thromboxane-a2 and Hypertension--Pulmonary

Eicosanoids may have many potential uses in paediatric practice. Since E-type prostaglandins were first applied to treat ductus-dependent congenital heart diseases in paediatric practice, many eicosanoid-related drugs have been examined for the treatment of pathophysiological conditions in children. Prostaglandins (PG), thromboxane (TX) and leukotrienes (LT), produced from arachidonic acid in the phospholipids of cell membranes, are considered to be biologically active eicosanoids. Corticosteroids reduce eicosanoid production by impairing phospholipase A2 activation, while cyclo-oxygenase inhibiting drugs such as the nonsteroidal anti-inflammatory drugs (NSAID) suppress PG and TX production. PGE1 (alprostadil) and PGE2 (dinoprostone) therapy has been shown to improve oxygenation in neonates whose pulmonary and systemic blood flow are dependent on a patent ductus arteriosus, while epoprostenol (prostacyclin, PGI2) and beraprost (beraprost sodium), another PGI2 analogue, are often effective as acute vasodilators in paediatric pulmonary hypertension. Synthetic PGE analogues such as misoprostol have gastric antisecretory and cytoprotective effects, and are effective in both prophylaxis and treatment of NSAID-induced gastroduodenal mucosal lesions. Both alprostadil and epoprostenol have been shown to be effective in treating peripheral vascular and skin diseases. Since TX, a platelet aggregator and vasoconstrictor, has been implicated as a potential mediator of asthma, its inhibition by agents such as seratrodast (AA-2414) and ozagrel (OKY-046) has proven effective in the treatment of adult patients with asthma; studies of these agents in paediatric patients is awaited with interest. Developing the clinical use of eicosanoid-related drugs and assessing the potential use of these drugs requires a 3-phase approach: reducing the complications in the treatment of neonates with ductus-dependent congenital heart diseases and primary pulmonary hypertension requiring PGE1, PGE2 and PGI2 therapy; conducting clinical trials of the synthesis inhibitors and receptor antagonists of TXA2 and LT that have already been used in the treatment of adult patients with bronchial asthma; and evaluating the efficacy of new modulators of eicosanoid biosynthesis, such as eicosapentaenoic acid and antiallergy drugs, in the treatment of eicosanoid-related diseases in children.

Topics: Child; Cyclooxygenase Inhibitors; Ductus Arteriosus, Patent; Eicosanoids; Eicosapentaenoic Acid; Humans; Hypertension, Pulmonary; Leukotriene Antagonists; Peripheral Vascular Diseases; Skin Diseases; Thromboxane A2

Topics: Animals; Arteriosclerosis; Coronary Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Thromboxane A2

Several selective and potent thromboxane synthetase inhibitors have now been described. In this paper I shall summarize their effects on platelet aggregation, endotoxin- and thrombin-induced pulmonary hypertension, the Forssman reaction-induced thrombocytopenia, and the rat tail vein bleeding time. Although any clinical utility of thromboxane synthetase inhibition remains to be demonstrated, it may be useful in conditions where vasoconstriction or vasospasm are involved, particularly where platelet activation is a contributing factor.

Topics: Animals; Bleeding Time; Blood Platelets; Hypertension, Pulmonary; Imidazoles; Platelet Aggregation; Prostaglandin Endoperoxides; Structure-Activity Relationship; Thrombocytopenia; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Topics: Arachidonic Acids; Asthma; Humans; Hypertension, Pulmonary; Lung; Prostaglandins; Thromboxane A2

Topics: Animals; Arachidonic Acids; Chemotaxis, Leukocyte; Chromones; Dogs; Guinea Pigs; Humans; Hypertension, Pulmonary; Inflammation; Ketanserin; Leukocyte Count; Leukocytes; Lung; Piperidines; Platelet Activating Factor; Pulmonary Embolism; Respiratory Distress Syndrome; Serotonin; Serotonin Antagonists; SRS-A; Thromboxane A2

To compare the therapeutic efficacy of recombinant human brain natriuretic peptide and prostaglandin E1 in the treatment of pulmonary hypertension after mitral valve replacement.. Sixty patients with postoperative pulmonary hypertension were divided randomly into 3 groups that received saline, prostaglandin E1, and natriuretic peptide infusions for 12 hours each. The hemodynamics data were monitored consecutively, and the levels of thromboxane A2 and cyclic guanosine monophosphate were detected pretreatment, after treatment, and 1 week after surgery.. The arterial pressure, pulmonary arterial pressure, and pulmonary capillary wedge pressure decreased 1 hour after prostaglandin E1 treatment and rebounded after treatment discontinuation. The pulmonary arterial pressure and pulmonary capillary wedge pressure in the natriuretic peptide group decreased 3 hours after treatment; pulmonary arterial pressure decreased less than that of the prostaglandin group, and there was no evidence of hemodynamic rebound after treatment discontinuation. The natriuretic peptide had no significant effects on arterial pressure. In both the prostaglandin and natriuretic peptide groups, cyclic guanosine monophosphate increased after the treatment, which was even higher in the latter group. Prostaglandin E1 could lead to the decrease of thromboxane A2, which was not seen in the natriuretic peptide group.. Both brain natriuretic peptide and prostaglandin E1 can effectively reduce pulmonary hypertension; however, natriuretic peptide has a slower and milder efficacy. The effects of these 2 drugs in reducing the pulmonary arterial pressure may be mediated through different pathways.

Topics: Alprostadil; Cyclic GMP; Double-Blind Method; Female; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mitral Valve; Natriuretic Agents; Natriuretic Peptide, Brain; Thromboxane A2; Vasodilator Agents

Idiopathic pulmonary arterial hypertension (IPAH) is characterised by in situ thrombosis and increased thromboxane (Tx) A2 synthesis; however, there are no studies of antiplatelet therapy in IPAH. The aim of the current study was to determine the biochemical effects of aspirin (ASA) and clopidogrel on platelet function and eicosanoid metabolism in patients with IPAH. A randomised, double-blind, placebo-controlled crossover study of ASA 81 mg once daily and clopidogrel 75 mg once daily was performed. Plasma P-selectin levels and aggregometry were measured after exposure to adenosine diphosphate, arachidonic acid and collagen. Serum levels of TxB2 and urinary metabolites of TxA2 and prostaglandin I2 (Tx-M and PGI-M, respectively) were assessed. A total of 19 IPAH patients were enrolled, of whom nine were being treated with continuous intravenous epoprostenol. ASA and clopidogrel significantly reduced platelet aggregation to arachidonic acid and adenosine diphosphate, respectively. ASA significantly decreased serum TxB2, urinary Tx-M levels and the Tx-M/PGI-M ratio, whereas clopidogrel had no effect on eicosanoid levels. Neither drug significantly lowered plasma P-selectin levels. Epoprostenol use did not affect the results. In conclusion, aspirin and clopidogrel inhibited platelet aggregation, and aspirin reduced thromboxane metabolite production without affecting prostaglandin I2 metabolite synthesis. Further clinical trials of aspirin in patients with idiopathic pulmonary arterial hypertension should be performed.

Topics: Adult; Aspirin; Clopidogrel; Cross-Over Studies; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane A2; Ticlopidine

U46619, a synthetic analogue of thromboxane A2 was used for modeling acute stable and reversible pulmonary arterial hypertension. Administration of U46619 in high doses led to vascular collapse and inhibition of cardiac function. The doses of U46619 were empirically selected that allow attaining the target level of pulmonary hypertension without systemic hemodynamic disturbances. The possibility of attaining the target level of pulmonary hypertension and reversibility of changes after termination of U46619 infusion make this model attractive for evaluation of the efficiency of different therapeutic methods of treatment of pulmonary hypertension in large animals.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Hemodynamics; Hypertension, Pulmonary; Male; Pulmonary Arterial Hypertension; Swine; Thromboxane A2; Vasoconstrictor Agents

The aim of this study was to test the effect of cardiac output (CO) and pulmonary artery hypertension (PHT) on volumetric capnography (VCap) derived-variables. Nine pigs were mechanically ventilated using fixed ventilatory settings. Two steps of PHT were induced by IV infusion of a thromboxane analogue: PHT25 [mean pulmonary arterial pressure (MPAP) of 25 mmHg] and PHT40 (MPAP of 40 mmHg). CO was increased by 50% from baseline (COup) with an infusion of dobutamine≥5 μg kg(-1) min(-1) and decreased by 40% from baseline (COdown) infusing sodium nitroglycerine≥30 μg kg(-1) min(-1) plus esmolol 500 μg kg(-1) min(-1). Another state of PHT and COdown was induced by severe hypoxemia (FiO2 0.07). Invasive hemodynamic data and VCap were recorded and compared before and after each step using a mixed random effects model. Compared to baseline, the normalized slope of phase III (SnIII) increased by 32% in PHT25 and by 22% in PHT40. SnIII decreased non-significantly by 4% with COdown. A combination of PHT and COdown associated with severe hypoxemia increased SnIII by 28% compared to baseline. The elimination of CO2 per breath decreased by 7% in PHT40 and by 12% in COdown but increased only slightly with COup. Dead space variables did not change significantly along the protocol. At constant ventilation and body metabolism, pulmonary artery hypertension and decreases in CO had the biggest effects on the SnIII of the volumetric capnogram and on the elimination of CO2.

Topics: Anesthesia; Animals; Capnography; Carbon Monoxide; Cardiac Output; Dobutamine; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Nitroglycerin; Propanolamines; Pulmonary Artery; Pulmonary Circulation; Respiration, Artificial; Sodium; Swine; Thromboxane A2

Pulmonary hypertension (PH) is a life-threatening disease that is characterized by elevated pulmonary blood pressure, abnormally thickened pulmonary arteries, and right ventricular hypertrophy. Monocrotaline (MCT) has been used to generate an experimental model of PH in rats, with PH initiated from injuries of lung vascular endothelium. Salvia Miltiorrhiza Bge.f.alba is a widely used traditional herb in China, known to exert protective effects on vascular endothelial cell injury in animal experiments. However, the role of Salvia Miltiorrhiza Bge.f.alba in PH remains unclear. Thus, we investigated the effects of the aqueous extract of Salvia Miltiorrhiza Bge.f.alba (AESM) on MCT-induced PH and explored the pertinent mechanism. PH was induced in rats by a single subcutaneous injection of MCT (60 mg/kg body weight). Low or high dose (4.6 g/kg or 14 g/kg body weight) of AESM was then administered orally for 21 days to PH rats. Hemodynamic study showed that AESM reduced mean pulmonary artery pressure and improved right ventricle function. Lung pathological analysis revealed that AESM reduced wall thickness and lumen stenosis of pulmonary vessels. Also AESM ameliorated right ventricular hypertrophy. Measurement of biochemical parameters indicated that AESM decreased endothelin-1 and thromboxane A2 in plasma and increased nitrogen monoxide and prostacyclin in the plasma and reduced the increase of transforming growth factor β1 in lung tissue. Our results suggest that AESM may ameliorate the progression of MCT-induced PH in rats, at least in part by its protective effect on endothelial injury. Therefore, Salvia Miltiorrhiza Bge.f.alba could be useful in the treatment of PH.

Topics: Animals; Endothelin-1; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Male; Monocrotaline; Nitric Oxide; Plant Extracts; Poisons; Prostaglandins I; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Thromboxane A2; Transforming Growth Factor beta1; Ventricular Function, Right

To study the effect of celecoxib on chronic hypoxia and hypercapnic pulmonary hypertension.. SD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia+ celecoxib group (C). The content of TXB2 and 6-keto-PGF1alpha in plasma and lung were detected by the technique of radioimmunology.. (1) Mean pulmonary arteria pressure(mPAP) was significantly higher in rats of B group than those of A group. mPAP was significantly higher in rats of C group than those of B group. Differences of mPAP were not significant in three groups. (2) The content of TXB2 in plasma and lung and the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A group. The ratio of TXB2/6-keto-PGF1alpha was significantly higher and the content of 6-keto-PGF1alpha in plasma and lung was significantly lower in rats of C group than those of B group. (3) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in rats of B group than those of A group. WA/TA and PAMT were significantly higher in rats of C group than those of B group. (4) Electron microscopy showed the thickening of vessel wall and the proliferation of collagen fiber in B group and augmentation of smooth muscle cell and abundance of myofilament in pulmonary arterioles in C group.. Celecoxib can aggravate hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling by increasing the ratio of TXA2/PGI2.

Topics: Animals; Celecoxib; Chronic Disease; Cyclooxygenase 2 Inhibitors; Epoprostenol; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Male; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Thromboxane A2

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

Acute respiratory failure is a major complication of severe pneumococcal pneumonia, characterized by impairment of pulmonary microvascular barrier function and pulmonary hypertension. Both features can be evoked by pneumolysin (PLY), an important virulence factor of Streptococcus pneumoniae. We hypothesized that platelet-activating factor (PAF) and associated downstream signaling pathways play a role in the PLY-induced development of acute lung injury.. Controlled, ex vivo laboratory study.. Female Balb/C mice, 8-12 wks old.. Ventilated and blood-free-perfused lungs of wild-type and PAF receptor-deficient mice were challenged with recombinant PLY.. Intravascular PLY, but not the pneumolysoid Pd-B (PLY with a Trp-Phe substitution at position 433), caused an impressive dose-dependent increase in pulmonary vascular resistance and increased PAF in lung homogenates, as detected by reversed-phase high-performance liquid chromatography coupled to tandem mass spectrometry. The pressor response was reduced in lungs of PAF receptor-deficient mice and after PAF receptor blockade by BN 50730. PLY and exogenous PAF increased thromboxane B2 in lung effluate, and thromboxane receptor inhibition by BM 13505 diminished the pressor response to PLY. Differential inhibition of intracellular signaling steps suggested significant contribution of phosphatidylcholine-specific phospholipase C and protein kinase C and of the Rho/Rho-kinase pathway to PLY-induced pulmonary vasoconstriction. Unrelated to the pulmonary arterial pressor response, microvascular leakage of PLY was diminished in lungs of PAF receptor-deficient mice as well.. PAF significantly contributed to PLY-induced acute injury in murine lungs. The PAF-mediated pressor response to PLY depends on thromboxane and on the downstream effectors phosphatidylcholine-specific phospholipase C, protein kinase C, and Rho-kinase.

Topics: Animals; Bacterial Proteins; Disease Models, Animal; Female; Humans; Hypertension, Pulmonary; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Platelet Activating Factor; Pneumonia, Pneumococcal; Protein Serine-Threonine Kinases; Respiratory Distress Syndrome; rho-Associated Kinases; Signal Transduction; Streptolysins; Thromboxane A2

To establish an estimate for the mean pulmonary arterial pressure (mPAP) derived from noninvasive data acquired with magnetic resonance (MR) velocity-encoded sequences.. In seven sedated pigs synchronous catheter-based invasive pressure measurements (IPM) and noninvasive MR were acquired in the main pulmonary artery (MPA) at different severities of pulmonary arterial hypertension (PAH) that were caused by infusion of thromboxane A2 (TxA2). The invasively measured mPAP was correlated with the noninvasive MR velocity data and linear combination equations (LCE) were computed.. Intravenously applied TxA2 induced a dose dependent level of severity of PAH with an mPAP of up to 54 mmHg without systemic effects. The acceleration time (AT) measured with MR demonstrated the best correlation with the mPAP (r(2) = 0.75). The LCE with the highest correlation (R = 0.945, alpha < 0.01) between IPM and MR revealed a mean difference of 0, a SD of s = 4.66 and a maximal difference of 12.2 mmHg using the Bland-Altman analysis.. Applying the identified LCE allowed the estimation of the mPAP in an acute and resistance-based model of PAH with high accuracy using noninvasive MR velocity-encoded sequences.

Topics: Acute Disease; Animals; Blood Flow Velocity; Catheterization; Evaluation Studies as Topic; Hypertension, Pulmonary; Infusions, Intravenous; Magnetic Resonance Spectroscopy; Pressure; Pulmonary Artery; Pulmonary Circulation; Swine; Thromboxane A2

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

Epoprostenol has improved the outcome of patients with primary pulmonary hypertension (PPH); however, its mechanism of action remains poorly understood. Isoprostanes are easily measured markers of oxidant stress and can activate platelets leading to increased thromboxane A2 (TxA2) production. We hypothesized that oxidant stress is associated with increased TxA2 synthesis and that epoprostenol decreases oxidant stress and TxA2 production in patients with PPH. Morning urine samples were obtained from 19 patients with PPH. We measured urinary metabolites of the isoprostane, 8-iso-PGF2alpha (F2-IsoP-M), and of TxA2 (Tx-M) before and after treatment with epoprostenol in patients with PPH. Mean (+/-SE) levels of F2-IsoP-M were elevated at baseline in our patients, 863 +/- 97 pg/mg creatinine. During treatment with epoprostenol, values decreased to 636 +/- 77 pg/mg creatinine (P = 0.011), and there was a strong correlation between the change in F2-IsoP-M and follow-up pulmonary vascular resistance (R2 = 0.69, P < 0.001). Tx-M levels were markedly elevated at baseline and were unchanged with therapy. These results indicate that oxidant stress decreases with epoprostenol therapy and is associated with hemodynamic and clinical improvement. The failure of Tx-M to decrease with therapy suggests that epoprostenol does not exert a beneficial effect through inhibition of TxA2 production in patients with PPH.

Topics: Adult; Antihypertensive Agents; Dinoprost; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Oxidative Stress; Thromboxane A2; Vascular Resistance

Bone morphogenetic protein receptor-2 (BMPR2)-heterozygous, mutant (BMPR2(+/-)) mice have a genetic trait similar to that of certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of BMPR2 in the development of IPAH, we examined the phenotype of BMPR2(+/-) mice and their response to inflammatory stress.. BMPR2(+/-) mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wild-type mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO), BMPR2(+/-) mice exhibited significantly higher RVSP than wild-type mice. The increase of RVSP occurred in the first 2 weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in BMPR2(+/-) mice 4 weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and PGE2 were all increased to a similar degree in both BMPR2(+/-) and wild-type mice during 5LO transgene expression, whereas urinary endothelin-1 remained undetectable. Urinary thromboxane A2 metabolites, in contrast, were significantly higher in BMPR2(+/-) than in wild-type mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and soluble P-selectin showed a trend toward higher concentrations in BMPR2(+/-) than wild-type mice. Cell culture studies found that BMP treatment reduced interleukin-1beta-stimulated thromboxane A2 production in the pulmonary epithelial cell line A549.. BMPR2(+/-) mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A2 production, and vascular remodeling than wild-type mice.

Topics: Adenoviridae; Animals; Arachidonate 5-Lipoxygenase; Bone Morphogenetic Protein Receptors, Type II; Dinoprostone; Gene Transfer, Horizontal; Heterozygote; Hypertension, Pulmonary; Inflammation; Interleukin-1; Lung; Mice; Mice, Inbred C57BL; Mutation; Platelet Activation; Systole; Thromboxane A2

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

Decreased expression of prostacyclin synthase (PGIS) is observed in the lung vasculature of patients with pulmonary arterial hypertension and the biosynthesis of prostacyclin (PGI2) may be impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Whether it is genetically determined or develops as the disease progresses is unclear. A variable-number tandem repeat (VNTR) polymorphism has been detected in the 5'-upstream promoter region of the PGIS gene. It has been demonstrated that the alleles vary in size from three to seven repeats of nine base pairs, and transcriptional activity increased with the number of repeats. The purpose of the present study was to elucidate the association between the VNTR polymorphisms of the PGIS gene and CTEPH in Japanese subjects.. Ninety patients with CTEPH and 144 control subjects were investigated for the presence of VNTR polymorphisms. Sixty-two blood samples were obtained from CTEPH patients and the plasma concentrations of prostacyclin and thromboxane A2 metabolites were measured.. VNTR polymorphisms in the prostacyclin synthase gene were grouped into L alleles (five, six and seven repeats) and S alleles (three and four repeats). The overall distribution of the alleles and genotypes were not significantly different between CTEPH patients and the control subjects. The patients with the LL genotype had higher plasma concentrations of 6-keto-prostaglandin F1alpha than patients with the LS and SS genotypes.. Our results suggested that the specific VNTR polymorphism in the 5'-upstream promoter region of the PGIS gene regulated prostacyclin production, but did not seem to be associated with the development of CTEPH in this patient population.

Topics: Chronic Disease; Cytochrome P-450 Enzyme System; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Intramolecular Oxidoreductases; Male; Middle Aged; Minisatellite Repeats; Polymorphism, Genetic; Promoter Regions, Genetic; Pulmonary Embolism; Thromboxane A2

To study the effect of aspirin on chronic hypoxia and hypercapnic pulmonary hypertension.. SD rats were randomly divided into normal control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + aspirin group (C). The concentration of TXB2 and 6-keto-PGF1alpha in plasma and in lung were detected by the technique of radioimmunology.. (1) mPAP was significantly higher in B group than those of A and C group. Differences of mCAP were not significant in three groups. (2) Light microscopy showed that WA/TA (vessel wall area/total area) and PAMT (the thickness of medial smooth cell layer) were significantly higher in B group than those of A and C group. (3) The concentration of TXB2 and 6-keto-PGF1alpha in plasma and lung as well as the ratio of TXB2/6-keto-PGF1alpha were significantly higher in rats of B group than those of A and C group.. Aspirin may inhibit hypoxic hypercapnia pulmonary hypertension and pulmonary vessel remodeling.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Carotid Arteries; Epoprostenol; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Thromboxane A2

Acute hemodynamic effects of beraprost sodium were tested in a canine vasoconstrictive pulmonary hypertension model induced by the continuous infusion of U-46619, a thromboxane A(2)mimetic. The effects of beraprost were compared with those of prostaglandin E(1), nitroglycerin and nifedipine. Beraprost and nitroglycerin decreased pulmonary arterial pressure. On the other hand, prostaglandin E(1)and nifedipine increased pulmonary arterial pressure. All drugs except nitroglycerin increased cardiac output and decreased pulmonary vascular resistance. Beraprost was selective to pulmonary circulation, while nitroglycerin, prostaglandin E(1), and nifedipine showed poor selectivity for the pulmonary vasculature. These results suggest that the vasodilative effect of beraprost is the most selective for the pulmonary circulation among these four vasodilators.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Animals; Antihypertensive Agents; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Nifedipine; Nitroglycerin; Oxygen; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

Bacterial endotoxins stimulate endothelin-mediated, thromboxane-dependent increases in pulmonary vascular resistance in mammals, and thromboxane has been shown to cause an immediate but transient pulmonary vasoconstriction in broiler chickens. In the present study, i.v. injections of 1 mg endotoxin into anesthetized male broilers caused a pulmonary vasoconstrictive response that was delayed in onset by 15 min and that elevated the pulmonary arterial pressure by 10 mm Hg within 25 min postinjection. Thereafter, pulmonary hemodynamic variables gradually (> or = 15 min) returned toward pre-injection levels, and supplemental injections of 4 mg endotoxin during this recovery period failed to reinitiate pulmonary hypertension. In contrast, injecting the thromboxane A2 mimetic U44069 during the endotoxin recovery period triggered pulmonary vasoconstriction and pulmonary hypertension similar in magnitude to the responses triggered by U44069 before endotoxin had been administered. The time course and magnitude of the pulmonary hemodynamic responses to endotoxin were highly variable among individual broilers, whereas the individual responses to U44069 were more consistent. Unanesthetized broilers resembled anesthetized broilers in the time course, magnitude, and variability of their pulmonary hemodynamic responses to endotoxin. Overall, these observations are consistent with the hypothesis that endotoxin initiates a biochemical cascade, culminating in the delayed onset of pulmonary vasoconstriction and pulmonary hypertension within 20 min postinjection. Subsequently, the pulmonary vasculature remains responsive to large bolus injections of exogenous thromboxane mimetic; however depletion of endogenous vasoconstrictive components of the endotoxin-mediated cascade, a compensatory increase in endogenous vasodilators, or the induction of a transient cellular tolerance to endotoxin prevented fourfold higher doses of endotoxin from reversing the return toward a normal pulmonary vascular tone. Individual differences among broilers in their susceptibility to pulmonary hypertension syndrome (ascites) may be related to innate or acquired variability in their pulmonary vascular responsiveness to vasoactive mediators.

Topics: Animals; Chickens; Endotoxins; Hypertension, Pulmonary; Injections, Intravenous; Male; Poultry Diseases; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Thromboxane A2; Vascular Resistance; Vasoconstriction

TXA(2) (thromboxane A(2)) is a lipid mediator believed to be produced primarily by platelets in normal subjects, although macrophages are capable of synthesis. There is increased production of TXA(2) in patients with primary pulmonary hypertension (PPH), which may reflect augmented production by macrophages. The objective of this study was to determine if macrophages are activated in PPH and whether they contribute to the increased production of TXA(2).. Case control.. University hospital.. We measured the urinary metabolites of three mediators that predominantly derive from different cell types in vivo: (1) TX-M (platelets and macrophages), a TXA(2) metabolite; (2) prostaglandin D(2) (PGD(2)) metabolite (PGD-M); and (3) N-methylhistamine (mast cells), a histamine metabolite, in 12 patients with PPH and 11 normal subjects.. The mean (+/- SEM) excretion of both TX-M and PGD-M at baseline was increased in PPH patients, compared to normal subjects (460 +/- 50 pg/mg creatinine vs 236 +/- 16 pg/mg creatinine [p = 0.0006], and 1,390 +/- 221 pg/mg creatinine vs 637 +/- 65 pg/mg creatinine [p = 0.005], respectively). N-methylhistamine excretion was not increased compared to normal subjects. There was a poor correlation between excretion of TX-M and PGD-M (r = 0.36) and between excretion of PGD-M and methylhistamine (r = 0.09) in individual patients.. In patients with PPH, increased levels of PGD-M, without increased synthesis of N-methylhistamine, suggest that macrophages are activated. The lack of correlation between urinary metabolite levels of TXA(2) and PGD(2) implies that macrophages do not contribute substantially to elevated TXA(2) production in patients with PPH. They may, however, have a role in the pathogenesis and/or maintenance of PPH, which warrants further investigation.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Female; Humans; Hypertension, Pulmonary; Macrophage Activation; Macrophages; Male; Methylhistamines; Middle Aged; Prostaglandin D2; Prostaglandins D; Thromboxane A2

The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Sixty-six adult rabbits of either sex.. The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs.. Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group.. The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Interactions; Endothelin Receptor Antagonists; Endothelin-1; Female; Hypertension, Pulmonary; In Vitro Techniques; Male; Peptides, Cyclic; Pulmonary Circulation; Pulmonary Wedge Pressure; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Bolus i.v. injections of 1.2 N HCl elicit a rapid but transient pulmonary vasoconstriction in broiler chickens. In mammals, the pulmonary vasoconstrictive response to bolus acid injection depends on increased synthesis of thromboxane A2; however, the vascular responsiveness of domestic fowl to thromboxane previously had not been evaluated. In the present study, we tested the hypothesis that, if HCl triggers pulmonary vasoconstriction by stimulating thromboxane A2 synthesis in broilers, then bolus i.v. injections of the potent thromboxane A2 mimetic U44069 (9,11-dideoxy-9alpha,11alpha-epoxy-methanoprostaglandin++ + F2alpha; 1 micromol/mL; 0.5 mL injected volume) should trigger hemodynamic responses similar to those elicited by HCl (1.2 N; 1.5 mL injected volume). Both HCl and the thromboxane mimetic elicited twofold or greater increases in pulmonary vascular resistance, which in turn increased pulmonary arterial pressure by 50% despite concurrent reductions in cardiac output. The reductions in cardiac output were associated with reductions in stroke volume but not heart rate. The thromboxane mimetic also increased the total peripheral resistance, which minimized the reduction in mean systemic arterial pressure associated with the decrease in cardiac output. In contrast, HCl injections did not increase total peripheral resistance; consequently, the reduction in cardiac output caused the mean systemic arterial pressure to decrease by 30 mm Hg. Mannitol (2.5%; 1.5 mL) was injected i.v. as a volume control, and had no influence on any of the variables. This study provides the first direct evidence that thromboxane is a potent pulmonary vasoconstrictor in broilers, and provides support for the hypothesis that thromboxane mediates the pulmonary vasoconstrictive response to bolus i.v. injections of HCl. The differential response of the systemic vasculature to the thromboxane mimetic and HCl may indicate that cardiopulmonary responses to HCl injections are not mediated solely via thromboxane production. Alternatively, a direct dilatory effect of elevated hydrogen ion concentrations on the systemic vasculature may have counteracted any tendency for simultaneously evolved endogenous thromboxane to elicit systemic vasoconstriction.

Topics: Animals; Chickens; Hydrochloric Acid; Hypertension, Pulmonary; Injections, Intravenous; Lung; Male; Syndrome; Thromboxane A2; Vasoconstriction

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

Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF). The purpose of this investigation was to a) examine temporal patterns of TNF and arachidonic acid metabolite release in a porcine model of bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and leukotrienes to determine the relationships among these inflammatory response mediators and the alterations in cardiorespiratory dysfunction for which they are required.. Prospective, nonrandomized, controlled trial.. Laboratory at a university medical center.. Thirty-four female Yorkshire swine.. Animals were divided into six experimental groups: five septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr, gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6; prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no mediator inhibitor and served as a septic control, and one anesthesia control group (n = 6) received no intervention.. PAF receptor blockade significantly increased systemic hypotension and mixed venous oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene inhibition increased mean arterial pressure, pulmonary and systemic vascular resistance indices, and arterial and mixed venous oxygen saturation and reduced pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption, and all measured mediators. Thromboxane receptor blockade lowered TNF and leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and significantly increased arterial and tissue oxygenation compared with septic controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations, arterial hypoxemia, and oxygen consumption during sepsis and increased circulating leukotriene B4.. Elevations in plasma TNF predictably precede peak levels of eicosanoids in this model. PAF, leukotrienes, and thromboxane A2 are necessary for pulmonary hypertension during bacteremia. Systemic hypotension and increased vascular permeability are mediated by both leukotrienes and PAF. There are complex interactions among mediators during sepsis and further studies are required to define these relationships.

Topics: Aeromonas hydrophila; Animals; Arachidonic Acid; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Eicosanoids; Female; Gram-Negative Bacterial Infections; Heart Diseases; Hemodynamics; Hypertension, Pulmonary; Lipoxygenase Inhibitors; Masoprocol; Oxazoles; Oxygen; Oxygen Consumption; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Thromboxane A2; Triazoles; Tumor Necrosis Factor-alpha

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

The role of vasoactive mediators, such as endothelin-1, nitric oxide, prostacyclin, and thromboxane, in pulmonary hypertension remains undefined. This study investigated the circulating levels and transpulmonary gradients of these vasoactive mediators in patients with primary and secondary pulmonary hypertension to define whether there is increased production or decreased clearance of these substances in the lung vasculature.

Topics: Adult; Antihypertensive Agents; Endothelin-1; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nitric Oxide; Thromboxane A2; Vasodilation

It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. 36 adult rabbits of either sex.. The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.. PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).. The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.

Topics: Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Perfusion; Phenylpropionates; Piperidines; Pulmonary Artery; Pulmonary Embolism; Pyrimidines; Rabbits; Radioimmunoassay; Thromboxane A2; Time Factors; Vascular Resistance

The aim of this study was to investigate the potential role of 5-hydroxytryptamine (5-HT) on development of pulmonary hypertension during chronic exposure to mild (15% O2) and severe (10% O2) hypoxia. In isolated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-12)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was suppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed with higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ketanserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodilator response to 5-HT was suppressed in lungs from rats exposed to 10% O2 but not 15% O2 (n = 6 each). In conscious rats, intravenous administration of 5-HT potentiated the pulmonary pressor response to acute hypoxia (10% O2, n = 5), an effect that remained unchanged after pretreatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuated after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4). Treatment with 5-HT (5 nmol/h i.v. by osmotic pumps) for 2 wk in rats simultaneously exposed to 10% O2 increased pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No changes occurred in 15% O2 hypoxic rats (n = 12 each). The present findings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cyclooxygenase Inhibitors; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Infusions, Intravenous; Lung; Male; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Thromboxane A2; Tropanes; Vasoconstriction; Vasodilation

We have previously demonstrated that arterial, but not venous, vasodilatory responses to endothelium-derived nitric oxide (EDNO)-dependent agonists are enhanced in lungs isolated from rats with chronic hypoxia (CH)-induced pulmonary arterial hypertension. These data suggest that CH is associated with increased endothelial nitric oxide synthase (eNOS) activity within the pulmonary arterial vasculature. In addition, the correlation of increased pulmonary arterial pressure with selectively enhanced arterial responsiveness to EDNO-mediated agonists suggests that arterial hypertension, rather than hypoxia per se, is a contributing factor in this response. Therefore, we hypothesized that 1) CH selectively upregulates eNOS within the pulmonary arterial vasculature and 2) monocrotaline (MC)-induced pulmonary arterial hypertension selectively enhances pulmonary arterial dilation to EDNO-dependent dilators and upregulates arterial eNOS. We examined the responses to the EDNO-dependent dilators arginine vasopressin and ionomycin in U-46619-constricted isolated perfused lungs from control and MC-treated rats. Microvascular pressure was assessed by the double-occlusion technique, allowing calculation of segmental resistances. Lungs from MC-treated rats exhibited augmented arterial dilation to arginine vasopressin compared with control lungs. However, the responses to ionomycin were not different between the two groups. Quantitative immunocytochemistry was used to compare pulmonary eNOS immunoreactivity in vessels from control, CH, and MC-treated rats. eNOS staining was more intense in the arteries of CH and MC-treated rats compared with those of control animals, whereas CH and MC treatment had no effect on eNOS staining in veins. We conclude that pulmonary arterial hypertension, or altered vascular mechanical forces associated with hypertension, may be responsible for the augmented EDNO-dependent arterial dilation and upregulation of arterial eNOS in lungs from CH and MC-treated rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine Vasopressin; Blood Pressure; Chronic Disease; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Ionomycin; Lung; Male; Monocrotaline; Nitric Oxide Synthase; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

Inhaled nitric oxide (NO) causes selective pulmonary vasodilation and improves gas exchange in acute lung failure. In experimental pulmonary hypertension, we compared the influence of the aerosolized vasodilatory prostaglandins (PG) PGI2 and PGE1 on vascular tone and gas exchange to that of infused prostanoids (PGI2, PGE1) and inhaled NO. An increase of pulmonary artery pressure (Ppa) from 8 to approximately 34 mmHg was provoked by continuous infusion of U-46619 (thromboxane A2 (TxA2) analogue) in blood-free perfused rabbit lungs. This was accompanied by formation of moderate lung oedema and severe ventilation-perfusion (V'/Q') mismatch, with predominance of shunt flow (>50%, assessed by the multiple inert gas elimination technique). When standardized to reduce the Pps by approximately 10 mmHg, inhaled NO (200 ppm), aerosolized PGI2 (4 ng x kg(-1) x min(-1)) and nebulized PGE1 (8 ng x kg(-1) x min(-1)) all reduced both pre- and postcapillary vascular resistance, but did not affect formation of lung oedema. All inhalative agents improved the V'/Q' mismatch and reduced shunt flow, the rank order of this capacity being NO > PGI2 > PGE1. In contrast, lowering of Ppa by intravascular administration of PGI2 and PGE1 did not improve gas exchange. "Supratherapeutic" doses of inhaled vasodilators in control lungs (400 ppm NO, 30 ng x kg(-1) x min(-1) of PGI2 or PGE1) did not provoke vascular leakage or affect the physiological V'/Q' matching. We conclude that aerosolization of prostaglandins I2 and E1 is as effective as inhalation of nitric oxide in relieving pulmonary hypertension. When administered via this route instead of being infused intravascularly, the prostanoids are capable of improving ventilation-perfusion matching, suggesting selective vasodilation in well-ventilated lung areas.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Aerosols; Alprostadil; Animals; Edema; Epoprostenol; Hypertension, Pulmonary; In Vitro Techniques; Muscle, Smooth, Vascular; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Gas Exchange; Rabbits; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents; Ventilation-Perfusion Ratio

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

In the fetal lamb, oxygen-induced pulmonary vasodilation is attenuated by the combined use of purinergic receptor P1 and P2y antagonists, which block the effect of adenosine and adenosine triphosphate (ATP), respectively, and by N(omega)-nitro-L-arginine [an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis]. In the newborn lamb, oxygen-induced pulmonary vasodilation is not blocked by N(omega)-nitro-L-arginine. We investigated the role of ATP and adenosine in oxygen-induced pulmonary vasodilation in eight newborn lambs with pulmonary hypertension induced by the thromboxane mimic, U46619. The hemodynamic effects of hyperoxia, ATP, adenosine, sodium nitroprusside (SNP), and acetylcholine (ACh) were compared before and after purinergic receptor blockade with Cibacron blue (CB, a P2y-receptor antagonist) and 8-phenyltheophylline (8PT, a P1-receptor antagonist) individually, together, and on a separate day, after infusion of N(omega)-nitro-L-arginine. During pulmonary hypertension, combined pretreatment with 8PT and CB attenuated the decrease in pulmonary arterial pressure caused by hyperoxia (11.3 vs. 35.2%), ATP (10.6 vs. 32.2%), and adenosine (1.9 vs. 33.7%) without change in the effect of ACh or SNP (p < 0.05). N(omega)-Nitro-L-arginine attenuated the pulmonary vasodilation caused by ATP and ACh but not by hyperoxia, adenosine, or SNP. In the newborn lamb, the pulmonary vasodilating effect of both oxygen and ATP are attenuated by combined P1 and P2y purinergic-receptor antagonists. Postnatally, oxygen-induced pulmonary vasodilation appears to be mediated by ATP through purinergic receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Adenosine Triphosphate; Animals; Animals, Newborn; Endothelium, Vascular; Enzyme Inhibitors; Hemodynamics; Hypertension, Pulmonary; Nitric Oxide; Nitroarginine; Oxygen; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Purinergic Antagonists; Sheep; Theophylline; Thromboxane A2; Triazines; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Acute lung injury is associated with pulmonary hypertension, intrapulmonary shunting, and increased microvascular permeability, leading to altered oxygenation capacity. Thromboxane A2 has been found to be a central mediator in the development of septic and oleic acid (OA)-induced acute lung injury. Our previous study demonstrated a beneficial effect of preinjury thromboxane A2 receptor blockade. The current study examines the efficacy of postinjury receptor blockade on oxygenation capacity and pulmonary hemodynamics in an isolated lung model of OA-induced acute lung injury.. Four groups of rabbit heart-lung preparations were studied for 60 minutes in an ex vivo perfusion-ventilation system. Saline control lungs received saline solution during the first 20 minutes of study. Injury control lungs received an OA-ethanol solution during the first 20 minutes. Two treatment groups were used: T10, in which the thromboxane receptor antagonist, SQ30741, was infused 10 minutes after the initiation of OA infusion; and T30, in which the thromboxane receptor antagonist was infused 30 minutes after OA infusion.. Significant differences were found in oxygenation (oxygen tension in T10 = 62.6 +/- 11.7 mm Hg, T30 = 68.2 +/- 21.2 mm Hg; injury control = 40.2 +/- 9.0 mm Hg, saline control = 123.5 +/- 16.01 mm Hg; p < 0.001) and percentile change in pulmonary artery pressure (T10 = 1.1% +/- 19.4% increase, T30 = 11.2% +/- 7.3% increase; injury control = 47.6% +/- 20.5%, saline control = 4.2% +/- 6.81%; p < 0.001).. This study demonstrates that blockade of the thromboxane A2 receptor, even after the initiation of acute lung injury, eliminates pulmonary hypertension and improves oxygenation.

Topics: Animals; Bacterial Infections; Blood Pressure; Capillary Permeability; Disease Models, Animal; Ethanol; Fibrinolytic Agents; Hypertension, Pulmonary; Infusions, Intravenous; Microcirculation; Oleic Acid; Oxygen; Pulmonary Artery; Pulmonary Circulation; Rabbits; Receptors, Thromboxane; Respiratory Distress Syndrome; Thromboxane A2; Tidal Volume; Time Factors; Ventilation-Perfusion Ratio

We sought to determine whether the intrinsic pulmonary hypertensive activity of the purported thromboxane A2/prostanoid (TP) receptor antagonist, daltroban, was mediated by TP receptors, using the high efficacy TP receptor agonist, U-46619, and the silent TP receptor antagonist, SQ 29,548. In pentobarbitone-anesthetized, open-chest rats (n = 4-10 per group), non-cumulative injections of U-46619, dose-dependently increased mean pulmonary arterial pressure (MPAP) with an ED50 (geometric mean with 95% confidence limits in parentheses) of 1.4 (1.1-2.3) microg/kg i.v.. Daltroban increased MPAP in a bell-shaped manner, with an apparent ED50 [29 (21-35) microg/kg i.v.] being 21 fold less potent than that of U-46619. The maximal pulmonary hypertensive responses evoked by daltroban represented about half those induced by U-46619 (25.4+/-1.0 vs. 12.7+/-2 mmHg; P < 0.05 between groups). The TP receptor antagonist SQ 29,548 fully antagonized increases in MPAP evoked by equihypertensive doses of U-46619 (1.25 microg/kg) or daltroban (80 microg/kg). Further experiments were carried out to determine whether daltroban antagonized the pulmonary hypertensive responses evoked by the high efficacy agonist, U-46619, or by itself as receptor theory would predict for a partial agonist. Daltroban (10-2500 microg/kg) antagonized, although not fully, U-46619 (20 microg/kg)-evoked pulmonary hypertensive responses, since prominent intrinsic pulmonary hypertensive effects of daltroban were observed in the same range of doses. Furthermore, in contrast to U-46619 (1.25 microg/kg), daltroban (80 microg/kg) failed to evoke a second pulmonary hypertensive response following a previous injection, as would be expected for a partial agonist. Collectively, the results strongly suggest that daltroban behaves as a partial agonist at TP receptors in the pulmonary vascular bed of the rat in vivo.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Male; Phenylacetates; Rats; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Monocrotaline (MCT)-induced pulmonary hypertension (PH) is a useful model for the investigation of this disorder in humans. The role of thrombocytes in the genesis of PH has already been addressed; however, the exact mechanism by which they induce PH remains to be elucidated. We investigated the effects of a thromboxane A2 (TXA2) synthase inhibitor (OKY-046) and a TXA2/prostaglandin H2 (PGH2) receptor antagonist (ONO-8809) on the development of MCT-induced PH. A single dose of MCT (60 mg/kg bodyweight; BW) was injected subcutaneously in Wistar rats 24 h after the administration of OKY-046 or ONO-8809. The TXA2 inhibitors were administered by gavage daily for 3 weeks. Urinary excretion of eicosanoids was determined by radioimmunoassay. At the end of the treatment period, the lungs, heart and kidneys were morphologically examined. The per cent medial thickness of the muscular pulmonary arteries (%MT) and the ratio of the right to the left ventricular mass including the septum (RV/LV + S) increased significantly in MCT-treated rats compared with the control rats. The %MT was attenuated by the administration of ONO-8809. Either OKY-046 or ONO-8809 attenuated the increase in RV/LV + S. In addition, both TXA2 inhibitors reduced urinary excretion of 11-dehydro-TXB2, particularly during the early phase of PH, suggesting that platelet aggregation was reduced. These findings suggest that the inhibition of TXA2 by synthase inhibition or receptor antagonism reduces or delays the development of MCT-induced PH in rats, probably by inhibiting platelet aggregation.

Topics: Animals; Bridged Bicyclo Compounds; Disease Models, Animal; Eicosanoids; Fatty Acids, Monounsaturated; Hypertension, Pulmonary; Male; Methacrylates; Monocrotaline; Prostaglandin Antagonists; Rats; Rats, Wistar; Reference Values; Thromboxane A2; Thromboxane-A Synthase

Adult respiratory distress syndrome remains a major cause of morbidity and mortality. We investigated the role of thromboxane receptor antagonism in an experimental model of acute lung injury that mimics adult respiratory distress syndrome.. Three groups of rabbit heart-lung preparations were studied for 30 minutes in an ex vivo blood perfusion/ventilation system. Saline control (SC) lungs received saline solution during the first 20 minutes of study. Injury control (IC) lungs received an oleic acid-ethanol solution during the first 20 minutes. Thromboxane receptor blockade (TRB) lungs received the same injury as IC lungs, but a thromboxane receptor antagonist (SQ30741) was added to the blood perfusate just prior to study. Blood gases were obtained at 10-minute intervals, and tidal volume, pulmonary artery pressure, and lung weight were continuously recorded. Oxygenation was assessed by measuring the percent change in oxygen tension over the 30-minute study period. Tissue samples were collected from all lungs for histologic evaluation.. Significant differences were found between SC and IC lungs as well as TRB and IC lungs when comparing pulmonary artery pressure (SC = 33.1 +/- 2.2 mm Hg, TRB = 35.4 +/- 2.1 mm Hg, IC = 60.4 +/- 11.1 mm Hg; p < 0.02) and percent change in oxygenation (SC = -20.6% +/- 10.3%, TRB = -24.2% +/- 9.5%, IC = -57.1% +/- 6.2%; p < 0.03). None of the other variables demonstrated significant differences.. Thromboxane receptor blockade prevents the pulmonary hypertension and the decline in oxygenation seen in an experimental model of acute lung injury that mimics adult respiratory distress syndrome.

Topics: Animals; Blood Gas Analysis; Disease Models, Animal; Hypertension, Pulmonary; Lung; Oxygen; Rabbits; Receptors, Thromboxane; Respiratory Distress Syndrome; Thromboxane A2

Chronic hypoxia (10% O2 for 2-3 weeks) causes pulmonary hypertension and vascular remodeling in the rat. To study the role of thromboxase A2 in chronic hypoxic pulmonary hypertension, the hemodynamic effects of intravenous administration of a thromboxane analogue (STA2) were measured in chronic hypoxic (H) and normoxic (N) Sprague-Dawley rats. During anesthesia baseline pulmonary arterial pressure (PAP) was higher in H rats (34.6 +/- 1.0 mmHg) than in N rats (18.4 +/- 1.2 mmHg). Intravenous STA2 (0.3 microgram) acutely increased pulmonary artery pressure by 74% +/- 11% (25 +/- 4 mmHg) in H rats and by 47% +/- 2% (9 +/- 1 mmHg) in N rats, which indicates that both the absolute and relative acute pulmonary vasoconstriction caused by STA2 were greater in H rats. The changes in systemic arterial pressure caused by STA2 were smaller than the changes in pulmonary arterial pressure both in H rats (11% +/- 3%) and in N rats (17% +/- 3%). Lungs were isolated and perfused with saline, and the vasoconstrictive response to 0.05 microgram of STA2 in lungs (14.5 +/- 2.4 mmHg) from H rats was greater than the response to 0.1 microgram of STA2 (5.6 +/- 1.3 mmHg) in lungs from N rats. To examine whether blockade of calcium channels could suppress the vasoconstrictor response to STA2, the effects of the calcium channel blocker nicardipine hydrochloride on vasoconstriction caused by STA2 were measured in H and N rats. In vivo, the blockade of calcium channels suppressed the increase in pulmonary artery pressure caused by STA2. This suppression was greater in H rats (56% +/- 11%) than in N rats (25% +/- 4%). Similar results were obtained with isolated perfused lungs. Blockade of calcium channels suppressed the vasoconstriction caused by STA2 and this suppression was greater in H rats than in N rats. The finding that thromboxane A2 induced greater vasoconstriction in H rats than in N rats indicates that thromboxane A2 may play an important role in pulmonary hypertension, and suggests that blockade thromboxane A2 may benefit some patients with primary and secondary pulmonary hypertension. Furthermore, the finding that suppression of thromboxane-induced vasoconstriction by blockade of calcium channels was greater in H rats than in N rats indicates that such treatment may also benefit some patients.

Topics: Animals; Blood Pressure; Female; Hypertension, Pulmonary; Hypoxia; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

The ischemia-reperfusion lung injury is characterized by increased pulmonary vascular resistance, edema, and subsequent deterioration of oxygenation. Other models of acute lung injury suggest that thromboxane A2 may contribute to the pulmonary hypertension after transplantation.. We studied the effects of the selective thromboxane A2 receptor antagonist SQ 30741 on pulmonary hemodynamics and gas exchange in porcine single lung transplantation using extracorporeal circulation (right heart bypass) with separate cannulations of the right and left pulmonary arteries. Pulmonary vascular resistance was measured at equal and constant flow to each lung. Flow distribution between the lungs was registered at equal pulmonary artery pressures. Twelve pigs (weight 17 to 23 kg) were studied. At the onset of reperfusion a bolus dose of the drug (5 mg/kg) was injected into both pulmonary arteries followed by an infusion (5 mg/kg/hr) for 1 hour (SQ group, n = 6). The control group (n = 6) received an equal amount of vehicle. The systemic and pulmonary hemodynamics and blood gas values were registered during 2 hours of reperfusion.. The pulmonary vascular resistance of the transplanted lung was significantly higher compared with the native lung (p < 0.001). Administration of SQ 30741 failed to ameliorate the pulmonary pressor response of the graft in comparison with the control group. No difference was found in the systemic arterial oxygen tension between the two groups.. Thromboxane does not seem to be among the principal mediators in the pulmonary hypertension after transplantation.

Topics: Animals; Hypertension, Pulmonary; Lung Transplantation; Pulmonary Circulation; Pulmonary Gas Exchange; Receptors, Thromboxane; Reperfusion Injury; Swine; Thromboxane A2

To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Triphosphate; Animals; Animals, Newborn; Arginine; Cyclic GMP; Endothelium, Vascular; Hemodynamics; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Phosphodiesterase Inhibitors; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Purinones; Sheep; Thromboxane A2; Vasoconstrictor Agents

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Animals, Newborn; Dose-Response Relationship, Drug; Drug Administration Schedule; Hypertension; Hypertension, Pulmonary; Hypoxia; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Sheep; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

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

In this study, we investigated the hemodynamic effects and receptor-blocking properties of the nonselective endothelin antagonist bosentan in pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertension was induced by decreasing the fraction of inhaled oxygen to 0.1. In a control group of pigs, hemodynamic parameters proved to be stable through 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, and sarafotoxin 6c into the pulmonary artery resulted in pulmonary and systemic vasoconstriction during normoxia, whereas endothelin administration during hypoxic pulmonary hypertension resulted in pulmonary vasodilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulmonary vasodilatory effect of endothelin-1 during hypoxia was reduced. Furthermore, the development of hypoxic pulmonary hypertension was significantly reduced by bosentan. In contrast, bosentan did not influence the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to be activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bosentan; Cardiac Output; Endothelin Receptor Antagonists; Endothelins; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Oxygen; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Sulfonamides; Swine; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Viper Venoms

1. Angiotensin II (AII) binding density and the effect of chronic AII receptor blockade were examined in the rat model of hypoxia-induced pulmonary hypertension. 2. [125I]-[Sar1,Ile2]AII binding capacity was increased in lung membranes from rats exposed to hypoxia (10% fractional inspired O2) for 7 days compared to normal rats (Bmax 108 +/- 12 vs 77 +/- 3 fmol mg-1 protein; P < 0.05), with no significant change in dissociation constant. Competition with specific AII receptor subtype antagonists demonstrated that AT1 is the predominant subtype in both normal and hypoxic lung. 3. Rats treated intravenously with the AT1 antagonist, GR138950C, 1 mg kg-1 day-1 rather than saline alone during 7 days of exposure to hypoxia developed less pulmonary hypertension (pulmonary arterial pressure: 21.3 +/- 1.7 vs 28.3 +/- 1.1 mmHg; P < 0.05), right ventricular hypertrophy (right/left ventricle weight ratio: 0.35 +/- 0.01 vs 0.45 +/- 0.01; P < 0.05) and pulmonary artery remodelling (abundance of thick-walled pulmonary vessels: 9.6 +/- 1.4% vs 20.1 +/- 0.9%; P < 0.05). 4. The reduction in cardiac hypertrophy and pulmonary remodelling with the AT1 antagonist was greater than that achieved by a dose of sodium nitroprusside (SNP) that produced a comparable attenuation of the rise in pulmonary arterial pressure during hypoxia. 5. The data suggest that AII, via the AT1 receptor, has a role in the early pathogenesis of hypoxia-induced pulmonary hypertension in the rat.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzofurans; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Receptors, Angiotensin; Thromboxane A2

Pulmonary capillary pressure (Ppc), the major factor responsible for pulmonary edema, cannot be directly measured in intact subjects but may be estimated by analysis of the pressure decay profile after pulmonary artery catheter balloon inflation. We compared three different methods of pulmonary artery occlusion pressure (Ppao) decay profile analysis to estimates of Ppc derived from lymph flow measurements in halothane-anesthesized sheep. The relationship between Ppc and lymph flow was first determined by increasing Ppc by left atrial balloon inflation, and was then used to determine Ppc during pulmonary hypertension produced by infusion of a thromboxane analog. All three methods of Ppao decay profile analysis demonstrated a correlation with Ppc estimated from lymph flow. However, the method using a single exponential analysis significantly overestimated Ppc, and none of the methods reliably estimated changes in the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension. These results suggest that Ppao decay profile analysis as currently performed has limited application.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthesia, Inhalation; Animals; Capillaries; Cardiac Catheterization; Catheterization; Halothane; Hypertension, Pulmonary; Lymph; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Edema; Pulmonary Wedge Pressure; Reproducibility of Results; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

Inhaled nitric oxide (NO) has been shown to selectively dilate the pulmonary vasculature. Zaprinast, an inhibitor of guanosine 3',5'-cyclic monophosphate-specific phosphodiesterase, augments smooth muscle relaxation induced by endothelium-dependent vasodilators. The present study was designed to determine whether intravenous administration of Zaprinast potentiates the vasodilating effects or prolongs the duration of action of intermittent NO inhalation. Eight awake lambs with U-46619-induced pulmonary hypertension breathed three concentrations of NO (5, 10, and 20 ppm) in a random order before and during an intravenous Zaprinast infusion (0.1 mg.kg-1.min-1). Inhaled NO decreased pulmonary arterial pressure (PAP) in a dose-dependent fashion, with mean PAP reduction at 5, 10, and 20 ppm NO inhalation of 6 +/- 1, 7 +/- 1, and 9 +/- 1 (SE) mmHg, respectively. Although the Zaprinast infusion did not change the magnitude of mean PAP reduction, it caused a statistically significant reduction of pulmonary vascular resistance and prolonged the duration of action of inhaled NO (half-times of vasodilator response to 5, 10, and 20 ppm NO inhalation: 1.9 +/- 0.1, 2.1 +/- 0.2, and 2.1 +/- 0.2 min, respectively; half-times of NO inhalation with Zaprinast: 9.7 +/- 1.7, 11.5 +/- 2.2, and 12.3 +/- 2.0, respectively). Plasma concentrations as well as the transpulmonary differences of guanosine 3',5'-cyclic monophosphate were increased by the Zaprinast infusion during NO inhalation. A stable level of pulmonary vasodilation was demonstrated in four additional lambs by combining intermittent NO breathing with an intravenous infusion of Zaprinast.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Cyclic GMP; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Purinones; Sheep; Thromboxane A2; Vascular Resistance; Vasodilation

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

Because the effects of inhaled nitric oxide (NO) may be localized to its site of delivery, we studied the effects of inhaled NO on the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension in perfused rabbit lungs. Before NO administration, pulmonary hypertension was produced by infusion of the thromboxane A2 mimetic U-46619 in all lungs. Pulmonary vascular resistance was divided into arterial, microvascular, and venous components by arterial and venous occlusion techniques. In the buffer-perfused lung, all doses of inhaled NO (5, 20, and 80 ppm) produced small decreases (approximately 3 mmHg) in pulmonary arterial pressure (Ppa), with equivalent proportional reductions in all segmental vascular resistances. Similar results were obtained after an extended inhaled NO dose range of 20, 80, and 240 ppm. In the buffer-perfused lung, inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) potentiated the effects of U-46619. Subsequent inhaled NO administration produced larger decreases (approximately 7 mmHg) in Ppa with equivalent proportional reductions in all segmental vascular resistances. In the blood-perfused lung, L-NAME did not alter baseline pulmonary pressures. Administration of inhaled NO during U-46619-induced pulmonary hypertension produced dose-related decreases in Ppa. The highest dose (80 ppm) of inhaled NO decreased Ppa by 3.5 mmHg, with equivalent proportional reductions in all segmental vascular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Arginine; Blood Pressure; Dose-Response Relationship, Drug; Hypertension, Pulmonary; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Wedge Pressure; Rabbits; Respiration, Artificial; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

The hemodynamic effects of endothelin-1 (ET-1) are mediated by at least two distinct receptors: ETa and ETb receptors. Recently, ETb receptor agonists (4 Ala ET-1 and IRL 1620) were developed. To investigate the role of ETb receptor activation on the pulmonary and systemic circulations, we studied the hemodynamic effects of intrapulmonary arterial injections of these receptor agonists in 10 intact newborn lambs. At rest, 4 Ala ET-1 (290-1,725 ng/kg) changed no hemodynamic variables. IRL 1620 (180-1,095 ng/kg) decreased mean pulmonary arterial pressure (PAP, 16.8% +/- 15.0 and 17.8% +/- 8.5, p < 0.05) and left pulmonary artery blood flow (21.6% +/- 22.1 and 33.4% +/- 27.7, p < 0.05) at the two highest doses only. During U46619-induced pulmonary hypertension, both 4 Ala ET-1 (3.2% +/- 8.0 to 15.9% +/- 6.4, p < 0.05) and IRL 1620 (8.7% +/- 6.3 to 21.9% +/- 4.1, p < 0.05) produced selective dose-dependent decreases in PAP. The decrease in mean PAP induced by 4 Ala ET-1 and IRL 1620 was attenuated by N omega-nitro-L-arginine [an inhibitor of endothelium-derived nitric oxide (EDNO) synthesis] (16.6% +/- 3.5 vs. 5.9% +/- 2.3 and 16.2% +/- 3.4 vs. 6.6% +/- 2.8, p < 0.05) and by glybenclamide (a blocker of ATP-dependent potassium channels) (18.2% +/- 7.9 vs. 7.5% +/- 8.3 and 14.7% +/- 3.6 vs. 6.3% +/- 3.2, p < 0.05). ETb receptor activation produces selective pulmonary vasodilation during pulmonary hypertension in intact newborn lambs. The vasodilating properties are mediated in part by release of ENDO and by potassium channel activation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Arginine; Blood Pressure; Disease Models, Animal; Endothelins; Endothelium, Vascular; Glyburide; Hypertension, Pulmonary; Injections, Intra-Arterial; Nitroarginine; Peptide Fragments; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Circulation; Regional Blood Flow; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; Vasodilation

By adding antigen cells into perfusate circulation, a great increase in pulmonary arterial pressure was observed in isolated perfused lung from rabbits previously immunized with human O-N type erythrocytes. To investigate whether thromboxane A2 is the main mediator in pulmonary vasoconstrictive response, we injected antigen erythrocytes into the reservoir after administration of putative inhibition as follows: indomethacin (5 mg/kg, thromboxane A2 synthetase inhibitor), KT2-962 (.1 mg/kg, thromboxane receptor blocker), and pyrilamine (.1 mumol, H1 blocker). Pulmonary vasoconstrictive response after antigen challenge was significantly blocked by both indomethacin and KT2-962, but not by H1 blocker. Although the H1 blocker, pyrilamine, did not significantly block the pulmonary vasoconstrictive response, it did significantly block the bronchoconstrictive response after antigen challenge; however, the bronchoconstrictive response was not blocked by either indomethacin or KT2-962. We conclude that thromboxane is the main mediator in the pulmonary vasoconstrictive response, and histamine is the main mediator in the bronchoconstrictive response.

Topics: Animals; Antigens; Benzenesulfonates; Blood Pressure; Bronchoconstriction; Cycloheptanes; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Erythrocytes; Histamine; Histamine H1 Antagonists; Humans; Hypertension, Pulmonary; In Vitro Techniques; Indomethacin; Perfusion; Pulmonary Artery; Pyrilamine; Rabbits; Receptors, Thromboxane; Thromboxane A2

Nitric oxide (NO), a labile humoral factor produced by vascular endothelial cells, is a potent vasodilator and an important mediator of pulmonary vascular tone. Nucleophile/NO adducts are a new class of compounds that spontaneously and predictively release NO. We investigated the hemodynamic effects of intravenous (i.v.) infusions of a recently developed NO-donor drug, the diethylamine-nitric oxide adduct (DEA/NO), in 17 intact newborn lambs. At rest, DEA/NO (1-2 microgram.kg-1.min-1) produced dose-dependent decreases in mean pulmonary (from 10.6 +/- 8.6 to 21.2 +/- 7.9%, p < 0.05) and systemic arterial pressure (from 13.2 +/- 11.7 to 31.0 +/- 15.4%, p < 0.05). Similarly, during pulmonary hypertension induced by infusion of U46619, DEA/NO (0.5-2.0 micrograms.kg-1.min-1) produced dose-dependent decreases in mean pulmonary (from 7.3 +/- 5.6 to 24.1 +/- 13.3%, p < 0.05) and systemic arterial pressure (from 2.2 +/- 3.8 to 20.3 +/- 12.9%, p < 0.05). Cardiac output (CO), heart rate (HR), systemic arterial blood gases, and pH were unchanged; atrial pressures decreased at higher doses. Equimolar infusions of S-nitroso-N-acetyl-penicillamine, nitroglycerin (NTG), and sodium nitroprusside (SNP) produced similar decreases in pulmonary and systemic arterial pressure. The nucleophile/NO adducts are potent vasodilators; their predictable and quantitative release of NO make them potentially useful research tools. In addition, because these compounds may decrease the incidence of tolerance and the risk from toxic metabolites associated with use of other nitrovasodilators, they may be clinically useful.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blood Pressure; Diethylamines; Dose-Response Relationship, Drug; Hemodynamics; Hypertension, Pulmonary; Infusions, Intravenous; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

HA1004, an isoquinolinesulfonamide and a cyclic nucleotide-dependent protein kinase inhibitor, is an intracellular calcium antagonist that produces vascular smooth muscle (VSM) relaxation in vitro. We studied the hemodynamic effects of intravenous (i.v.) infusions of HA1004 (0.1-2.0 mg/kg) in vivo in 8 newborn lambs, at rest and during pulmonary hypertension induced either by the i.v. infusion of U46619, a thromboxane A2 (TXA2) mimic, or by alveolar hypoxia. For comparison, we also studied the hemodynamic effects of i.v. infusions of nifedipine (15 and 40 micrograms/kg/min), a calcium entry blocker. At rest, HA1004 produced slight but significant changes in pulmonary and systemic arterial pressure (PAP, SAP) and pulmonary and systemic vascular resistances (PVR, SVR) (p < 0.05). During pulmonary hypertension induced by U46619, HA1004 decreased PAP 12-23% and PVR 9-33% (p < 0.05), whereas SAP decreased 7% and SVR decreased 14% at only one dose (p < 0.05). During pulmonary hypertension induced by alveolar hypoxia, HA1004 decreased PAP 6-32% and PVR 11-30% (p < 0.05), whereas SAP decreased 15% only at the highest dose (p < 0.05). Linear regression analysis of the pooled data demonstrated that HA1004 caused selective pulmonary vasodilation during pulmonary hypertension. Nifedipine decreased PAP 6 and 14% and SAP 5 and 17% during pulmonary hypertension. In newborn lambs with pulmonary hypertension, HA1004, an intracellular calcium antagonist, is more selective and potent than nifedipine, a calcium entry blocker, in decreasing PAP and therefore may be useful in treatment of children with pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Calcium Channel Blockers; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Infusions, Intravenous; Isoquinolines; Muscle Relaxation; Nifedipine; Prostaglandin Endoperoxides, Synthetic; Protein Kinase Inhibitors; Pulmonary Alveoli; Regression Analysis; Sheep; Sulfonamides; Thromboxane A2

We investigated the possibility that the selective angiotensin II type 1 (AT1) receptor antagonist, losartan, interacts with thromboxane A2/endoperoxide (TxA2/PGH2) receptors. We measured changes in mean pulmonary arterial pressure (MPAP) induced by the stable TxA2 analogue, U-46619, during blockade of either TxA2/PGH2 or AT1 receptors, in anesthetized, open chest rats (n = 4-8 per group). U-46619 (1.25 and 10 micrograms/kg) dose-dependently increased MPAP. The U-46619 (1.25 micrograms/kg)-evoked increase in MPAP (approximately 51%; p < 0.01) was dose-dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 (approximately 94 and 102% at 0.63 and 2.5 mg/kg, respectively; both p < 0.05). Losartan also dose-dependently reduced this increase (approximately 11 and 65% at 2.5 and 10 mg/kg, respectively; p = NS and p < 0.05, respectively). Furthermore, losartan dose-dependently prevented the increase in MPAP (approximately 112%) induced by an 8 fold higher dose of U-46619 (10 micrograms/kg) by approximately 9 and 75% at doses of 10 and 40 mg/kg, respectively; p = NS and p < 0.05, respectively. Thus, selective activation of TxA2/PGH2 receptors by the TxA2 analogue, U-46619, induced pulmonary hypertension, which was specifically inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 and the AT1 receptor antagonist, losartan, suggesting that the latter compound exerts antagonist activity at TxA2/PGH2 receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Antihypertensive Agents; Biphenyl Compounds; Hypertension, Pulmonary; Imidazoles; Losartan; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Tetrazoles; Thromboxane A2; Vasoconstrictor Agents

Endothelin-1 (ET-1) is a polypeptide that has potent hemodynamic effects on the pulmonary circulation. To determine whether there are changes in these effects with increasing postnatal age, we investigated the effects of ET-1 (250 ng/kg) at rest and during pulmonary hypertension in eight lambs (< 1 wk old) and 11 juvenile sheep (6-12 mo old). At rest, ET-1 did not change pulmonary arterial pressure in lambs, but increased pulmonary arterial pressure by 64.0 +/- 37.5% (p < 0.05) in sheep. During pulmonary hypertension, ET-1 produced greater decreases in pulmonary arterial pressure in lambs than in sheep (26.6 +/- 3.4% versus 18.7 +/- 8.3%, p < 0.05). In juvenile sheep, the increase in resting pulmonary arterial pressure produced by ET-1 was inhibited by meclofenamic acid, an inhibitor of prostaglandin synthesis (40.3 +/- 9.9% versus 2.3 +/- 4.7%, p < 0.05); during pulmonary hypertension, the decrease in pulmonary arterial pressure produced by ET-1 was inhibited by N omega-nitro-L-arginine, an inhibitor of endothelium-derived nitric oxide synthesis (21.4 +/- 10.7% versus 8.0 +/- 3.6%, p < 0.05) and by glybenclamide, an ATP-dependent potassium-channel blocker (18.8 +/- 8.4% versus 4.0 +/- 4.4%, p < 0.05). The hemodynamic effects of ET-1 on the pulmonary circulation are dependent on postnatal age. Pulmonary vasoconstriction is mediated by prostaglandin production, and pulmonary vasodilation is mediated, in part, by release of endothelium-derived nitric oxide and activation of ATP-dependent potassium channels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aging; Animals; Arginine; Endothelins; Glyburide; Hemodynamics; Hypertension, Pulmonary; Meclofenamic Acid; Nitric Oxide; Nitroarginine; Potassium Channel Blockers; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Pulmonary Circulation; Sheep; Thromboxane A2; Vasoconstrictor Agents

Cardiorespiratory variables were measured continuously in five conscious goats before and after the infusion of U-46619 at a dose of either 2, 4, or 6 micrograms.kg-1.5 min-1. Infusion of U-46619 led to immediate increases in pulmonary arterial blood pressure (ABP) that were sustained for up to 15 min after the end of the infusion. Systemic ABP also increased, but the relative increase from control was less than the pulmonary pressor response. At the highest dose, U-46619 elicited a delayed tachypneic response that was greatest several minutes after the infusion was stopped. U-46619 was also infused simultaneously with sodium nitroprusside to clamp ABP pressure at baseline levels to determine whether stimulation of baroreceptors might contribute to the latency of the tachypneic response. Although sodium nitroprusside infusion prevented the increase in ABP, the increase in breathing frequency was still delayed 3-4 min from the start of the infusion. We conclude that U-46619 elicits pulmonary and systemic arterial hypertension in the conscious goat. At the higher dose U-46619 also elicits a delayed tachypnea that remains delayed even if ABP is normal.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Gas Analysis; Blood Pressure; Female; Goats; Hypertension; Hypertension, Pulmonary; Nitroprusside; Phenylephrine; Pressoreceptors; Prostaglandin Endoperoxides, Synthetic; Respiration Disorders; Respiratory Mechanics; Thromboxane A2; Vasoconstrictor Agents

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 whether the physiological effects of prostaglandin B2 (PGB2) in the pulmonary circulation might be due to stimulation of thromboxane A2-prostaglandin H2 (TxA2/PGH2) receptors. In seven anesthetized rabbits, intravenous infusion of PGB2 (5.0 micrograms/kg) caused pulmonary hypertension as evidenced by increases in right ventricular systolic blood pressure. The magnitude of the pulmonary hypertension was comparable to that observed after infusion of the TxA2 mimetic U-46619 at a significantly lower dose (0.5 micrograms/kg), indicating that the effects of PGB2 in the intact animal are similar to TxA2 but less potent. Additionally, the TxA2/PGH2-receptor antagonist SQ-29548 blocked the pulmonary blood pressure responses elicited by PGB2. Receptor-binding studies using the TxA2 receptor ligand [3H]SQ-29548 indicated that PGB2 was a potent competitor for TxA2/PGH2 receptor binding. In agreement with the results from the intact animal, however, the efficacy of inhibition with PGB2 was significantly less than that measured for the TxA2 agonist U-46619. All of these results are consistent with the hypothesis that the physiological effects of PGB2 are mediated by stimulation of TxA2/PGH2 receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension, Pulmonary; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins B; Prostaglandins H; Pulmonary Circulation; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Adenosine is a potent pulmonary vasodilator that has been used in therapy for clinical and experimental pulmonary hypertension. To determine the receptor responsible for adenosine-induced pulmonary vasodilation, we studied the relative potency of four adenosine agonists in the isolated buffer-perfused rabbit lung during pulmonary hypertension due to infusion of the thromboxane A2 mimetic U46619. The ED50 values for pulmonary vasodilation were 1.9 x 10(-8) mol/L for 5'-N-ethylcarboxamidoadenosine (NECA), 4.5 x 10(-8) mol/L for 2-phenylaminoadenosine (CV-1808), 2.6 x 10(-6) mol/L for R(-)-N6-(2-phenylisopropyl) adenosine (R-PIA), and 6.5 x 10(-6) mol/L for cyclopentyladenosine, results consistent with an adenosine A2 receptor. Pretreatment with the adenosine A1 receptor antagonist cyclopentyltheophylline did not affect the dose-response curve to NECA, and pretreatment with the adenosine A2 receptor antagonist CGS 15943A increased the ED50 of NECA to 2.7 x 10(-7) mol/L. These results suggest that adenosine produces pulmonary vasodilation via activation of an adenosine A2 receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Animals; Hypertension, Pulmonary; Lung; Male; Perfusion; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Rabbits; Receptors, Adrenergic, alpha-2; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

Losartan is a potent, nonpeptide, angiotensin II type 1 receptor antagonist. We investigated the possibility that losartan may interact with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors. We measured changes in mean systemic (MS) and pulmonary (MP) arterial pressures (AP) as well as in hematocrit induced by the TxA2 analog, U-46619 (9, 11-dideoxy-9 alpha, 11 alpha-methanoepoxy PGF2 alpha, during pharmacological blockade of either TxA2/PGH2 receptors or the renin-angiotensin system. In anesthetized, open chest rats, U-46619 dose dependently increased MPAP whereas MSAP presented a biphasic evolution. The U-446619 (1.25 micrograms/kg)-increased MPAP (52.4 +/- 12.1%; P < .005) was dose dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha (5z),3 alpha, 4 alpha]]-7- [3-[[2-[(phenylamino)-carbonyl)hydrazino]methyl]-7-oxabiacyclo [2.2.1]hept-2-yl]-5-heptenoic acid) (10.6 +/- 2 and 2.1 +/- 1.4% at 0.63 and 2.5 mg/kg, respectively; both P < .05 vs. U-46619 in control rats). Losartan dose dependently reduced this increase (45.5 +/- 5.8 and 11.9 +/- 1.8% at 2.5 and 10 mg/kg, respectively; P = N.S. and P < .05 vs. U-46619 in control rats) whereas chronic suppression of angiotensin II generation by the converting-enzyme inhibitor enalapril (10 mg/kg/day per os for 4-5 days) did not affect this response. None of these treatments significantly reduced the U-46619-associated increase in MSAP. Moreover, the angiotensin II-evoked increases in MSAP and MPAP were suppressed by pretreatment with losartan but not with SQ 29,548.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Enalapril; Fatty Acids, Unsaturated; Hematocrit; Hydrazines; Hypertension, Pulmonary; Imidazoles; Losartan; Male; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Tetrazoles; Thromboxane A2

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

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

Clinically, it is well established that cardiopulmonary bypass results in pulmonary dysfunction. Using a recently developed preparation for cardiopulmonary bypass in the rabbit, we have been able to mimic a similar, but more severe, condition. We found that, despite normal histologic structure of the myocardium, hearts could not be weaned from bypass because of a serious increase in pulmonary vascular resistance. Histologic studies of the lungs showed severe intravascular neutrophil aggregation and marked vasoconstriction. To identify the nature and origin of the mediator responsible for the changes in the pulmonary vasculature, we subjected groups of rabbits (n = 4 per group) to bypass with cooling to 18 degrees C, circulatory arrest for 1 hour, and rewarming on bypass to 33 degrees C. Pulmonary vascular resistance was measured at the same temperature before and after bypass. Four groups were studied: group I were untreated controls; group II received the cyclooxygenase inhibitor, indomethacin (0.2 mg/kg intravenously), before operation; group III received the thromboxane A2 synthetase inhibitor, Dazmegral (5 mg/kg intravenously), before operation together with the thromboxane A2 receptor blocker GR 32191B (2 mg/kg per 30 minutes intravenously); and group IV were treated with mustine hydrochloride (1.75 mg/kg intravenously) 3 days before the experiment to deplete the neutrophils by 90%. During circulatory arrest, the heart was protected with an initial infusion (10 ml at 4 degrees C over 1 minute) of St. Thomas' Hospital cardioplegic solution. At the end of the experiment, the heart and lungs were histologically examined. In the control group, a significant increase (+395% when compared with the value recorded before bypass) in pulmonary vascular resistance was observed after bypass. However, in none of the treated groups did pulmonary vascular resistance increase significantly (percentage changes in groups II, III, and IV were -24%, 0%, and +33%, respectively). Pulmonary histologic characteristics were normal in all treated groups, and all animals were successfully weaned from bypass. These results indicate that the increase in pulmonary vascular resistance that arises as a consequence of bypass in rabbits is primarily a result of the production of thromboxane A2, a process in which the neutrophil plays a pivotal role.

Topics: Animals; Blood Cell Count; Blood Gas Analysis; Cardiopulmonary Bypass; Hypertension, Pulmonary; Lung; Neutrophils; Pulmonary Artery; Rabbits; Thromboxane A2; Vascular Resistance

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

Anisodamine, an anticholinergic drug, is widely used in China for treatment of infants with septic shock and has been reported to inhibit thromboxane synthesis in cultured cells. Thromboxane A2 plays an important role in the early pulmonary hypertension in sepsis; however, the role of thromboxane A2 later in sepsis is unclear. We tested the hypothesis that thromboxane A2 synthesis inhibition with dazmegrel, and cholinergic blockade with anisodamine, would attenuate the later phase of pulmonary hypertension induced by 4 h of group B streptococcus (GBS) infusion. 1 mg/kg of dazmegrel reversed the pulmonary hypertension and slightly increased cardiac output; these hemodynamic improvements persisted for 30-60 min. Plasma thromboxane B2 levels returned toward pre-GBS baseline values after dazmegrel treatment. Thus, thromboxane A2 is still a major mediator of pulmonary hypertension in piglets after 4 h of continuous GBS infusion. 0.5 mg/kg of anisodamine had no significant hemodynamic effect. 2 and 4 mg/kg of anisodamine each caused transient, dose-related decreases in systemic artery pressure; cardiac output also fell after the highest anisodamine dose. Pulmonary hypertension was not alleviated by anisodamine. All hemodynamic changes induced by anisodamine were short-lived and returned to preanisodamine values within 10 min. Anisodamine did not ameliorate thromboxane-mediated pulmonary hypertension in this animal model, and therefore may not inhibit thromboxane synthesis in vivo. The results of this study do not support the use of anticholinergic therapy to improve hemodynamics in GBS sepsis, but do suggest that thromboxane synthesis inhibition may be a clinically useful therapy in advanced GBS sepsis.

Topics: Animals; Blood Gas Analysis; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Parasympatholytics; Pulmonary Circulation; Solanaceous Alkaloids; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasodilator Agents

The changes of hemodynamics, hemorheology and blood gas were investigated in 28 stable COPD patients with pulmonary hypertension after short-term treatment by Radix Angelicae. The level of TXA2, PGI2 were measured in 10 of the 28 patients before and after treatment. The results show that Radix Angelicae produced significant improvement on pulmonary hypertension, blood viscosity, hematocrit and the level of TXA2 decreased significantly. But the blood gas, blood pressure and the level of PGI2 remained unchanged in all of the patients.

Topics: Blood Pressure; Blood Viscosity; Drugs, Chinese Herbal; Humans; Hypertension, Pulmonary; Lung Diseases, Obstructive; Pulmonary Artery; Thromboxane A2

Heparin neutralization by protamine after cardiac surgery and cardiopulmonary bypass may be associated with complement activation, transient leukopenia, thromboxane A2 release, and severe pulmonary hypertension. The role of leukocytes in the heparin-protamine reaction was studied in leukopenic pigs (n = 9) and a control group (n = 8). Leukopenia was induced by pretreatment with cyclophosphamide (30 mg.kg-1.day-1) for 6-7 days. During general anesthesia and after catheterization, baseline recordings of hemodynamics were performed and blood samples were withdrawn. Heparin (250 IU/kg) was injected and measurements were repeated after 10 min. Protamine sulfate (100 mg) was then infused over 2 min and measurements were performed after 2, 5, and 15 min. Prostanoid concentrations were measured by radioimmunoassays. In additional in vitro experiments, the release of thromboxane B2 from washed platelets and leukocytes after heparin-protamine stimulation was measured. Pretreatment with cyclophosphamide reduced leukocyte counts by 95.5% and the number of neutrophils by greater than 99.9%. Protamine infusion increased mean pulmonary arterial pressure by 74 and 46% and pulmonary vascular resistance by 185 and 384% in control and leukopenic animals, respectively. Thromboxane B2 concentrations increased in both groups. Stimulation by heparin, protamine, or heparin and protamine in sequence did not induce any thromboxane A2 release from washed blood cells. It is concluded that leukocytes do not contribute to pulmonary hypertension after heparin-protamine.

Topics: Animals; Blood Gas Analysis; Blood Platelets; Cyclophosphamide; Hemodynamics; Heparin; Hypertension, Pulmonary; In Vitro Techniques; Leukocyte Count; Leukocytes; Leukopenia; Prostaglandins; Protamines; Radioimmunoassay; Swine; Thromboxane A2

Intravenous injection of the ultrasound contrast agent Albunex (manufactured by Nycomed AS, Oslo, Norway; 400 million air-filled albumin microspheres per ml, mean diameter 4 +/- 1 microns) caused a dose-dependent increase of mean pulmonary arterial pressure in nine pigs. The highest dose (0.014 +/- 0.002 ml kg-1) increased mean pulmonary arterial pressure from 17 +/- 1 mmHg to 42 +/- 3 mmHg and decreased mean systemic arterial pressure from 111 +/- 9 to 93 +/- 12 mmHg. The pressure responses began 22 +/- 1 s after particle injection, and reached maximum after 51 +/- 3 s. No changes in mean pulmonary arterial pressure or mean systemic arterial pressure were observed after Albunex injections during treatment with indomethacin (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 6) or the thromboxane A2 receptor antagonist HN-11500 (10 mg kg-1 + 5 mg kg-1 h-1 i.v., n = 3). No Doppler enhancement could be detected in a carotid artery following injection of 0.12 ml kg-1 Albunex during indomethacin treatment. In five rabbits, Albunex caused Doppler enhancement in a carotid artery, and 0.48 ml kg-1 did not affect mean pulmonary arterial pressure or other haemodynamic parameters in five rabbits or in three cynomolgus monkeys. The pressure response in pigs may be explained by release of thromboxane A2 from the pulmonary intravascular macrophages during phagocytosis of the microspheres. This response to Albunex was totally absent in rabbits and monkeys.

Topics: Albumins; Animals; Blood Pressure; Contrast Media; Hypertension, Pulmonary; Indomethacin; Injections, Intravenous; Macaca fascicularis; Microspheres; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Species Specificity; Swine; Thromboxane A2

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

A case of thromboembolic pulmonary hypertension associated with long-standing thrombocytosis is presented. In this patient we found a significant local pulmonary platelet activation and thrombin generation as indicated by the existence of a transpulmonary gradient for thromboxane A2, beta thromboglobulin and fibrinopeptide A. Prolonged heparin and acetylsalicylic acid treatment resulted in improvement of clinical and hemodynamic conditions. These findings support the usefulness of anticoagulating and antiaggregating therapy in selected cases of pulmonary hypertension.

Topics: Adult; Aspirin; beta-Thromboglobulin; Fibrinopeptide A; Heparin; Humans; Hypertension, Pulmonary; Male; Platelet Activation; Splenectomy; Thalassemia; Thrombocytosis; Thromboxane A2; Time Factors

Isoproterenol, dobutamine, dopamine, and nitroprusside are four vasoactive drugs used to decrease pulmonary arterial pressure and increase cardiac output in newborns, infants, and children with sepsis. Thromboxane A2 likely produces some of the hemodynamic changes in sepsis, and U46619, a thromboxane A2 mimetic, produces similar changes in lambs. We studied the hemodynamic effects of these four vasoactive drugs in 10 spontaneously breathing newborn lambs during an infusion of U46619. After baseline hemodynamic measurements, U46619 (1-2 micrograms/kg/min) was infused to increase pulmonary arterial pressure and to decrease cardiac output. Then, either isoproterenol (0.05-1.0 micrograms/kg/min), dobutamine (5-20 micrograms/kg/min), dopamine (3-30 micrograms/kg/min), or nitroprusside (0.5-10.0 micrograms/kg/min) was infused. Every 10 min, measurements were repeated and the dose increased. U46619 significantly increased pulmonary arterial pressure by 182% and decreased cardiac output by 25% (p less than 0.05). Isoproterenol decreased pulmonary arterial pressure by 30% (p less than 0.05) and increased cardiac output by 25% (p less than 0.05) at low doses, and increased cardiac output by 115% at the maximum dose (p less than 0.05). Dobutamine decreased pulmonary arterial pressure by 11% (p less than 0.05) at low doses, and increased cardiac output by 28% (p less than 0.05) at low doses, and increased cardiac output by 71% at the maximum dose (p less than 0.05). Dopamine did not decrease pulmonary arterial pressure or increase cardiac output. Nitroprusside decreased pulmonary arterial pressure by 11% at the maximum dose (p less than 0.05). Isoproterenol and dobutamine may be more useful than dopamine and nitroprusside in the management of pulmonary hypertension and decreased cardiac output during sepsis.

Topics: Animals; Animals, Newborn; Cardiovascular Agents; Dobutamine; Dopamine; Hemodynamics; Hypertension, Pulmonary; Isoproterenol; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Sheep; Thromboxane A2

Repetitive total lung lavage in adult rabbits leads to a reproducible severe surfactant-deficient lung injury. Hypoxemia requiring mechanical ventilation occurs, accompanied by a substantial pulmonary hypertension, a large intra-alveolar protein leak, peripheral neutropenia, and pathological features of marked neutrophil infiltration with extensive hyaline membrane formation. Pretreatment with indomethacin abolishes postlavage pulmonary hypertension, preserves a slightly better lung function with higher arterial PO2, and prevents the postlavage peripheral neutropenia found in untreated animals. Pretreatment with a thromboxane A2 receptor blocker (L 655,240, Merck Frosst, Canada) also completely attenuated pulmonary hypertension, providing evidence that thromboxane A2 mediates pulmonary arterial hypertension after lung lavage. However, specific thromboxane receptor blockade had no other long-lasting beneficial effects on the ongoing injury in this model.

Topics: Animals; Hypertension, Pulmonary; Indoles; Indomethacin; Leukocyte Count; Lung; Neutrophils; Platelet Count; Pulmonary Surfactants; Rabbits; Therapeutic Irrigation; Thromboxane A2

When protamine reverses heparin anticoagulation a small fraction of patients develops pulmonary hypertension. This response is variably expressed in other species and thromboxane may be one of its mediators. We have compared the pulmonary vascular responses of pigs and monkeys to protamine (3 mg/kg, i.v.) administered 15 min after heparin (300 U/kg, i.v.). The role of thromboxane A2/prostaglandin H2 (TxA2/PGH2)-receptor activation in this response was investigated with the selective TxA2/PGH2-receptor antagonist, SQ 30,741, at a dose (1 mg/kg, i.v.) shown to inhibit U-46,619-induced pulmonary vasoconstriction by greater than or equal to 99%. SQ 30,741 or vehicle (1.5 ml saline) was given 2 min before protamine in Yucatan minipigs (n = 6-7) and African green monkeys (n = 8-9). In saline-treated monkeys and pigs, protamine increased pulmonary vascular resistance (131 +/- 46 and 478 +/- 18%, respectively) primarily by increasing pulmonary artery pressures (54 +/- 19 and 166 +/- 42%, respectively). In pigs only, pulmonary artery flow was also reduced by 33 +/- 9%. These responses peaked within 1 to 3 min and returned to baseline in approximately 5 (monkey) and approximately 15 (pig) min. In monkeys and pigs pretreated with SQ 30,741 the increases in pulmonary vascular resistance (17 +/- 4 and 16 +/- 9%, respectively, p less than 0.05) and pulmonary artery pressure (10 +/- 3 and 16 +/- 9%, respectively, p less than 0.05) were significantly inhibited. SQ 30,741 also accelerated reversal of established hypertension in pigs when given 1 min after protamine. However, transient reductions in circulating monkey leukocytes (approximately 70%) and platelets (approximately 16%) were unaffected by SQ 30,741.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Chlorocebus aethiops; Drug Interactions; Heparin; Hypertension, Pulmonary; Kinetics; Lung; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Protamines; Pulmonary Artery; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Swine; Swine, Miniature; Thromboxane A2; Vascular Resistance; Vasoconstriction

We used competitive thromboxane A2-prostaglandin endoperoxide receptor blockade (SQ 30,741) as a probe to evaluate the role of thromboxane in ovine pulmonary vasoconstriction associated with protamine reversal of heparin anticoagulation. Control heparin-protamine reactions induced rapid release of thromboxane into arterial plasma (more than 1 ng/ml plasma), a 2.5-fold increase of pulmonary artery pressure, a 20% decrease of PaO2, and a 30% reduction in arterial white blood cell concentration. After giving SQ 30,741 despite similar thromboxane release into arterial plasma after heparin-protamine challenge, acute pulmonary hypertension was significantly reduced when 94% of pulmonary vascular smooth muscle thromboxane receptors were occupied with SQ 30,741 (p less than 0.01 at 1 minute after protamine versus control heparin-protamine reaction) and was completely abolished by a 10 mg/kg i.v. bolus (p less than 0.0001 at 1 minute after protamine versus control). Peripheral leukopenia was not affected by SQ 30,741 prophylaxis, but hypoxemia was prevented. We conclude that thromboxane causes pulmonary vasoconstriction in ovine heparin-protamine-induced pulmonary hypertension. Pulmonary vasoconstriction and hypoxemia can be completely prevented by thromboxane receptor blockade.

Topics: Animals; Consciousness; Heparin Antagonists; Hypertension, Pulmonary; Hypoxia; Protamines; Receptors, Prostaglandin; Receptors, Thromboxane; Sheep; Thromboxane A2

Topics: Animals; Extracorporeal Circulation; Heparin Antagonists; Heparin, Low-Molecular-Weight; Hexadimethrine Bromide; Humans; Hypertension, Pulmonary; Protamines; Sheep; Thromboxane A2

The early increase of pulmonary artery pressure observed in different models of experimentally induced lung injury have been shown to be associated with the release of vasoconstrictive agents by activated platelets. The aim of this study was to evaluate the pattern of these metabolites, in particular TxA2, and the effects of the inhibition of their production by ASA on the modifications of pulmonary hemodynamics induced by oleic acid administration in sheep. Group I (8 sheep) was infused with oleic acid (0.09 ml/kg at 0.02 ml/min) while in group II (6 sheep) ASA (10 mg/kg i.v.) was administered 30 minutes before oleic acid infusion. In group I pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were significantly higher at the end of the infusion while cardiac output (CO) significantly decreased in comparison to baseline values. A marked increase in plasma TxB2 levels paralleled pulmonary hemodynamic changes. Also plasma 6 keto PGF levels increased after OA infusion. The early increase in PAP and PVR was significantly lower in group II (p less than 0.005) while CO did not undergo any significant change. ASA pretreatment significantly blunted the rise of TxB2 concentrations and prevented the elevation of 6 keto PGFa. These results indicate that early pulmonary hypertension in oleic acid induced injury is mainly related to TxA2 released from platelets and leukocytes and that pulmonary hemodynamic changes are significantly inhibited by ASA pretreatment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Leukocytes; Oleic Acid; Oleic Acids; Sheep; Thromboxane A2; Vascular Resistance

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Infusions, Intravenous; Premedication; Pulmonary Gas Exchange; Swine; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha

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

Escherichia coli hemolysin has been implicated as a pathogenicity factor in extraintestinal E. coli infections including sepsis. In the present study the effects of intravascular administration of hemolysin were investigated in isolated blood-free perfused rabbit lungs. Low concentrations of the toxin in the perfusate (0.05-5 hemolytic units/ml, corresponding to approximately 5-500 ng/ml), caused a dose- and time-dependent release of potassium, thromboxane A2, and prostaglandin I2, but not of lactate dehydrogenase, into the recirculating medium, as well as a dose-dependent liberation of the prostanoids into the bronchoalveolar space. These events were paralleled by a dose-dependent pulmonary hypertension, and studies with different inhibitors collectively indicated that the vasoconstrictor response was mediated predominantly by pulmonary thromboxane generation. In addition, E. coli hemolysin elicited a protracted, dose-dependent increase in the lung capillary filtration coefficient, which was independent of the prostanoid-mediated pressor response and resulted in severe pulmonary edema formation. We conclude that E. coli hemolysin can elicit thromboxane-mediated pulmonary hypertension combined with severe vascular leakage in isolated lungs in the absence of circulating inflammatory cells and humoral mediator systems, mimicking the key events in the development of acute respiratory failure in states of septicemia.

Topics: Animals; Arachidonic Acids; Calcium; Cyclooxygenase Inhibitors; Epoprostenol; Escherichia coli; Escherichia coli Infections; Hemolysin Proteins; Hypertension, Pulmonary; In Vitro Techniques; Lung; Organ Size; Potassium; Rabbits; Respiratory Insufficiency; Thromboxane A2

Leukotrienes C4 and D4 and thromboxane A2 are potent vasoconstrictors that may mediate pulmonary vasoconstriction in many clinical situations. There is a complex interaction among leukotrienes and thromboxane A2, because inhibition of thromboxane synthesis prevents some of the hemodynamic effects of exogenous leukotrienes. Similarly, if leukotrienes mediate thromboxane A2-induced pulmonary vasoconstriction, then leukotriene antagonists should attenuate the effects of a thromboxane A2-mimetic such as U46619. First, dose response curves for the hemodynamic effects of U46619 were performed on seven spontaneously breathing newborn lambs. Then a putative leukotriene receptor antagonist, FPL57231, 1 mg/kg/min, or a putative leukotriene synthesis antagonist, U60257, 30 mg/kg, was given before infusing U46619 (1 microgram/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p less than 0.05) and significant dose-dependent decreases in cardiac output and heart rate (p less than 0.05). A 1 microgram/kg/min infusion of U46619 increased pulmonary arterial pressure by 155.4% +/- 8.9 and systemic arterial pressure by 8.9% +/- 7.7 and decreased cardiac output by 19.7% +/- 12.2 and heart rate by 9.9% +/- 10.6. FPL57231 attenuated the effects of U46619. U60257 had similar effects. Therefore, the hemodynamic effects of thromboxane A2, an important mediator of the pulmonary vasoconstriction produced, for example, by group B streptococci and Escherichia coli, may be mediated by the secondary production of leukotrienes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blood Pressure; Cardiac Output; Chromones; Epoprostenol; Hypertension, Pulmonary; Lipoxygenase Inhibitors; Prostaglandin Endoperoxides, Synthetic; Sheep; SRS-A; Thromboxane A2

We evaluated the dose response to a stable thromboxane (Tx) A2 analogue (sTxA2; 0.3-30 micrograms) in the pulmonary circulation and its effect on the distribution of pressure gradients determined by the occlusion technique in isolated nonblood perfused newborn lamb lungs. The total pulmonary pressure gradient (delta Pt) was partitioned into pressure drops across the relatively indistensible arteries and veins (delta Pv) and relatively compliant vessels. We also evaluated the effects of prostacyclin (PGI2) and a Tx receptor antagonist (ONO 3708) on the sTxA2-induced pulmonary responses. Injection of sTxA2 caused a dose-related increase in the pulmonary arterial pressure, with the primary component of the increase in delta Pt (4.1 +/- 0.8 to 13.9 +/- 0.4 Torr) at 30 micrograms derived from the prominent rise in delta Pv (1.8 +/- 0.3 to 9.8 +/- 0.9 Torr). Infusion of PGI2 (0.4 microgram.kg-1.min-1) reduced the response to sTxA2 mainly by attenuating the delta Pv elevation. Infusion of ONO 3708 (100 micrograms.kg-1.min-1) completely abolished the sTxA2-induced pulmonary hypertension. Injection of sTxA2 resulted in pulmonary edema characterized by a significant increase in wet-to-dry lung weight ratio (9.13 +/- 0.35 vs. 7.15 +/- 0.41 in control lungs). The sTxA2-induced pulmonary edema was increased by PGI2 and inhibited by ONO 3708. We conclude that thromboxane-induced pulmonary hypertension is primarily produced by venoconstriction and prostacyclin may worsen the edema induced by thromboxane.

Topics: Animals; Animals, Newborn; Blood Pressure; Drug Synergism; Epoprostenol; Female; Hypertension, Pulmonary; In Vitro Techniques; Male; Pulmonary Edema; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstriction

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

Platelet-activating factor causes pulmonary hypertension, shock, hypoxemia, neutropenia, and increased pulmonary vascular permeability; some of its effects are due to thromboxane A2 release. Evidence for a possible role of these mediators in the genesis of group B Streptococcus (GBS)-induced pulmonary hypertension was sought using specific receptor antagonists for PAF and thromboxane A2 (TxA2) in anesthetized, ventilated piglets (less than or equal to 12 d of age; n = 22). Infusion of 1 X 10(8) GBS/kg/min for one hour resulted in a sustained and significant increase in pulmonary artery pressure (PPA) from 17 +/- 1 to 35 +/- 3 torr. Pretreatment with the TxA2 antagonist SQ 29548 (0.75 mg/kg intravenous), completely inhibited the effect of GBS on PPA. Pretreatment with either platelet-activating factor antagonists SRI 63072 (3 mg/kg intravenous) or SRI 63441 (1 mg/kg) did not affect the pulmonary hypertension due to GBS infusion. GBS-induced pulmonary hypertension could be reversed by SQ 29548; SRI 63072 did not affect PPA when administered to pigs with GBS-induced elevation in PPA. Inasmuch as prevention and reversal of GBS-induced pulmonary hypertension are accomplished with the TxA2 antagonist but not with PAF antagonists, these data suggest that TxA2, rather than PAF, is responsible for the early pulmonary hypertension in this model of neonatal GBS sepsis. Therefore, TxA2 antagonists may be clinically useful in treating pulmonary hypertension related to GBS sepsis.

Topics: Animals; Animals, Newborn; Blood Pressure; Epidermal Growth Factor; Hypertension, Pulmonary; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane A2

Limb ischemia in experimental animals leads to white blood cell (WBC) and thromboxane (Tx)A2 dependent pulmonary dysfunction. This study examines the pulmonary sequelae of lower torso ischemia in 20 consecutive patients aged 63 +/- 5 years (mean +/- SEM) who underwent elective abdominal aortic aneurysm surgery. After 30 minutes of aortic cross-clamping, plasma TxB2 levels had risen from 77 +/- 26 pg/ml to 359 +/- 165 pg/ml (p less than 0.01) and was temporally related to increases in mean pulmonary artery pressure (MPAP) from 18 +/- 1 to 23 +/- 3 mmHg (p less than 0.01), as well as to increases in pulmonary vascular resistance (PVR) from 0.07 +/- 0.02 to 0.12 +/- 0.02 mmHg sec/ml (p less than 0.01). Each time that the aortic clamp was repositioned and with final declamping, after 83 +/- 10 minutes, there were further increases in MPAP to a peak of 32 +/- 2 mmHg (p less than 0.01) and in PVR to 0.26 +/- 0.030 mmHg sec/ml (p less than 0.01), corresponding to a plasma TxB2 level of 406 +/- 177 pg/ml (p less than 0.01). MPAP and PVR returned to baseline values within 30 minutes of declamping. Ten minutes after removal of the aortic clamp, platelet levels had fallen from 180 +/- 41 to 97 +/- 17 X 10(3)/mm3 (p less than 0.01) and WBC levels from 8900 +/- 1100 to 4700 +/- 400/mm3 (p less than 0.01). Both platelets and WBC returned towards normal levels, but at 24 hours, while WBC was elevated at 13000 +/- 900/mm3 (p less than 0.01), platelets were 44% of baseline at 135 +/- 14 X 10(3)/mm3 (p less than 0.01). Four to 8 hours after surgery, pulmonary dysfunction was manifest by increases in physiologic shunt from 9 +/- 2% to 16 +/- 2% (p less than 0.01), and peak inspiratory pressure (PIP) from 23 +/- 2 to 33 +/- 2 cmH2O (p less than 0.01). Chest radiography demonstrated interstitial pulmonary edema in all patients, whereas pulmonary artery wedge pressure was 12 +/- 2 mmHg, excluding the possibility of left ventricular failure. After 24 hours, pulmonary edema had resolved, and the PIP and PaO2 had both returned to baseline. These data indicate that reperfusion of the ischemic lower torso leads to the synthesis of TxA2, an event temporally related to pulmonary hypertension and transient leukopenia with subsequent pulmonary microvascular injury manifest by interstitial edema.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Blood Pressure; Cardiac Output; Female; Humans; Hypertension, Pulmonary; Ischemia; Leg; Leukocyte Count; Male; Middle Aged; Platelet Count; Postoperative Complications; Pulmonary Edema; Reperfusion; Respiratory Function Tests; Thromboxane A2; Time Factors

We determined the effect of H2O2 on both the physiological and biochemical lung changes seen in the adult sheep after endotoxin. Fourteen unanesthetized adult sheep with chronic lung lymph fistula were given Escherichia coli endotoxin (1 microgram/kg) over 30 min. Seven sheep were given catalase (32,500 U/kg body wt) as an intravenous bolus 30 min before endotoxin. Four sheep were given catalase alone. Oxidant lung changes were measured using arterial plasma conjugated dienes and lung tissue malondialdehyde (MDA) content, both reflecting the lipid peroxidation process. Animals were killed 5 h after endotoxin. We found that endotoxin alone caused an early increase in pulmonary arterial pressure lung lymph flow (QL), plasma thromboxane B2, 6-keto-prostaglandin F1 alpha, and plasma conjugated dienes. A decrease in cardiac output and arterial PO2 was also seen. A three- to four-fold increase in protein-rich QL was noted at 3-4 h as well as a continued increase in arterial conjugated dienes. Lung MDA and water content were also significantly increased from base line. Catalase pretreatment significantly attenuated both the physiological changes and the prostanoid and conjugated diene release. Lung MDA and water content also remained at base line. We conclude that H2O2 plays a major role in endotoxin-induced lung injury as well as the resulting lipid peroxidation process.

Topics: Animals; Catalase; Endotoxins; Hydrogen Peroxide; Hypertension, Pulmonary; Lipid Peroxides; Lung; Prostaglandins; Sheep; Thromboxane A2; Toxemia

Acute hypoxic pulmonary vasoconstriction is attenuated by respiratory alkalosis. It is unknown if alkalosis similarly reduces pulmonary vasoconstriction produced by thromboxane A2. Respiratory alkalosis does not always attenuate persistent pulmonary hypertension in newborns, some of whom have elevated serum thromboxane B2 levels. We hypothesized that alkalosis attenuates thromboxane-induced pulmonary vasoconstriction less than it does hypoxic pulmonary vasoconstriction in infants. Hemodynamic responses to respiratory alkalosis during pulmonary vasoconstriction produced in random order by breathing 12% inspired oxygen and by infusing 0.1 micrograms/kg/min of the thromboxane-mimetic U46,619 were compared in eight 2-wk-old piglets. Hypoxia increased mean pulmonary artery pressure from 12 +/- 3 to 29 +/- 2 mm Hg and pulmonary vascular resistance (PVR) from 11 +/- 4 to 25 +/- 8 mmHg/L/min; U46,619 increased pulmonary artery pressure from 16 +/- 5 to 37 +/- 6 mm Hg and PVR from 14 +/- 5 to 51 +/- 17 mm Hg/liter/min. U46,619 also decreased cardiac output accounting in part for the greater increase in PVR compared to hypoxia-induced vasoconstriction. Respiratory alkalosis decreased PVR to 14 +/- 6 mm Hg/liter/min during exposure to hypoxia and to 28 +/- 9 mm Hg/liter/min during infusion of U46,619. In six additional piglets with U46,619-induced pulmonary vasoconstriction, the effects of lung stretch and hypocapnic alkalosis were separated by doubling tidal volume and then adding inspired CO2 to return PaCO2 to prehyperventilation levels. Respiratory alkalosis decreased PVR from 52 +/- 36 to 35 +/- 21 mm Hg/liter/min. Despite the increased tidal volume, PVR increased to 53 +/- 35 Hg/liter/min when PaCO2 returned to 44 +/- 5 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Alkalosis, Respiratory; Animals; Hemodynamics; Hypertension, Pulmonary; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pulmonary Gas Exchange; Swine; Thromboxane A2; Tidal Volume; Vasoconstriction

Chronic sepsis was induced by administering endotoxin (lipopolysaccharide--LPS) at 12-hr intervals to sheep. The animals (n = 7) responded to the first dose of LPS with increased pulmonary arterial pressure (PAP), systemic vascular resistance, plasma and lymph thromboxane B2 (TxB2) concentrations, and lung lymph flow rate concurrent with a reduction in the cardiac index (CI). Subsequent doses of LPS produced an elevation of PAP and TxB2 which was progressively attenuated and eventually disappeared. With LPS the lung lymph flow was markedly elevated and CI increased. This latter was transient and associated with a reduction in systemic vascular resistance. Concomitant with the cardiopulmonary changes prekallikrein levels were not diminished, but there was a statistically significant reduction in C1-esterase inhibitor. The administration of LPS was discontinued after 5 days and the cardiopulmonary variables rapidly returned to baseline levels. Chronic endotoxemia appears to be associated with an elevated pulmonary microvascular permeability and a tendency toward a hyperdynamic circulation but with an appreciable degree of refractoriness associated with regional hemodynamics and eicosanoid biosynthesis.

Topics: Animals; Cardiac Output; Chronic Disease; Complement C1 Inactivator Proteins; Disease Models, Animal; Drug Administration Schedule; Endotoxins; Escherichia coli; Heart Rate; Hemodynamics; Hypertension, Pulmonary; Lipopolysaccharides; Lung; Lymph; Prekallikrein; Sheep; Shock, Septic; Thromboxane A2; Time Factors; Vascular Resistance

MCT produces pulmonary vascular injury and pulmonary hypertension in rats by unknown mechanisms and provides a useful animal model with which to study chronic pulmonary hypertension. Several arachidonic acid metabolites including TxA2 and LT are present in increased concentration in lungs of rats made chronically pulmonary hypertensive with MCT or MCTP. The lack of protection afforded by cotreatment with drugs that inhibit the biosynthesis or antagonize the actions of TxA2 indicates that TxA2 does not play a major role in the pathogenesis of cardiopulmonary injury in this model. Results with DEC suggest the possibility of involvement of LT in the response to MCT and MCTP; additional work is needed to clarify the exact role of LT in this model. The roles of other biologically active lipid mediators such as platelet activating factor and HETEs are currently unknown. Increased understanding of the role of various mediators will come partly from the identification and careful use in vivo of improved drugs that have specific effects as synthesis inhibitors or receptor antagonists.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Hypertension, Pulmonary; Leukotriene B4; Lung; Monocrotaline; Pyrrolizidine Alkaloids; Rats; SRS-A; Thromboxane A2

The effects of two selective thromboxane (Tx) A2 antagonists (SQ 29,548 and SQ 28,668) on endotoxin-induced pulmonary hypertension were determined in anesthetized pigs. SQ 29,548 (10 micrograms/kg/min, i.v., n = 6) or vehicle (n = 7) was infused from 15 min before until 60 min after an intravenous infusion of Salmonella enteritidis endotoxin (1.0 microgram/kg). Within 20 min, vehicle-treated animals developed an acute 350 +/- 25% increase in pulmonary vascular resistance (PVR) with a 43% survival rate. In the presence of SQ 29,548 this initial pulmonary vasoconstriction was absent and all animals survived. However, a delayed increase in PVR of 58 +/- 20% was detected. The primary manifestation of the increase in PVR was an increase in pulmonary arterial pressure. In a similar preparation, septicemia was produced by Escherichia coli endotoxin (0.5 microgram/kg, i.v.) and SQ 28,668 (3, 10, 30 or 100 micrograms/kg/min, i.v., n = 5-6 per dose level) and vehicle (n = 6) treatments were compared. SQ 28,668 doses of 30 and 100 micrograms/kg/min mitigated the early, but not late, increases in PVR. These data demonstrate that endotoxemia in pigs produces an initial TxA2-receptor-dependent vasoconstriction and also a more slowly developing pulmonary hypertension which is probably due to other mediators.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Endotoxins; Escherichia coli; Fatty Acids, Unsaturated; Female; Hydrazines; Hypertension, Pulmonary; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Swine; Thromboxane A2

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

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

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

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

High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 +/- 27 (mean +/- SD) to 35 +/- 13 mm HG (P less than .01). The mean arterial pressure (MAP) remained at 50 +/- 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 +/- 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 +/- 4 to 20 +/- 4 mm HG (P less than .01) whereas the PVR increased 70% (P less than .01). TxB2 rose from 147 +/- 85 to 271 +/- 154 pg/mL (P less than .05), and 6-keto-PGF1 alpha rose from 105 +/- 96 to 142 +/- 110 pg/mL. These substances are the hydrolysis products of TxA2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O2, values for MAP, CO, and PVR were similar to those of the nontreatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Epoprostenol; Female; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Lung; Male; Methacrylates; Oxygen; Sheep; Thromboxane A2

Topics: Copper; Humans; Hypertension, Pulmonary; Melatonin; Thromboxane A2

Intravascular complement activation results in thromboxane (TxA2) production, pulmonary hypertension, hypoxemia, and increased lung vascular permeability. The purpose of this study was to determine the role of TxA2 as a mediator of these responses. Experiments were made in anesthetized sheep subjected to intravenous injections of zymosan-activated plasma (ZAP) every 30 min for 4 h. Sheep were pretreated with dazoxiben, a TxA2 synthetase inhibitor, or SK and F 88046, a TxA2 end-organ antagonist, and the results were compared with those from untreated sheep. Dazoxiben, but not SK and F 88046, inhibited TxA2 release. The hypertensive response averaged 74 +/- 3 cm H2O after each injection of ZAP in untreated sheep. Neither drug altered this response. Pao2 decreased an average of 20 +/- 1 mmHg in untreated sheep, 3 +/- 1 mmHg in dazoxiben-treated sheep, and 11 +/- 1 mmHg in SK and F 88046-treated sheep. Increases in lung lymph flow and lymph protein clearance were unaffected by treatment. TxA2 appears to be an important mediator of hypoxemia during intravascular complement activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Complement Activation; Hypertension, Pulmonary; Hypoxia; Imidazoles; Leukocytes; Lung Diseases; Plasma; Pulmonary Circulation; Sheep; Sulfonamides; Thromboxane A2; Zymosan

Drugs with pharmacological activity limited to the pulmonary circulation are not at present available. Serotonin antagonists, specific thromboxane A2 inhibitors and prostacyclin may offer new possibilities for the treatment of certain forms of pulmonary arterial hypertension (PAH), but their clinical efficacy remains to be evaluated. Vasodilators simultaneously influence the pulmonary and systemic vascular resistances, and their overall hemodynamic effects in patients with PAH are therefore unpredictable. Therapeutic trials with such drugs should be closely monitored to avoid serious adverse reactions. Oral administration of beta-adrenergic agents, such as salbutamol or terbutaline, is preferable to digoxin in the treatment of patients with right ventricular failure due to chronic obstructive bronchitis. Right ventricular failure following massive pulmonary embolism may be aggravated by reduced blood flow through the right coronary artery. Increase of aortic perfusion pressure (e.g. noradrenaline) should be considered as a therapeutic measure in patients with arterial hypotension.

Topics: Adrenergic beta-Agonists; Epoprostenol; Fibrinolytic Agents; Humans; Hypertension, Pulmonary; Phenylephrine; Pulmonary Circulation; Pulmonary Embolism; Serotonin Antagonists; Theophylline; Thromboxane A2; Vascular Resistance; Vasodilator Agents

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

We studied the vasoactive profile of a term infant with congenital diaphragmatic hernia and intractable pulmonary hypertension who was refractory to conventional medical management despite an early stable period. Plasma prostanoid vasoconstrictor thromboxane A2 (TxB2) levels were elevated prior to ECMO at 150pg/mL, rose to 310pg/mL with the first hour of bypass and remained elevated until 72 hours by which time they fell to less than 50pg/mL. This coincided with the decreased extracorporeal circulatory support needed to maintain systemic arterial pO2 between 70 to 90 torr. Pulmonary vasodilator prostacyclin (6-keto-PGF1 alpha) was minimally elevated prior to bypass a 50pg/mL and became undetectable. Catecholamine levels were markedly elevated prior to ECMO at 4,000pg/mL with no demonstrable pulmonary extraction of norepinephrine. Though catecholamine levels remained nonspecifically elevated, pulmonary metabolism of norepinephrine improved with bypass time to 48% at 96 hours and coincided with the overall improvement of the infant's respiratory function. These data suggest pulmonary hypertension associated with congenital diaphragmatic hernia is at least partially precipitated by alterations in prostanoid homeostasis as selective activation of thromboxane synthetase pathways rather than nonspecific activation of the entire archidonate cascade. While ECMO per se may have no lasting effect on prostanoid homeostasis, ECMO can allow a period of cardiopulmonary rest during which more physiologic prostanoid levels are established. Although activation of the sympatho-adrenal axis may contribute to pulmonary hypertension, the role of catecholamines in this infant is not clear. Return of the lungs ability to clear norepinephrine may be an additional marker of biologic lung recovery.

Topics: 6-Ketoprostaglandin F1 alpha; Epinephrine; Extracorporeal Circulation; Hernia, Diaphragmatic; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Lung; Male; Norepinephrine; Oxygenators, Membrane; Pulmonary Circulation; Respiratory Distress Syndrome, Newborn; Thromboxane A2

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

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

The lung is very susceptible to sepsis or endotoxin injury in the trauma patient. We studied the effect of an episode of hemorrhagic shock and resuscitation on the prostaglandin-induced pulmonary hypertension and leukocyte-induced increased permeability phase of endotoxin lung injury. Eight unanesthetized sheep with chronic lung lymph fistula were bled 50% of blood volume for 2 hr, then resuscitated. Thromboxane, TxA2, levels increased from 0.1 to 0.6 ng/ml during shock, while blood white cell count decreased. Both parameters returned to baseline while lung lymph flow increased twofold during resuscitation with lymph being protein-poor, indicating no increase in permeability. Lung water was not increased but some pulmonary leukostasis was evident histologically after resuscitation. We then studied the effect of this process on all immediate endotoxin insult. Seven unanesthetized sheep were given 0.7 microgram/kg E. coli endotoxin alone, and again after shock and resuscitation, in paired studies performed 3 days apart. There was no difference in either the early pulmonary hypertension or the later increased permeability phase of endotoxin lung injury when comparing the paired studies, as measured by lymph flow and protein flux. Hemorrhagic shock, despite producing a transient increase in thromboxane and pulmonary leukocyte sequestration, does not accentuate the lung injury of endotoxin if the shock state is adequately resuscitated.

Topics: Animals; Capillary Permeability; Endotoxins; Escherichia coli; Hemodynamics; Hypertension, Pulmonary; Leukocyte Count; Sheep; Shock, Hemorrhagic; Thromboxane A2

The effects of pretreatment with methylprednisolone on the reaction to a toxin isolated from group B beta-hemolytic streptococci, type III, were studied in seven sheep instrumented for chronic measurements of pulmonary lymph flow and pulmonary artery and left atrial pressure. Each sheep was infused with toxin alone on one day and with methylprednisolone plus toxin on a different day in random order. The toxin alone caused a two-phase reaction. After the infusion of toxin, alone, in the initial phase, pulmonary artery pressure increased from 16 +/- 1 to 45 +/- 5 mm Hg and the rectal temperature rose from 39.5 +/- 0.14 to 40.8 +/- 0.18 degree C. During the second phase, the peripheral blood granulocyte count decreased to 10% of baseline values and the lung lymph protein clearance increased from 5.1 +/- 1.1 to 11.2 +/- 1.8 ml/h, suggesting increased pulmonary vascular permeability. Methylprednisolone pretreatment did not alter the initial phase of pulmonary hypertension or the febrile response but completely abolished the granulocytopenia and the increased pulmonary vascular permeability. These effects are unlikely to be related to inhibition of prostaglandin synthesis. Prevention of the lung vascular injury by methylprednisolone may be related to inhibition of granulocyte accumulation in the lung.

Topics: Animals; Bacterial Toxins; Blood Pressure; Epoprostenol; Hypertension, Pulmonary; Lymph; Methylprednisolone; Polysaccharides, Bacterial; Pulmonary Artery; Sheep; Streptococcus agalactiae; Thromboxane A2

1 The administration of E. coli endotoxin (2 mg/kg i.v.) to anaesthetized cats results in a characteristic acute pulmonary response. This consists of increases in pulmonary artery pressure and airways resistance and a reduction in lung compliance. 2 Plasma concentrations of prostaglandin E2 (PGE2), PGF2 alpha, thromboxane B2 and 6-keto PGF1 alpha were measured by radioimmunoassay in aortic and pulmonary arterial blood samples before, during and after the acute pulmonary response to endotoxin. 3 Endotoxin administration resulted in the rapid release of PGF2 alpha and thromboxane B2 from the lungs. The time course of this release was parallel to that of the pulmonary hypertensive and airways responses to endotoxin. PGE2 and 6-keto PGF1 alpha were released more gradually and with greater variations between individual animals. 4 During the delayed shock phase (2 h after endotoxin) the concentrations of PGE2, PGF2 alpha and 6-keto PGF1 alpha were once again elevated in both the aorta and pulmonary artery. Thromboxane B2 concentrations were not increased at this time. 5 These results suggest that PGF2 alpha and thromboxane A2 may be mediators of the acute pulmonary responses to endotoxin.

Topics: Anesthesia; Animals; Cats; Dinoprost; Endotoxins; Escherichia coli; Female; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Prostaglandins; Prostaglandins F; Thromboxane A2

Macrophages, neutrophils, and platelets may play a role in acute edematous lung injury, such as that seen in the adult respiratory distress syndrome (ARDS), but their potential actions and interactions are unclear. Because stimulated human macrophages and neutrophils can release acetyl glyceryl ether phosphorylcholine (AGEPC), a potent platelet activator, we hypothesized that in ARDS, leukocyte release of AGEPC might stimulate platelets to release thromboxane A2 (TXA2), which then produces pulmonary hypertension and lung edema. In support of this premise, we found that pulmonary hypertension and edema occurred in isolated rabbit lungs perfused with human platelets and AGEPC, but not with platelets or AGEPC alone. Infusion of a vasodilator (nitroglycerin) to maintain base-line pulmonary artery pressures in lungs perfused with platelets and AGEPC prevented the development of lung edema suggesting that platelet and AGEPC-induced edema was hydrostatic in nature. Additional experiments suggested that the increased pressure was a result of TXA2 release from platelets stimulated by AGEPC. Specifically, preincubation of platelets with imidazole, a thromboxane synthetase blocker, prior to infusion with AGEPC significantly diminished pulmonary hypertension and prevented lung edema. Furthermore, pretreating lung preparations with 13-azaprostanoic acid, a TXA2 antagonist, before infusion of AGEPC and untreated platelets also reduced the pulmonary hypertension and blocked the lung edema. The role of TXA2 was further suggested when perfusates from lungs infused with platelets and AGEPC developed high levels of TXA2, whereas perfusates from controls did not. These results suggest that platelet aggregation induced by AGEPC may contribute to ARDS by releasing TXA2, which raises microvascular pressure and increases edema formation, especially when an underlying permeability defect is present.

Topics: Animals; Blood Platelets; Female; Hypertension, Pulmonary; Imidazoles; Lung; Male; Perfusion; Platelet Activating Factor; Pressure; Prostanoic Acids; Pulmonary Edema; Rabbits; Thromboxane A2

Topics: Albumins; Animals; Blood Platelets; Hypertension, Pulmonary; Lung; Neutrophils; Platelet Activating Factor; Pulmonary Edema; Rabbits; Thromboxane A2; Thromboxanes

Topics: Animals; Endotoxins; Epoprostenol; Escherichia coli; Female; Fistula; Hypertension, Pulmonary; Lung; Prostaglandins; Prostaglandins F; Sheep; Thromboxane A2; Thromboxanes

Topics: Animals; Burns; Capillary Permeability; Dogs; Epoprostenol; Hypertension, Pulmonary; Infections; Microcirculation; Prostaglandin Antagonists; Prostaglandins; Pulmonary Circulation; Pulmonary Embolism; Pulmonary Valve Insufficiency; Sheep; Shock, Hemorrhagic; Thromboxane A2

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