolizidine Alkaloids; Rats; Thromboxane B2; Time Factors

The direct and indirect actions of two active components of slow-reacting substance of anaphylaxis, leukotrienes C4 (LTC4) and D4 (LTD4), were studied in chronically instrumented unanesthetized sheep. Intravenous injection of 3 micrograms of LTD4 caused immediate marked pulmonary arterial hypertension which returned to baseline in 6.5 +/- 1.0 min. Dynamic compliance of the lungs (Cdyn) and left atrial (PLA) and aortic (Paorta) blood pressure fell concomitantly with the increases in pulmonary artery pressure (PPA). PLA and Paorta then increased above baseline and heart rate deceased significantly. LTD4 caused only small increases in lung lymph flow but did increase lung lymph concentrations of thromboxane B2. Lung lymph concentrations of 6-keto-prostaglandin F1 alpha did not increase following LTD4 infusion. The increase in PPA after 3-micrograms injections of LTD4 was greater than that caused by 10-micrograms injections of prostaglandin H2-analog. Injections of 10-30 micrograms of LTC4 caused only minor increases in PPA but did cause bradycardia and delayed increases in PLA and Paorta. The cyclooxygenase inhibitors meclofenamate and ibuprofen inhibited the increases in PPA caused by LTD4 but not the later bradycardia or increases in PLA and Paorta. The thromboxane synthetase inhibitor UK-38485 attenuated the early increase in PPA and moderated the later increases in PLA and Paorta and bradycardia caused by LTD4 injection. The response of unanesthetized sheep to LTD4 is mediated, at least in part, indirectly by stimulation of the cyclooxygenase pathway of arachidonate metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Arachidonate 5-Lipoxygenase; Blood Pressure; Female; Hypertension, Pulmonary; Ibuprofen; Imidazoles; Lung; Lung Compliance; Lymph; Male; Meclofenamic Acid; Prostaglandin-Endoperoxide Synthases; Pulmonary Wedge Pressure; Sheep; SRS-A; Thromboxane B2; Thromboxane-A Synthase

The characteristic pulmonary hypertensive effect of the heparin and protamine interaction has been studied in the isolated pig lung preparation using sequential autologous blood perfusate and dextran perfusate. A significant (p less than 0.001) increase in pulmonary artery pressure at constant flow was seen in 10 of 14 dextran and 12 of 15 blood perfusions. The average increase for dextran was 112 percent and for blood, 109 percent. Antihistamines did not inhibit the response. However, this was abolished in all 11 animals treated with aspirin. In 11 intact swine, thromboxane B2 blood levels increased significantly (p less than 0.01) from 0.46 +/- 0.38 ng/dl to 2.97 +/- 1.5 ng/dl. Thus, pulmonary hypertension associated with protamine reversal of heparinization is associated with prostaglandin release from the lung, and this does not require mediation of platelets or leukocytes.

Topics: Animals; Blood Pressure; Drug Interactions; Heparin; Hypertension, Pulmonary; Lung; Protamines; Swine; Thromboxane B2

We have studied the effect of continuous endotoxin infusion on rat pulmonary structure and function (69.4 ng/100 gm body weight/min for 24 hours). After 6 days of endotoxin infusion, lack of filling of pre- and intraacinar arteries was evident on pulmonary arteriograms. Microscopy demonstrated lumen narrowing in preacinar arteries and occlusion of intraacinar arteries. Morphometry of patent intraacinar arteries established dilation and increased wall muscle. Widespread alveolar wall injury was evident. After 24 hours of infusion, pulmonary artery pressure was raised (delta 9 mmHg; p less than or equal to 0.001); it then fell but was again increased by day 6 (delta 6 mmHg; p less than or equal to 0.05). Pulmonary vascular resistance was markedly increased at 24 hours (day 0 = 0.1 +/- 0.011 dyne/sec/cm-5; 24 hours endotoxin = 0.572 +/- 0.102 dyne/sec/cm-5; p less than or equal to 0.02). It remained elevated during the infusion period but was not significant. At day 6 the alveolar-arterial oxygen diffusion gradient (A-aDO2) was increased (day 0 = 19.6 +/- 1.39 mmHg, day 6 endotoxin = 33.8 +/- 0.1 mmHg; p less than or equal to 0.001). The arterial oxygen tension (PaO2) was decreased (day 0 = 86.5 +/- 1.8 mmHg, day 6 endotoxin = 74 +/- 2.52 mmHg; p less than or equal to 0.05), as was the arterial carbon dioxide tension (PaCO2) (day 0 = 36.0 +/- 0.73 mmHg, day 6 endotoxin = 30 +/- 1.9 mmHg; p less than or equal to 0.05). Thrombocytopenia occurred during the first 72 hours of infusion (day 0 = 7.41 +/- 0.41 X 10(5)/mm3, day 1 endotoxin = 2.43 +/- 0.30 X 10(5)/mm3, day 3 endotoxin = 2.32 +/- 0.31 X 10(5)/mm3; p less than or equal to 0.001) but by day 6 the platelet count had returned to basal levels (9.9 +/- 0.65 X 10(5)/mm3). Endotoxin increased the number of leukocytes in peripheral blood (day 0 = 12.8 +/- 1.2 X 10(3)/mm3, day 3 endotoxin = 17.0 +/- 1.86 X 10(3)/mm3, day 6 endotoxin = 22.5 +/- 1.8 X 10(3)/mm3; p less than or equal to 0.01 for day 6). Plasma concentrations of 6-keto-prostaglandin F1 alpha decreased during the first 24 hours of infusion (day 0 = 0.56 +/- 0.076 ng/ml, 24 hours endotoxin = 0.27 +/- 0.026 ng/ml; p less than or equal to 0.05) and thromboxane (TX) B2 in the first 15 hours (day 0 = 0.23 +/- 0.058 ng/ml, 15 hours endotoxin = 0.09 +/- 0.14 ng/ml; p less than or equal to 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Endotoxins; Escherichia coli; Hemodynamics; Hypertension, Pulmonary; Male; Microscopy, Electron; Pulmonary Artery; Rats; Rats, Inbred Strains; Thromboxane B2

Thromboxane synthetase inhibitors have been shown to reduce thromboxane, a potent vasoconstrictor, and increase prostacyclin, a potent vasodilator, in normal subjects. We evaluated the acute and chronic (three months) effects of the thromboxane synthetase inhibitor CGS13080 administered 200 mg every six hours on the resting hemodynamics in ten patients with primary pulmonary hypertension (PPH), and on their response to 20 mg of nifedipine given sublingually before and after the thromboxane synthetase inhibitor treatment. It was concluded that one can modulate the levels of endogenous thromboxane and prostacyclin in patients with primary pulmonary hypertension using a thromboxane synthetase inhibitor. Although the thromboxane synthetase inhibitor alone produced only modest hemodynamic changes over time, the addition of nifedipine was able to produce a further lowering of pulmonary artery pressure and pulmonary vascular resistance.

Topics: Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Nifedipine; Pyridines; Thromboxane B2; Thromboxane-A Synthase

We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Airway Resistance; Animals; Blood Pressure; Cats; Chromones; Dinoprost; Endotoxins; Escherichia coli; Evaluation Studies as Topic; Hypertension, Pulmonary; Infusions, Intravenous; Lung Compliance; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Pulmonary Circulation; Shock, Septic; SRS-A; Thromboxane B2

Monocrotaline pyrrole (MCTP), a metabolite of the plant toxin monocrotaline, produces pulmonary vascular injury, pulmonary hypertension, and right ventricular enlargement (RVE) in rats by an unknown mechanism. A role for platelets has been suggested by the observation that antibody-induced thrombocytopenia reduces the RVE caused by MCTP. The platelet can release a number of vasoconstrictive agents, such as 5-hydroxytryptamine (5HT) and thromboxane A2 (TxA2), that could possibly contribute to pulmonary hypertension. It was of interest to determine whether treatment with MCTP alters platelet 5HT content or alters the release of TxA2 in platelet-rich plasma (PRP) in response to aggregation. Fourteen days following treatment with MCTP when pulmonary hypertension is well-established and RVE is present, the concentration of 5HT in washed platelets or in platelet-poor plasma was not different in treated and control rats. One day following treatment with MCTP, before lung injury is evident, the concentration of TxB2, a stable metabolite of TxA2, was higher in unstimulated PRP from treated rats than in control rats. The concentration of TxB2 was also examined in PRP at 4 days (when lung injury first appears), 7 days (when pulmonary arterial pressure first increases), and 14 days after treatment with MCTP (when RVE is evident). At 4, 7, or 14 days following treatment there was no difference in the concentration of TxB2 in unstimulated PRP from MCTP-treated and control rats. Following stimulation with arachidonic acid, the release of TxB2 at maximal aggregation was not different in PRP from MCTP-treated and control rats at any time after treatment. The rate of release of TxB2 was lower in PRP from rats treated with MCTP 7 days earlier, but was not different at any other time following treatment. At concentrations up to 250 micrograms/ml, MCTP added in vitro to PRP from untreated rats did not affect the concentration of TxB2 released during aggregation induced by arachidonic acid. Only at very high concentrations (1 mg/ml) did MCTP abolish the aggregation response and depress TxB2 release in PRP. These results indicate that MCTP treatment does not affect platelet 5HT content and does not affect basal TxB2 production or TxB2 release by platelets stimulated in vitro.

Topics: Animals; Blood Platelets; Hypertension, Pulmonary; Male; Monocrotaline; Platelet Aggregation; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; Serotonin; Thromboxane B2; Thromboxanes; Time Factors

Ischemia stimulates thromboxane (Tx) synthesis. This study tests the hypothesis that the cardiopulmonary dysfunction that may follow aortic declamping is related to Tx. Anesthetized dogs (N = 15) were subjected to 4 hours of infrarenal aortic cross-clamping. In untreated control animals (N = 7), plasma levels of TxB2 rose from 654 +/- 74 pg/mL to 1238 +/- 585 pg/mL at 5 min (p less than 0.05), and to 3174 +/- 912 pg/mL 3 hours after declamping (p less than 0.05). Mean pulmonary artery pressure (MPAP) rose 5 min after declamping from 13 +/- 2 mmHg to 21 +/- 2 mmHg (p less than 0.05). Cardiac Index (CI) declined during ischemia from 181 +/- 30 mL/kg.min to 128 +/- 16 mL/min.kg (p less than 0.05), and to 80 +/- 8 mL/min.kg after 4 hours of reperfusion (p less than 0.05). Platelet counts declined but platelets labeled with In 111 did not accumulate in the lungs, whereas quantitative counts of polymorphonuclear leukocytes (PMN) in the lungs 4 hours after declamping yielded 213 +/- 33 PMN/25 high power fields (HPF) in dependent areas of the lung and 153 +/- 26 PMN/25 HPF in nondependent areas. The wet/dry weight ratio of the lungs was not elevated, although foci of proteinaceous exudate and PMNs in alveoli were noted. Another group of dogs (N = 8) were pretreated by random choice with the Tx synthase inhibitor OKY-046 2 mg/kg IV every 2 hours, which led to: lower TxB2 levels at baseline 95 +/- 35 pg/mL (p less than 0.05), 5 min after ischemia 140 +/- 93 pg/mL and after 3 hours of reperfusion 122 +/- 36 (p less than 0.05); lower MPAP, 16 +/- 2 mmHg (p less than 0.05); higher CI throughout (p less than 0.05); normal histology and reduced pulmonary PMN sequestration both in dependent 127 +/- 15 PMN/25 HPF and nondependent areas of the lungs 95 +/- 11 PMN/25 HPF (p less than 0.05). In animals undergoing sham ischemia (N = 3), levels of TxB2 and cardiopulmonary function remained unchanged from baseline. There were 150 PMN/25 HPF in dependent and 85 PMN/25 HPF in nondependent lung areas. The results indicate that ischemia-generated Tx mediates a rise in MPAP, a fall in CI, and PMN entrapment in the lungs.

Topics: Animals; Blood Pressure; Cardiac Output; Dogs; Female; Hypertension, Pulmonary; Ischemia; Leg; Leukocyte Count; Lung; Methacrylates; Neutrophils; Platelet Count; Respiratory Insufficiency; Thromboxane A2; Thromboxane B2; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Thromboxane B2

Marked leukopenia and sequestration of granulocytes in the lung are consistently seen in severe early onset group B streptococcal (GBS) disease in human infants. To investigate the role of granulocytes as potential mediators in the pulmonary pathophysiology of this disease, the effects of intravenously administered GBS type III toxin were studied in young lambs before and after granulocyte depletion with hydroxyurea. Granulocyte depletion markedly reduced the 4-fold increase in total lung resistance and the decrease in dynamic compliance observed after GBS toxin. Granulocyte depletion significantly attenuated the pulmonary hypertension, hypoxemia and increased minute ventilation present during the first phase of the response (0.5-1 h after GBS toxin). It did not significantly alter the increase in body temperature, the marked increase in lung lymph thromboxane B2 concentrations during the first phase or the increase in lung lymph flow and protein clearance during the second phase of the response (3.5-5 h after GBS toxin). The results indicate that granulocytes are involved as mediators of the changes in lung mechanics seen after GBS toxin infusion in young lambs. Granulocytes contribute to the pulmonary hypertension and decrease in arterial oxygenation, but other mediators appear to be responsible for the injury of the vascular endothelium.

Topics: Animals; Capillary Permeability; Granulocytes; Hydroxyurea; Hypertension, Pulmonary; Leukopenia; Lung; Polysaccharides, Bacterial; Sheep; Temperature; Thromboxane B2

In animals, monocrotaline induces an acute lung injury secondary to capillary endothelial damage. To date, no reports have appeared dealing with the role of prostaglandins in monocrotaline-induced injury. Our studies, in dogs, revealed that monocrotaline (30 mg/kg iv) caused an acute and persistent thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased extravascular lung water (EVLW). The pulmonary hypertensive response was biphasic. Thromboxane B2 levels were similarly biphasic, peaking at 5 min and 2 h. The levels of 6-keto-PGF1 alpha peaked at 30 min and returned to base line at 3 h. Pulmonary vascular resistance paralleled thromboxane levels. Infusion of prostacyclin (PGI2) at 50 ng X kg-1 X min-1 effectively prevented the thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased EVLW; and it decreased excess thromboxane production by 79%. These results suggest that platelet activation and lung sequestration play a role in acute lung injury due to monocrotaline, and that the resultant thromboxane production may contribute to the pulmonary hypertension. PGI2 ameliorates monocrotaline-induced injury, perhaps by preventing platelet activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cell Count; Blood Platelets; Body Water; Dogs; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Lung; Lung Injury; Monocrotaline; Pyrrolizidine Alkaloids; Thrombocytopenia; 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

This review highlights newer insights into possible pathogenic mechanisms, clinical features, and treatment of primary pulmonary hypertension. A disease once believed to be found only in younger women, it has now been well documented to occur in both the young and elderly, with a female to male distribution of approximately 1.7:1 at all ages. Several possible etiologic mechanisms have recently been elucidated. Evidence has been forthcoming suggesting a possible role for thromboxane being produced by the pulmonary vascular bed, an underlying abnormality in clot lysis, the presence of antinuclear antibodies which could represent a collagen vascular disorder involving the lung, and a potential aggravating role of female hormones. Unfortunately, the major frustration with primary pulmonary hypertension remains its treatment. Some investigators suggest that anticoagulation may have beneficial effects on long-term survival, although this remains controversial. Most of the recently published articles on therapy have dealt with the use of vasodilators. A careful review of the effectiveness of vasodilators in these patients has failed to show that their chronic use alters either the patient's clinical course, survival, or the disease process itself. It does appear, however, that sustained beneficial effects can be realized in some patients if a substantial reduction in the pulmonary artery pressure is achieved with drug treatment. A thorough understanding of the physiologic characteristics of the pulmonary vascular bed is necessary in order to avoid misinterpreting the effects of vasodilators, which can also be detrimental. The development of vasodilators that are more specific for the pulmonary vascular bed may lead to better clinical results. Strategies for making an earlier diagnosis, however, may be equally important in our attempts to improve the prognosis.

Topics: Antibodies, Antinuclear; Anticoagulants; Blood Platelets; Collagen Diseases; Digitalis Glycosides; Diuretics; Epoprostenol; Humans; Hypertension, Pulmonary; Myocardial Contraction; Platelet Count; Pulmonary Artery; Pulmonary Circulation; Thromboxane B2; Vascular Resistance; Vasodilator Agents

We investigated the effect of a thromboxane antagonist, BM 13.177, during endotoxin-induced pulmonary vasoconstriction in sheep. In control animals intravenous E-coli endotoxin (1 microgram/kg) caused a transient increase of pulmonary artery and airway pressure paralleled by large concentration increases of TXB2: in comparison peak plasma concentrations of 6-keto-PGF1 alpha (a prostacyclin metabolite) were small and delayed in time. Pre-treatment with BM 13.177 (bolus 5 mg/kg), followed by 0.75 mg/kg/min intravenously) abolished the rise of pulmonary artery and airway pressure. Plasma concentrations of TXB2 and 6-keto-PGF1 alpha were similar to controls. These and previous investigations imply that BM 13.177 specifically antagonizes TXA2 on the putative receptor in pulmonary vascular and airway smooth muscle.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Female; Hypertension, Pulmonary; Lung; Sheep; Sulfonamides; Thromboxane A2; Thromboxane B2; Vasoconstriction

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

Topics: beta-Thromboglobulin; Dipyridamole; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Male; Middle Aged; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Thromboxanes

Our purpose was, in general, to determine the effect of a body burn on the pulmonary response to endotoxemia and, specifically, to determine whether increased thromboxane (TxA2) production by the burn wound was responsible for the accentuated lung injury. Thirty-two unanesthetized sheep with lung and soft tissue lymph fistulae were studied. Twelve sheep were given a sublethal dose of intravenous E. coli endotoxin (2 micrograms/kg). A characteristic two-phase injury was noted as evidenced by early pulmonary hypertension and hypoxia and later increased lung permeability. TxA2 was significantly increased in lung lymph as well as aortic plasma relative to venous plasma, indicating the lung to be the source. Twelve of 12 sheep survived. Five of 13 sheep died from endotoxemia when given 3-5 days after a 25% total body surface (TBS) burn and five of seven died with endotoxin (2 micrograms/kg) and a 50% burn. Physiologic parameters were at preburn levels before endotoxin. Animals died both during the early phase from hypoxia and the later phase due, in large part, to increasing pulmonary dysfunction. Absolute levels of TxA2 were not increased in the postburn animals, nor was there a clear release of TxA2 from burn tissue to explain the accentuated response. Prostacyclin levels were, however, less elevated in postburn animals in response to endotoxin, thereby altering the TxA2/PGI2 ratio in favor of TxA2. However, a cause and effect relationship between the increased lung injury and TxA2 remains undetermined. Lymph flow or lymph protein content was not altered in burn tissue in response to endotoxin.

Topics: Animals; Burns; Endotoxins; Epoprostenol; Escherichia coli; Female; Hemodynamics; Hypertension, Pulmonary; Lung; Lymph; Oxygen; Partial Pressure; Sheep; Thromboxane A2; Thromboxane B2; Time Factors

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

We determined the effects of extracorporeal perfusion with a constant flow (75 ml . min-1 . kg-1) of autologous blood on hemodynamics and fluid balance in sheep lungs isolated in situ. After 5 min, perfusate leukocyte and platelet counts fell by two-thirds. Pulmonary arterial pressure (Ppa) increased to a maximum of 32.0 +/- 3.4 Torr at 30 min and thereafter fell. Lung lymph flow (QL), measured from the superior thoracic duct, and perfusate thromboxane B2 (TXB2) concentrations followed similar time courses but lagged behind Ppa, reaching maxima of 4.1 +/- 1.2 ml/h and 2.22 +/- 0.02 ng/ml at 60 min. Lung weight gain, measured as the opposite of the weight change of the extracorporeal reservoir, and perfusate 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration increased rapidly during the first 60 min and then more gradually. After 210 min, weight gain was 224 +/- 40 g and 6-keto-PGF1 alpha concentration, 4.99 +/- 0.01 ng/ml. The ratio of lymph to plasma oncotic pressure (pi L/pi P) at 30 min was 0.61 +/- 0.06 and did not change significantly. Imidazole (5 mM) reduced the changes in TXB2, Ppa, QL, and weight and platelet count but did not alter 6-keto-PGF1 alpha, pi L/pi P, or leukocyte count. Indomethacin (0.056 mM) reduced TXB2, 6-keto-PGF1 alpha, and the early increases in weight, Ppa, and QL but did not alter the time courses of leukocyte or platelet counts. Late in perfusion, however, Ppa and QL were greater than in either untreated or imidazole-treated lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Hypertension, Pulmonary; Imidazoles; Indomethacin; Lung; Lymph; Organ Size; Perfusion; Pulmonary Circulation; Sheep; Thromboxane B2; Time Factors; Water-Electrolyte Balance

We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Blood Gas Analysis; Body Fluids; Consciousness; Endotoxins; Escherichia coli; Hemodynamics; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Leukocyte Count; Lung; Methacrylates; Oxidoreductases; Platelet Count; Pulmonary Edema; Sheep; Thromboxane B2; Thromboxane-A Synthase

The endothelium regulates the concentrations of several types of vasoactive substances that affect pulmonary vascular tone, and endothelia can oppose vasoconstriction in some circumstances by releasing vasodilators. To assess some of these endothelial functions in patients with pulmonary hypertension, we made measurements of selected vasoactive substances before and during attempts at pharmacologic vasodilatation. Studies were performed in 16 patients (1 1/2 to 23 years of age) with either idiopathic pulmonary hypertension (n = 11) or pulmonary hypertension as a consequence of unexpected early pulmonary vascular disease accompanying congenital heart defects (n = 5). In six of ten children, norepinephrine levels were elevated, and in two of the six, the concentrations of norepinephrine were greater in the aorta than in the pulmonary artery. In four out of 16 patients, thromboxane levels were increased, and in three of the four, the concentrations of thromboxane were greater in the aorta than in the pulmonary artery. These concentration gradients suggest pulmonary release of these vasoconstrictors. Identification of the contribution to pulmonary vasoconstriction made by changes in the endothelial metabolism of vasoactive substances may lead to a more fundamental understanding of the control of the pulmonary circulation, and hence lead to more specific modes of therapy for pulmonary hypertension.

Topics: Adolescent; Adult; Blood Pressure; Child; Child, Preschool; Endothelium; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Norepinephrine; Thromboxane A2; Thromboxane B2; Vasoconstriction; Vasodilation

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Gas Analysis; Cell Adhesion; Complement Activation; Hypertension, Pulmonary; Leukocytes; Lung; Prostaglandin-Endoperoxide Synthases; Sheep; Thromboxane B2; Zymosan

We tested the hypothesis that monocrotaline would activate arachidonic acid metabolism in rats. If activation occurred before the pulmonary hypertension developed, arachidonate metabolites could play a role in the hypertensive monocrotaline injury. We found that 1 wk after monocrotaline administration 6-ketoprostaglandin F1 alpha and leukotriene C4 were increased in lung lavages. At 3 wk when pulmonary hypertension was well developed, lung lavage contained increased 6-ketoprostaglandin F1 alpha and thromboxane B2. In addition, the number and activity of white blood cells in the lavages was increased, and abnormal alveolar macrophages were present. The lung extract contained slow-reacting substances including leukotriene D4. Indomethacin administration inhibited the formation of cyclooxygenase metabolites but did not prevent pulmonary hypertension. Diethylcarbamazine administration reduced the numbers and activity of inflammatory cells, increased pulmonary hypertension, prevented right ventricular hypertrophy, and inhibited the formation of slow-reacting substances. We concluded that arachidonate metabolism was activated before pulmonary hypertension developed, that the inflammatory cells in the alveolus accompanied the hypertensive process, and that diethylcarbamazine attenuated both the monocrotaline-induced inflammatory response and the pulmonary hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Biological Assay; Diethylcarbamazine; Enzyme Activation; Guinea Pigs; Hypertension, Pulmonary; Indomethacin; Leukocyte Count; Lipoxygenase; Male; Monocrotaline; Muscle Contraction; Pneumonia; Prostaglandin-Endoperoxide Synthases; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; SRS-A; Therapeutic Irrigation; 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

The effects of cyclooxygenase inhibition on the reaction to a toxin isolated from group B beta-hemolytic streptococci, type III, were studied in seven sheep instrumented for chronic measurement of pulmonary lymph flow, pulmonary artery and left atrial pressures. Each sheep was infused with toxin alone on one day and with indomethacin plus toxin on a different day in random order. The toxin alone caused a two-phased reaction. After the infusion of toxin, alone, in the initial phase, pulmonary artery pressure increased from 16.5 +/- 1.2 mmHg to 47.1 +/- 4.8 mmHg and the rectal temperature rose from 39.7 +/- 0.13 degree C to 40.9 +/- 0.16 degree C. During the second phase, the granulocyte count decreased to less than 10% of baseline values and the lymph protein clearance increased from 4.8 +/- 1.2 ml/h to 10.02 +/- 1.4 ml/h, suggesting increased pulmonary vascular permeability. Indomethacin pretreatment prevented the initial phase of pulmonary hypertension, the increases in thromboxane and prostacyclin metabolites in lung lymph, and the febrile response to toxin infusion but did not modify the granulocytopenia or the increased pulmonary vascular permeability. It appears that the hemodynamic changes are independent from the pulmonary vascular changes, and that prostaglandin endoperoxides or their metabolites are necessary for the fever and the acute pulmonary hypertension.

Topics: Animals; Bacterial Toxins; Capillary Permeability; Cyclooxygenase Inhibitors; Fever; Granulocytes; Hypertension, Pulmonary; Indomethacin; Lung; Lymph; Lymphopenia; Prostaglandins F; Sheep; Streptococcus agalactiae; Thromboxane B2

Infusion into sheep of plasma containing zymosan-activated complement produces leukopenia, pulmonary leukostasis, and pulmonary artery hypertension. We previously demonstrated a close relationship between the pulmonary vascular response and elevations of plasma thromboxane. We have investigated the source of thromboxane synthesis in this model. Plasma containing zymosan-activated complement added to whole blood did not stimulate thromboxane synthesis. This observation suggested that leukocytes do not synthesize thromboxane directly in response to complement added to whole blood did not stimulate thromboxane synthesis. This observation suggested that leukocytes do not synthesize thromboxane directly in response to complement. Sheep rendered severely thrombocytopenic by the administration of antiplatelet serum responded to complement infusion in the usual way. Pretreatment with aspirin (10 mg/kg) protected sheep against the pulmonary vascular response and completely blocked thromboxane synthesis. Transfusion of functional platelets did not restore these responses. Twenty-four hours after aspirin treatment, in vivo thromboxane synthesis was significantly greater than platelet thromboxane synthesis in vitro. Thromboxane is synthesized by a tissue which recovers cyclooxygenase enzyme activity at a rate that is more rapid than platelet turnover. Sheep lung synthesizes thromboxane actively in vitro. It is postulated that leukocytes exposed to activated complement components damage pulmonary vascular endothelial cells and stimulate synthesis of thromboxane A2 which causes pulmonary vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Complement Activation; Female; Hypertension, Pulmonary; In Vitro Techniques; Leukocytes; Lung; Male; Pulmonary Artery; Sheep; Thrombocytopenia; Thromboxane B2; Thromboxanes

Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG) F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 +/- 0.82 to 0.147 +/- 0.032 ng/ml (P less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Hypertension, Pulmonary; Male; Methacrylates; Oxidoreductases; Papio; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase

Topics: Animals; Dinoprost; Endotoxins; Escherichia coli; Hemodynamics; Hypertension, Pulmonary; Leukopenia; Lung; Nitrogen Mustard Compounds; Prostaglandins F; Pulmonary Circulation; Sheep; Thromboxane B2; Thromboxanes

We assessed the effect of a specific thromboxane synthetase inhibitor (an imidazole derivative) on pulmonary hemodynamics and the concentrations of TxB2 (TxA2), 6-keto-PGF1 alpha (PGI2), and PGF2 in pulmonary lymph and transpulmonary blood samples following intravenous administration of E. coli endotoxin (1 microgram/kg) in sheep. In control animals the rise in pulmonary artery pressure correlated with increases in plasma and lymph TxB2 concentrations and large transpulmonary concentration gradients of this metabolite were measured. In imidazole treated animals both pulmonary hypertension as well as increases in plasma and lymph TxB2 concentrations were substantially reduced. In contrast, peak concentrations of 6-keto-PGF1 alpha (PGI2) and PGF2 alpha were severalfold higher than those measured in control animals. This suggests a shunting of endoperoxide metabolism towards prostacyclin and primary prostaglandins and documents the specificity of the thromboxane synthetase inhibitor. Our study provides evidence that endotoxin-induced pulmonary hypertension is mediated by pulmonary synthesis of TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Endotoxins; Escherichia coli; Female; Hypertension, Pulmonary; Imidazoles; Lymph; Oxidoreductases; Prostaglandins F; Sheep; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

We measured serial plasma concentrations of thromboxane B2 (TXB2), the stable metabolite of the putative pulmonary vasoconstrictor thromboxane A2 (TXA2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolite of the pulmonary vasodilator prostacyclin (PGI2) by double-antibody radioimmunoassay during partial venovenous bypass in 25 awake sheep. The onset of bypass caused mean pulmonary artery pressure (PAP) to increase from 16 +/- 1 to 28 +/- 2 mmHg at 12 +/- 2 min, due to an increase of pulmonary vascular resistance, followed by a return to control within 45 min. There was no systemic hypoxia. TXB2 increased simultaneously with the onset of pulmonary hypertension (PH) (236 +/- 36 to 700 +/- 120 pg/ml at 0 and 5 min) and peaked at 1,724 +/- 172 pg/ml 10 min after maximum PAP was achieved. Positive pulmonary artery-to-aortic differences of TXB2 were measured. 6-Keto-PGF1 alpha increased from 51 +/- 3 to 842 +/- 367 pg/ml at 35 min. PGF2 alpha was unchanged (130 +/- 45 pg/ml). PH, TXB2, and 6-keto-PGF1 alpha increases were blocked by pretreatment with indomethacin or ibuprofen. PH and TXB2 increases were prevented with an imidazole derivative. PH caused by a continuous infusion of an endoperoxide analog did not induce lung release of TXB2 or PGF2 alpha. We conclude that 1) transient pulmonary vasoconstriction is caused by thromboxane; 2) the lung is the primary site of thromboxane synthesis; and 3) bypass causes selective alterations in arachidonic acid metabolism rather than general activation of the cascade.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Dinoprost; Epoprostenol; Hypertension, Pulmonary; Indomethacin; Prostaglandins F; Sheep; Thromboxane A2; Thromboxane B2; Thromboxanes; Time Factors; Vascular Resistance

Topics: Animals; Cardiopulmonary Bypass; Epoprostenol; Hypertension, Pulmonary; Leukocyte Count; Platelet Count; Prostaglandins; Prostaglandins F; Radioimmunoassay; Sheep; Thromboxane B2; Thromboxanes