thromboxane-a2 and Hypoxia

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSA-induced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches.

Topics: Animals; Atherosclerosis; Humans; Hypoxia; Molecular Targeted Therapy; Sleep Apnea, Obstructive; Thromboxane A2

Chronic non-specific pulmonary diseases are frequently followed by the development of inflammatory-degenerative and erosive-ulcerative processes in the mucous membrane of the stomach and duodenum. The literature date are presented on the frequency of combination of these conditions, the attempt is made to assess their link from the viewpoint of pathogenesis. Disturbances of respiratory lung function and hypoxia as well as non-respiratory metabolic functions of the pulmonary tissue are regarded as etiological factors of pathological processes in the gastro-duodenal area.

Topics: Adult; Angiotensins; Arachidonic Acid; Arachidonic Acids; Chronic Disease; Duodenal Diseases; Duodenitis; Female; Gastritis; Histamine; Humans; Hypoxia; Leukotriene B4; Lung; Lung Diseases; Male; Middle Aged; Peptic Ulcer; Prostaglandins; SRS-A; Stomach Diseases; Thromboxane A2

Topics: Arteries; Arteriosclerosis; Carbon Monoxide; Cholesterol Esters; Epoprostenol; Glycosaminoglycans; Humans; Hypoxia; Muscle, Smooth, Vascular; Platelet Aggregation; Thromboxane A2

Clinical trials use placebos with the assumption that they are inert, thus all placebos are considered to be equal. Here we show that this assumption is wrong and that different placebo procedures are associated to different therapeutic rituals which, in turn, trigger different mechanisms and produce different therapeutic outcomes. We studied high altitude, or hypobaric hypoxia, headache, in which two different placebos were administered. The first was placebo oxygen inhaled through a mask, whereas the second was placebo aspirin swallowed with a pill. Both placebos were given after a conditioning procedure, whereby either real oxygen or real aspirin was administered for three consecutive sessions to reduce headache pain. We found that after real oxygen conditioning, placebo oxygen induced pain relief along with a reduction in ventilation, blood alkalosis and salivary prostaglandin (PG)E2, yet without any increase in blood oxygen saturation (SO2). By contrast, after real aspirin conditioning, placebo aspirin induced pain relief through the inhibition of all the products of cyclooxygenase, that is, PGD2, PGE2, PGF2, PGI2, thromboxane (TX)A2, without affecting ventilation and blood alkalosis. Therefore, two different placebos, associated to two different therapeutic rituals, used two different pathways to reduce headache pain. The analgesic effect following placebo oxygen was superior to placebo aspirin. These findings show that different placebos may use different mechanisms to reduce high altitude headache, depending on the therapeutic ritual and the route of administration. In clinical trials, placebos and outcome measures should be selected very carefully in order not to incur in wrong interpretations.

Topics: Adult; Dinoprost; Dinoprostone; Epoprostenol; Female; Headache; Humans; Hypoxia; Male; Oxygen; Prostaglandin D2; Thromboxane A2

Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)-induced inflammation. Cyclooxygenase (COX)-formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH.. Twelve healthy, male participants underwent three, 6-hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex(®) (selective COX-2 inhibitor) in a double-blind, randomized, crossover study design. Pre- and post-IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre-IH blood pressure (P ≤ 0.04) and decreased pre-IH CBF (P=0.04) while neither physiological variable was affected by COX-2 inhibition (P ≥ 0.90). Post-IH, MAP was elevated (P ≤ 0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX-2 inhibition abrogated the IH-induced MAP increase (P=0.19), but resulted in lower post-IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P ≤ 0.4) and COX-1 formed thromboxane A2 concentrations (P=0.02).. COX-2 and COX-1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX-1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA.. www.clinicaltrials.gov. Unique identifier: NCT01280006.

Topics: Adult; Blood Pressure; Celecoxib; Cerebrovascular Circulation; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Double-Blind Method; Epoprostenol; Female; Heart Rate; Humans; Hypoxia; Indomethacin; Male; Middle Aged; Pyrazoles; Sleep Apnea, Obstructive; Sulfonamides; Thromboxane A2

The prevalence of procoagulant state under prolonged hypoxic exposures and the complications and lack of specificity associated with use of existing anti-thrombotic agents have necessitated the search for safer and natural therapeutics. Codonopsis, a widely studied medicinal herb, has been reported to decrease whole blood viscosity but the bioactive ingredients involved, and their mechanism of action therein however remain to be investigated.. The present study aimed at evaluating the efficacy of C. clematidea root extract and mechanism of action of its bioactive constituent flavonoid, Kaempferol, in ameliorating hypobaric hypoxia induced procoagulant state.. Fingerprinting analysis of methanolic extract of C. clematidea root was performed by RP-HPLC. In vitro toxicity study was conducted using HUVEC cell line and in vivo acute and sub-acute toxicity were done according to OECD guidelines (section-4, number-420 and 407 respectively). Adult male Sprague-Dawley rats weighing 230-250 g were exposed to global hypoxia simulating an altitude of 7600 m (282 mmHg), in animal decompression chamber for 3, 7, 14 and 21 days for in vivo studies. Dose optimisation of the extract was done by quantification of Thromboxane A2 in the serum of hypoxic rats. C. clematidea root extract was also evaluated for its in vitro and in vivo antioxidant properties. Procoagulant changes were studied by biochemical plasma coagulation assays and expression analysis of the signalling molecules of the platelet activation cascade like vWF, platelet activation marker CD41, GpIb-IX-V (CD42), Lyn kinase, p-PI3K, p-ERK and p-PLCγ were conducted to investigate C. clematidea mediated signalling mechanisms.. Methanolic extract of C. clematidea root showed improved antioxidant status and improvement in bleeding time and in vitro coagulation assays like pT, aPTT, INR. Decreased concentrations of D-Dimers along with that of platelet activation marker CD41 and serum concentration of Thromboxane A2 were observed in C. clematidea root extract supplemented hypoxic animals. Phosphorylation of Lyn kinase, was reduced despite increase in concentration of activating ligand vWF.. C. clematidea root extract was effective in preventing hypoxia induced platelet activation and resultant procoagulant state by inhibiting Lyn kinase, a serine threonine kinase effector of vWF signalling cascade.

Topics: Animals; Blood Coagulation; Codonopsis; Enzyme Activation; Hypoxia; Kaempferols; Male; Methanol; Phosphorylation; Plant Extracts; Plant Roots; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Rats, Sprague-Dawley; Signal Transduction; src-Family Kinases; Thromboxane A2

Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.

Topics: Adult; Animals; Animals, Newborn; Cell Line, Tumor; Female; Fetal Growth Retardation; Humans; Hypoxia; Male; Mice, Inbred C57BL; Mice, Transgenic; Placenta; Pregnancy; Protein Isoforms; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Trophoblasts

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

The roles of arachidonic acid (AA) metabolites in hypoxia-induced pulmonary vasoconstriction (HPV), a critical physiological mechanism that prevents ventilation/perfusion mismatch, are still incompletely understood.. Pulmonary arterial pressure was measured in ventilated/perfused rat lungs. Isometric tones of rat intralobar pulmonary arteries were also measured, using a myograph.. Hypoxia (Po₂, 3%)-induced pulmonary arterial pressure increases (ΔPAP(hypox)) were stable with blood-mixed perfusate, but decayed spontaneously. ΔPAP(hypox) was inhibited by 29%, 16%, and 28% by the thromboxane A₂ (TXA₂) antagonist SQ-29548, the 5-lipoxygenase inhibitor, MK886, and the leukotriene D₄ antagonist, LY-171883, respectively. The prostacyclin synthase inhibitor tranylcypromine augmented ΔPAP(hypox) by 5%, whereas inhibition of cytochrome P450 did not affect ΔPAP(hypox). Consistently, the TXA₂ analogue U46619 increased ΔPAP(hypox) whereas prostacyclin abolished ΔPAP(hypox). However, leukotriene D₄ had no direct effect on ΔPAP(hypox). In the isolated pulmonary arteries, pretreatment with U46619 was essential to demonstrate hypoxia-induced contraction.. The above results suggest that TXA₂ and cysteinyl leukotrienes, other than leukotriene D₄, are endogenous factors that facilitate HPV in rats. The indispensable role of TXA₂-induced pretone in the HPV of isolated pulmonary arteries indicates that the signal from thromboxane receptors might be a critical component of oxygen sensation mechanisms.

Topics: Animals; Arachidonic Acid; Cyclooxygenase Inhibitors; Hypoxia; Leukotrienes; Male; Pulmonary Artery; Rats; Thromboxane A2; Vasoconstriction

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

Platelets undergoing anoxia-reoxygenation (AR) simultaneously increase reactive oxygen species (ROS) and thromboxane (Tx) B(2). Our aim was to assess whether there is an interplay between activation of NOX2, the catalytic subunit of NADPH oxidase, and platelet TxB(2) in vitro and in vivo.. Platelets that underwent AR had enhanced ROS. This was associated with NOX2 activation and was inhibited by incubation with NOX2-blocking peptide. AR was associated with TxB(2) and isoprostane production, which were inhibited by NOX2-blocking peptide, vitamin C, and the inhibitor of phospholipase A(2). Platelet incubation with 100 μmol/L aspirin fully prevented AR-induced TxA(2) but did not affect isoprostane production. We included 56 aspirin-treated patients undergoing elective percutaneous coronary intervention (PCI) who were randomly allocated to receive either placebo or intravenous infusion of 1 g of vitamin C. Blood TxB(2), isoprostanes, and soluble NOX2-derived peptide, a marker of systemic NADPH oxidase activation, significantly increased at 60 and 120 minutes after PCI in placebo-treated but not in vitamin C-treated patients.. AR is associated with overproduction of platelet TxB(2) and isoprostanes, which is dependent on NOX2-dependent ROS generation. Low doses of aspirin are unable to prevent TxB(2) formation in patients who undergo PCI.

Topics: Aged; Angioplasty, Balloon, Coronary; Blood Platelets; Female; Humans; Hypoxia; In Vitro Techniques; Isoprostanes; Male; Membrane Glycoproteins; Middle Aged; Myocardial Reperfusion; Myocardial Reperfusion Injury; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Platelet Activation; Reactive Oxygen Species; Thromboxane A2

This study determined if altered vascular prostacyclin (PGI(2)) and/or thromboxane A(2) (TxA(2)) production with reduced Po(2) contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in Po(2) under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced Po(2). Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular PGI(2) production with reduced Po(2) was similar between strains, although TxA(2) production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of PGH(2)/TxA(2) receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of TxA(2), which competes against the vasodilator influences of PGI(2). These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular TxA(2) production and may blunt vascular sensitivity to PGI(2).

Topics: Animals; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Unsaturated; Free Radical Scavengers; Hydrazines; Hypoxia; Imidazoles; Indomethacin; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Obesity; Oxidative Stress; Polyethylene Glycols; Rats; Rats, Zucker; Receptors, Thromboxane; Superoxide Dismutase; Thromboxane A2; Thromboxane-A Synthase; Up-Regulation; Vasodilation

Hypoxia-induced neonatal persistent pulmonary hypertension (PPHN) is characterized by sustained vasospasm and increased thromboxane (TxA2)-to-prostacyclin ratio. We previously demonstrated that moderate hypoxia induces myocyte TxA2 hypersensitivity. Here, we examined TxA2 prostanoid receptor (TP-R) localization and kinetics following hypoxia to determine the mechanism of hypoxia-induced TxA2 hypersensitivity. Primary cultured neonatal pulmonary artery myocytes were exposed to 10% O2 (hypoxic myocytes; HM) or 21% O2 (normoxic myocytes; NM) for 3 days. PPHN was induced in neonatal piglets by in vivo exposure to 10% FiO2 for 3 days. TP-R was studied in whole lung sections from pigs with hypoxic PPHN- and age-matched controls; intracellular localization was studied by immunocytochemistry. TP-R affinity was studied in cultured myocytes by saturation binding kinetics using 3H-SQ-29548 and competitive binding kinetics by coincubation with U-46619. Phosphorylation and coupling were examined in immunoprecipitated TP-R. We report distal propagation of TP-R expression in PPHN, extending to pulmonary arteries <50 microm. In HM, intracellular TP-R moves towards the perinuclear region, mirroring a change in endoplasmic reticulum (ER) morphology. TP-R kinetics also alter in HM membranes, with decreased Kd and Bmax (maximal binding sites). Additionally, in hypoxia, 3H-SQ-29548 is displaced at lower concentration of U-46619 than in normoxia, suggesting increased agonist affinity. Phosphorylation of serine residues on HM TP-R was significantly decreased compared with NM; this difference correlated with increased Galphaq coupling in hypoxia and was ablated by incubation with PKA. We conclude that the TP-R is normally desensitized in the neonatal pulmonary circuit by PKA-mediated regulatory phosphorylation, decreasing ligand affinity and coupling to Galphaq; this protection is lost following hypoxic exposure. Also, the appearance of TP-R in resistance arteries after development of hypoxic PPHN may contribute to increased pulmonary arterial pressure.

Topics: Animals; Animals, Newborn; Binding, Competitive; Calcium; Cells, Cultured; Disease Models, Animal; GTP-Binding Protein alpha Subunits, Gq-G11; Hypoxia; Immunoenzyme Techniques; Immunoprecipitation; Kinetics; Ligands; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Pulmonary Artery; Receptors, Thromboxane A2, Prostaglandin H2; Swine; Thromboxane A2; Vasoconstriction

The ability of the smooth muscle of the human umbilical artery to relax may vary under physiological and pathological conditions. We investigated the responsiveness of that preparation to relaxation, as well as the influence of reduced oxygen condition on these responses. Rings of human umbilical arteries from full-term Caesarian deliveries were suspended in modified Krebs-Henseleit solutions bubbled with a gas mixture of 95% O2:5% CO2 (normal oxygen condition) or 2.5% O2:8% CO2 balanced with N2 (reduced oxygen condition). These rings were contracted with potassium chloride, serotonin or the thromboxane A2 mimetic U46619, before being exposed to either the nitrovasodilator sodium nitroprusside, the potassium channel opener levcromakalim or the calcium channel antagonist amlodipine. While sodium nitroprusside elicited relaxation in this blood vessel, the maximal relaxation to the nitric oxide donor was significantly smaller than that induced by levcromakalim and amlodipine. The nature of the constrictor agent used, or changes of oxygen conditions did not significantly affect the relaxation profile of this human blood vessel. These data suggest that the smooth muscle of the human umbilical artery may be less responsive to vasodilators that act via the nitric oxide pathway. Moreover, vascular responses of umbilical arterial smooth muscle to relaxing agents do not alter under hypoxic or different vasoconstricting conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amlodipine; Cromakalim; Humans; Hypoxia; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Potassium Chloride; Serotonin; Thromboxane A2; Umbilical Arteries; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The goal of this study was to determine the effect of angiotensin type 1 (AT(1)) receptor antagonism on vasodilator responses in isolated skeletal muscle resistance arteries. Normotensive Sprague-Dawley rats were fed normal rat chow with the AT(1) receptor antagonist losartan (1mg/ml) in the drinking water for 7 days and compared with untreated control rats. Changes in the diameter of isolated resistance arteries supplying the gracilis muscle were assessed with a video micrometer. Arteriolar responses to acetylcholine, iloprost, and sodium nitroprusside were unaffected by losartan administration, whereas dilation to reduced Po(2) was converted into a constriction. Hypoxia-induced constriction of vessels from losartan-treated rats was inhibited by endothelium removal or indomethacin (1 microM). Blockade of the PGH(2)-thromboxane A(2) receptor with SQ-29548 (10 microM), thromboxane synthase inhibition with dazoxiben (10 microM), or the addition of the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL, 100 microM) converted hypoxic vasoconstriction to a dilation that was blocked by inhibiting nitric oxide synthase with N(omega)-nitro-l-arginine methyl ester (100 microM). These data suggest that AT(1) receptor activation has an important role in maintaining the vascular release of prostaglandins responsible for mediating hypoxic dilation in skeletal muscle microvessels.

Topics: Acetylcholine; Angiotensin II Type 1 Receptor Blockers; Animals; Arteries; Cardiovascular Agents; Enzyme Inhibitors; Epoprostenol; Hypoxia; In Vitro Techniques; Indomethacin; Losartan; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Oxygen; Partial Pressure; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane A2; Thromboxanes; Time Factors; Vascular Resistance; Vasoconstriction; Vasodilation; Vasodilator Agents

The effects of hypoxia-reoxygenation on internal mammary (IMA) and radial (RA) arteries used for coronary artery bypass grafting (CABG) were examined to identify mechanisms regulating contractile function and differences that could contribute to vasospasm. Isolated endothelium-intact IMA and RA rings precontracted with KCl (30 mM) rapidly dilated to hypoxia (95% N(2)/5% CO(2)) with a greater relaxation in RA than IMA. Inhibitors of cyclooxygenase (10 microM indomethacin) and the thromboxane A(2) (TxA)(2) receptor [1 microM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[2-(phenylamino)carbonyl]hydrazine]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-29548)] potentiated the relaxation to hypoxia in IMA, but not RA, a response associated with increases in TxA(2). Relaxation of IMA and RA to hypoxia appears to involve a calcium-reuptake mechanism inhibited by cyclopiazonic acid (0.2 mM), and it was not attenuated by a blocker of potassium channels (10 mM TEA). The recovery of force generation of IMA, but not RA, upon reoxygenation after 30 min of hypoxia was significantly reduced in the initial phase of reoxygenation by indomethacin and SQ-29548 and by endothelin receptor blocker BQ-123 [cyclo(l-Leu-d-Trp-d-Asp-l-Pro-d-Val)]. Thus, hypoxia relaxes IMA and RA by a prostaglandin-independent mechanism potentially involving enhanced intracellular calcium reuptake. The prostaglandin-mediated alterations of responses to hypoxia-reoxygenation seen in IMA, but not in RA, may predispose IMA to vasospasm-related complications of CABG.

Topics: Adrenergic alpha-Agonists; Calcium; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypoxia; In Vitro Techniques; Mammary Glands, Human; Oxygen; Potassium Channel Blockers; Prostaglandin Antagonists; Prostaglandins; Protein Kinase C; Radial Artery; Thromboxane A2; Vasodilation

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

Blood-derived monocytes are found at sites of inflammation as well as in solid tumors and atherosclerotic arteries. They are an abundant source of inflammatory eicosanoids such as prostaglandin E2 (PGE2) and thromboxane A2, which are formed via arachidonic acid (AA) metabolism by cyclooxygenase-1/2 (COX-1/2). In vitro studies of inflammatory mediator production are conducted invariably in room air, which does not reflect the oxygen tensions found in monocyte-containing lesions, which are frequently hypoxic. In this work we examined the effects of hypoxia at levels reported in these lesions, on monocyte COX-2 expression, the related events that lead to eicosanoid synthesis, and relationships with tumor necrosis factor (TNF)-alpha synthesis. In fresh human monocytes exposed to hypoxia (1% O2), there was an increase in COX-2 protein compared with cells in normoxia, and this was attributable to increased transcription and mRNA stability. However, the synthesis of PGE2 and thromboxane A2 was reduced in hypoxia and did not reflect the increased level of COX-2. Monocytes prelabeled with [3H]AA followed by lipopolysaccharide stimulation in the presence of hypoxia showed a reduced release of AA compared with cells in normoxia. In addition, hypoxia resulted in decreased phosphorylation of the p44/42 mitogen-activated protein kinase and of cytosolic phospholipase A2. Hypoxia also increased TNF-alpha synthesis, which appeared to play a role in COX-2 expression, and the observed increase TNF-alpha synthesis appeared to result from reduced PGE2 synthesis. Overall, the results suggest the existence of an autocrine loop of regulation between monocyte eicosanoid and TNF-alpha production, which is dysregulated in hypoxia and establishes hypoxia as being an important environmental determinant of inflammatory mediator production.

Topics: Blotting, Northern; Blotting, Western; Cyclooxygenase 2; Cytosol; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Enzyme-Linked Immunosorbent Assay; Genes, Reporter; Heme; Humans; Hypoxia; Inflammation; Interleukin-1; Isoenzymes; Lipopolysaccharides; Membrane Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Models, Biological; Monocytes; Oxygen; Phosphorylation; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Thromboxane A2; Time Factors; Transfection; Tumor Necrosis Factor-alpha; U937 Cells; Zinc

The issue of whether the acinar microvessel response to alveolar hypoxia and hypercapnia is impaired in injured lungs has not been vigorously addressed, despite the importance of knowing whether it is or not when treating patients with serious lung injury in terms of permissive hypercapnia. Applying a real-time laser confocal luminescence microscope, we studied hypoxia- and hypercapnia-induced changes in the diameter of the intra-acinar arterioles, venules, and capillaries of isolated rat lungs harvested from animals exposed for 48 h to 21% O(2) (group N) or 90% O(2) (group H). Measurements were made with and without inhibition of nitric oxide (NO) synthase (NOS) by N(omega)-nitro-L-arginine methyl ester or of cyclooxygenase (COX) by indomethacin at different basal vascular tones evoked by thromboxane A(2) (TXA(2)) analog. Hypoxia in the absence of TXA(2) contracted arterioles in group N but not in group H. Attenuated hypoxia-induced arteriole constriction was restored almost fully by inhibiting NOS and partially by inhibiting COX. Hypercapnia induced venule dilation in group N, but did not dilate venules in group H, irrespective of TXA(2). NOS inhibition in hypercapnia unexpectedly enhanced venule and arteriole dilation in group H. These responses no longer occurred when NOS and COX were inhibited simultaneously. In conclusion, microvessel reactions to hypoxia and hypercapnia are abnormal in hyperoxia-injured acini, in which NO directly attenuates hypoxia-induced arteriole constriction, whereas COX inhibited by excessive NO impedes hypercapnia-induced microvessel dilation.

Topics: Animals; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Hypercapnia; Hypoxia; In Vitro Techniques; Lung; Male; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxygen; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Thromboxane A2

Previous studies concerning ischemic priapism revealed that hypoxia alters the erectile and contractile responses of penis. But the effects of accompanying acidosis on those responses have not been fully evaluated or understood yet. We performed this study to elucidate the role of acidosis on the trabecular smooth muscle contractility like in ischemic priapism. Under the general anesthesia, 55 mature male cats were conditioned to systemic metabolic acidosis by hypoventilation by animal ventilator. The changes of intracavernous pressure (ICP) to erectogenic agents (acetylcholine, L-arginine, prostaglandin E1: PGE1), erectolytic agents (epinephrine, thromboxane A2; TXA2), K channel-related drugs (pinacidil, 4-aminopyridine, tetraethylammonium; TEA, glibenclamide) and calcium ionophore were monitored at Set 1 (PO2 > 60 mmHg, pH > 7.25), Set 2 (PO2 < 30 mmHg, 7.25 > pH > 7.0), Set 3 (PO2 < 30 mmHg, pH < 7.0), and Set 4 (PO2 > 60 mmHg, pH < 7.0) in vivo. At Set 1 and Set 2, epinephrine, TXA2, and ionomycin decreased the ICP by acetylcholine or PGE1 (n = 9, P < 0.01). The decrease of ICP was in order of epinephrine, TXA2 and ionomycin. Acidosis reduced the increase of ICP to acetylcholine or PGE1 (n = 8, P < 0.01), TXA2 or ionomycin did not affect ICP under severe acidosis but epinephrine decreased ICP even under severe acidosis (n = 7, P < 0.05). Pretreatment of potassium channel blockers did not suppress the increase of ICP by erectogenic agents under acidosis (n = 6, P < 0.05). Pinacidil did not affect ICP under acidosis (n = 6, P < 0.01). These results suggest that acidosis impairs the contractile response of cavernous smooth muscle to erectolytic agents. It may be the results of the interference by [H+] with the intra and extracellular mechanisms that regulate the homeostasis of [Ca2]. Conclusively, besides hypoxia, acidosis is another limiting factor of trabecular smooth muscle contractility like in ischemic priapism.

Topics: Acetylcholine; Acidosis; Alprostadil; Animals; Arginine; Cats; Epinephrine; Hypoxia; Ionomycin; Male; Muscle Contraction; Muscle, Smooth; Penile Erection; Penis; Potassium Channel Blockers; Pressure; Thromboxane A2

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

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

The 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

We have recently reported in normal isolated-perfused rat lungs that low basal tone appears to be regulated by nitric oxide (NO)-dependent and -independent mechanisms of soluble guanylate cyclase activation. In this study, we examined the role of NO in the regulation of pulmonary artery (PA) tone from rats with renin-dependent hypertension. Rats were made hypertensive by ligating the abdominal aorta above the left and below the right renal artery (aortic coarctation, AC). Mean arterial pressure significantly increased from 119 +/- 8.4 mmHg in control animals to 156 +/- 15 mmHg 7-14 days after AC surgery. PA pressures, however, remained unchanged (8.5 +/- 3.4 mmHg in control animals vs. 11 +/- 3.3 mmHg in AC animals). Hypoxic contractions in U-46619 precontracted isolated small PA (160-260 microns diameter) were significantly increased from 51 +/- 13 mg in the control group to 142 +/- 38 mg (P < or = 0.05) in AC animals. Nitro-L-arginine (NLA; 100 microM) contractions were also enhanced in the AC animal. The enhanced NLA response may correlate with an increase in endothelial cell NO synthase (NOS) as detected by Western blotting (132 +/- 28% of control; P < 0.05). These data suggest that, in this renin-dependent model of systemic hypertension, there is increased endothelial cell NOS activity that maintains low PA tone, preventing the lung from developing increased pressures.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Abdominal; Aortic Coarctation; Blood Pressure; Endothelium, Vascular; Guanylate Cyclase; Hypertension; Hypoxia; In Vitro Techniques; Male; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Regression Analysis; Renin; Thromboxane A2; Vasoconstrictor Agents

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

We have previously demonstrated that chronic hypoxia (CH) augments pulmonary arterial dilation to the endothelium-derived nitric oxide (EDNO)-dependent pulmonary vasodilator arginine vasopressin (AVP). The present study examined 1) whether this enhanced vasoreactivity is observed with other agents that act by stimulating constitutive NO synthase (cNOS), 2) whether CH increases arterial vascular smooth muscle sensitivity to NO, and 3) whether endogenous endothelin (ET) or an endothelium-derived hyperpolarizing factor (EDHF) contributes to this altered arterial reactivity following CH. We examined responses to the receptor-mediated EDNO-dependent dilators histamine and ET-1, the nonreceptor-mediated EDNO-dependent dilator ionomycin, and the NO donors 1, 3-propanediamine, N-4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino] butyl (spermine NONOate) and S-nitroso-N-acetylpenicillamine (SNAP) in U-46619-constricted, isolated perfused lungs from control and CH rats. Additional experiments examined responses to AVP in the presence of the ET-receptor antagonist PD-145065 or the K+ channel blockers glibenclamide or tetraethylammonium (TEA) in lungs from each group. Microvascular pressure was assessed by double occlusion, allowing calculation of segmental resistances. Total and arterial vasodilatory responses to histamine, ET-1, and ionomycin were augmented in lungs from CH vs. control animals. However, CH did not alter the vasodilation to spermine NONOate or SNAP. PD-145065, glibenclamide, and TEA had no effect on responses to AVP in either group. We conclude that increased activity of arterial cNOS may be responsible for the augmented pulmonary arterial dilation to EDNO-dependent vasodilators following CH.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biological Factors; Endothelins; Endothelium, Vascular; Histamine; Hypoxia; Ionomycin; Ionophores; Male; Muscle, Smooth, Vascular; Nitric Oxide; Oligopeptides; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

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

The effect of in vitro hypoxia for 1 h on concentration-response curves to vasoconstrictor spasmogens was examined in rat isolated pulmonary arteries. Hypoxia, like levcromakalim (KATP channel opener), did not affect contractions to endothelin-1 but attenuated contractions to U46619 ((1,5,5,)-hydroxy-11 alpha, 9 alpha-epoxymethano) prosta 5Z, 13E-dienoic acid; thromboxane-mimetic), angiotensin II, noradrenaline and 5-hydroxytryptamine. The attenuation was prevented by glybenclamide. In pre-contracted arteries, subsequent exposure to hypoxia caused a response consisting of four phases (transient relaxation due to endothelium-derived nitric oxide; transient contraction; slow relaxation; sustained contraction). Glybenclamide, if added before hypoxia, did not eliminate either of the relaxant phases but, if added during the sustained contractile phase, caused further contraction. We conclude that exposure of pulmonary arteries to prolonged hypoxia causes KATP channels to open, as in systemic arteries; this diminishes contractions to some, but not all, vasoconstrictor spasmogens. The data suggest that endothelin-1, unlike other vasoconstrictors, would remain a highly effective pulmonary vasoconstrictor under severe hypoxic conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzopyrans; Cromakalim; Drug Interactions; Glyburide; Hypoxia; In Vitro Techniques; Male; Potassium Channel Blockers; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pyrroles; Rats; Rats, Wistar; Thromboxane A2; Vasoconstrictor Agents

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

The present study was designed to point out similarities between the effects on pulmonary circulation caused by hypoxia and by a chemoreceptor stimulant (S1867, an almitrine analog). Isolated rat lungs were perfused at a constant flow with homologous blood and ventilated under normoxic, hypoxic or hyperoxic conditions. (1) At 0.25 microgram/ml, S1867 potentiated the hypoxic pressor response, while at 1 microgram/ml, it induced a significant increase in pulmonary artery pressure (PAP) at 21% O2. (2) Since the expression of an oxygen-binding protein (NADPH-oxidase like) has been demonstrated in the rat carotid bodies, we studied the effects of the NADPH-oxidase inhibitor diphenyleneiodonium (DPI) on HPV and on S1867-induced pulmonary vascular responses. Both responses were totally abolished by DPI (40 microM), whereas the vasoconstriction induced by a thromboxane A2 analog (U46619) remained unchanged. (3) Vascular responses to hypoxia and S1867 (1 microgram/ml) were both reversed by a bolus of the sulfhydryl oxidant diamide (3 mg). (4) The S1867-induced response was prevented and reversed by the supply of inhaled oxygen, which was without action on the vasoconstriction induced by U46619. These results suggest that the almitrine analog and hypoxia act at least partly through the same cellular mechanism, involving a DPI-sensitive protein.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Almitrine; Animals; Blood Pressure; Chemoreceptor Cells; Disease Models, Animal; Enzyme Inhibitors; Hypoxia; In Vitro Techniques; Male; NADPH Oxidases; Nitric Oxide Synthase; Onium Compounds; Perfusion; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Respiratory System Agents; Thromboxane A2; Vasoconstriction

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

The high risk of vaso-occlusive events in children younger than 4 years with cyanotic congenital heart disease and polycythaemia has been attributed to increased thromboxane (Tx) A2 formation. In older children with cyanotic congenital heart disease, however, the risk of vaso-occlusive events is much lower. We therefore hypothesized that the formation of TxA2 and prostacyclin is not disturbed in this age group. We measured urinary excretion of stable index metabolites of in vivo TxA2 and prostacyclin formation by gas chromatography-mass spectrometry in nine children (age 5.9-14.4, median 8.7 years) with cyanotic congenital heart disease, and in nine healthy, age-matched control subjects. The patients excreted less 2,3-dinor-TxB2 (systemic TxA2 formation, P = 0.03), 2,3-dinor-6-keto-PGF1 alpha (systemic prostacyclin formation. P = 0.03) and TxB2 (renal TxA2 formation, P = 0.01) than the control subjects. We conclude that in children older than 5 years with cyanotic congenital heart disease, endogenous synthesis of TxA2 and prostacyclin is not stimulated. This result may explain the lower risk of vaso-occlusive events in this age group as compared with younger children. In addition, our results suggest that chronic hypoxaemia may affect the in vivo formation of TxA2 and prostacyclin and the metabolic disposition of TxB2.

Topics: Adolescent; Child; Child, Preschool; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypoxia; Male; Statistics, Nonparametric; Thromboxane A2

We designed experiments to determine in vitro the influence of hypoxia on endothelium function in porcine pulmonary artery and vein. Rings of large isolated intralobar pulmonary arteries and veins were mounted in organ chambers for isometric tension recording. In veins and arteries with endothelium (precontracted with histamine and U 46619, respectively), hypoxia induced a transient contractile response that was significantly greater in veins. These contractile responses were fully blocked by L-nitro arginine (LNA) in arteries but only partially in veins. In pulmonary vessels without endothelium, only venous rings produced a contractile response to hypoxia; this contraction was blocked by indomethacin. In precontracted pulmonary arterial and venous rings, bradykinin (BK) induced endothelium-dependent relaxations unaffected by indomethacin. Venous relaxations were fully blocked by LNA, but arterial relaxations were only partially inhibited by the nitric oxide (NO) synthase inhibitor. In KCl (30 mM)-precontracted vessels, the endothelium-dependent relaxations were minimally affected in veins but significantly inhibited in arteries. Identical results were obtained in tissue contracted with histamine or U 46619 in presence of tetraethyl ammonium (TEA 10 mM). Hypoxia (30 mm Hg) abolished the venous relaxation but did not significantly influence the arterial relaxation. In arterial rings, the effects of KCl and LNA (or hypoxia) were additive. These results suggest that in isolated porcine pulmonary veins, endothelium-dependent relaxation to BK is exclusively dependent on NO formation. In arteries, however, NO production is partially involved. Another mechanism, possibly endothelium-dependent hyperpolarization, exists. These differences in endothelial responsiveness lead to different patterns of response to hypoxia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine; Bradykinin; Endothelium, Vascular; Female; Hypoxia; In Vitro Techniques; Indomethacin; Male; Nitric Oxide; Nitroarginine; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Veins; Swine; Tetraethylammonium Compounds; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused rabbit lungs. J. Appl. Physiol. 78(4): 1509-1515, 1995.--We investigated the role of nitric oxide (NO) generation in hypoxic pulmonary vasoconstriction in buffer-perfused rabbit lungs. Exhaled NO was detected by chemiluminescence, and intravascular NO release was quantified as perfusate accumulation of nitrite, peroxynitrite, and nitrate (NOx). Under baseline conditions, exhaled NO was 45.3 +/- 4.1 parts per billion (1.8 +/- 0.2 nmol/min), and lung NOx release into the perfusate was 4.1 +/- 0.4 nmol/min. Alveolar hypoxia (alveolar PO2 of approximately 23 Torr) induced readily reproducible pressor responses preceded by a sharp drop in exhaled NO concentration. In contrast, perfusate NOx accumulation was not affected. Vasoconstrictor responses to U-46619 and angiotensin II were not accompanied by a decrease in NO exhalation. NG-monomethyl-L-arginine dose-dependently suppressed NO exhalation and amplified pressor responses to hypoxia > U-46619 and angiotensin II. In conclusion, portions of baseline NO generation originating from sites with ready access to the gaseous space sharply decrease in response to alveolar hypoxia, whereas the intravascular release of NO is unchanged. Such differential regulation of lung NO synthesis in response to hypoxia may suggest a complex role in the regulation or modulation of hypoxic pulmonary vasoconstriction.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arginine; Female; Hypoxia; In Vitro Techniques; Lung; Male; Nitric Oxide; omega-N-Methylarginine; Perfusion; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Rabbits; Thromboxane A2; Vasoconstriction

1. Using isolated pulmonary resistance vessels from mature fetal lamb and chronically instrumented lambs (8-17 days old), we have examined whether hypoxic pulmonary vasoconstriction is sustained by activation of a constrictor mechanism or suppression of a dilator mechanism. 2. Hypoxia contracted both arteries and veins in vitro, and the contraction was greater with the former. After removing the endothelium, arteries responded faster to hypoxia, but the magnitude of the response remained unchanged. 3. Hypoxic arteries, unlike normally oxygenated arteries, did not contract with either indomethacin (2.8 microM) or N omega-nitro-L-arginine methyl ester (L-NAME, 100 microM). The same vessels relaxed with sodium nitroprusside (SNP, 0.001-10 microM) but not with bradykinin (0.1-100 nM). 4. Endothelin-1 (ET-1, 0.01-10 nM) contracted isolated arteries and veins under normoxic and hypoxic conditions. In both vessels, the contraction was fast in onset and subsidence, and was inhibited by the ETA receptor antagonist BQ123 (1 microM). The ET-1 precursor, big ET-1 (100 nM), also contracted arteries and veins, but compared with ET-1 its action was slower in development. Big ET-1 contraction, unlike ET-1 contraction, was curtailed by the inhibitor of the ET-1-converting enzyme, phosphoramidon (50 microM). 5. ET-1 (0.1-10 nM) had no effect on isolated arteries precontracted with a thromboxane A2 (TXA2) analogue (ONO-11113) and treated with BQ123 (10 microM). Under the same conditions, ET-1 relaxed the veins. Accordingly, in the absence of BQ123 treatment, the selective ETB receptor agonist IRL-1620 (0.1-100 nM) relaxed the contracted veins but not the arteries. 6. BQ123 (10 microM) inhibited the constriction of isolated arteries and veins to hypoxia. Likewise, in the conscious lamb a bolus of BQ123 (0.4 mg kg-1, injected into the pulmonary artery) curtailed the rise in pulmonary vascular resistance (Rpa) brought about by alveolar hypoxia without changing significantly systemic vascular resistance (Rao). Under normoxia, Rpa was insignificantly affected by BQ123. 7. The results indicate that pulmonary resistance arteries are more susceptible to hypoxia than the veins, and that hypoxic vasoconstriction does not require an intact endothelium to occur. Hypoxic tone is ascribed primarily to intramural generation of ET-1, while removal of the tonic action of a relaxant may only have an accessory role in the response.

Topics: Animals; Arginine; Bradykinin; Endothelins; Endothelium; Female; Hypoxia; Indomethacin; NG-Nitroarginine Methyl Ester; Nitroprusside; Peptide Fragments; Peptides, Cyclic; Pregnancy; Pulmonary Circulation; Sheep; Thromboxane A2; Vasoconstriction

The sites of relaxation in response to inhaled nitric oxide (NO) were investigated using the vascular occlusion technique in isolated blood-perfused lungs from 1- to 3-mo-old lambs. In one group of 10 lungs, inhaled NO (45 ppm) was administered during hypoxia- and U-46619-induced pulmonary vasoconstriction. In a second group of 5 lungs, responses to inhaled NO and infused sodium nitroprusside (SNP, 3 micrograms.kg-1.min-1) during U-46619-induced hypertension were compared. Hypoxia caused significant pulmonary vasoconstriction, with increases in the pressure gradients of large and small arteries and small veins, as defined by vascular occlusion. Inhaled NO significantly reduced the total pulmonary pressure gradient by 67% and relaxed both large and small arteries. Infusion of U-46619 caused significant increases in all segmental pressure gradients. While inhaled NO was effective in relaxing the large and small arteries and the small veins, it had no effect on the large veins. Infusions of SNP, a nitrosovasodilator thought to act like endogenous NO, caused a similar degree of total relaxation as NO (81 vs. 77%, respectively). However, in contrast to inhaled NO, SNP was effective in reducing the pressure gradient of the large pulmonary veins. These results suggest that rapid binding to and thus inactivation of inhaled NO by hemoglobin limit its efficacy as a pulmonary venous dilator.

Topics: Administration, Inhalation; Animals; Citrate (si)-Synthase; Hypoxia; In Vitro Techniques; Injections, Intravenous; Nitric Oxide; Nitroprusside; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Sheep; Thromboxane A2; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Both increases and decreases in endothelium-derived nitric oxide (EDNO) activity have been described in the developing pulmonary vasculature. We hypothesized that differences in baseline vasomotor tone and/or oxygen tension may contribute to this variability. Pulmonary arterial dose responses to endothelium-dependent and -independent vasodilators acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were measured in indomethacin-treated lungs of 1- to 2-day-old (2D) and 1-mo-old (1M) lambs. During 4% O2 ventilation, baseline pulmonary vascular resistance (PVR) and the dilator response to both ACh and SNP were greater in 2D lungs. However, when baseline PVR values were matched at both ages during either hypoxia or infusion of a thromboxane mimetic under normoxic conditions, developmental differences in ACh-induced vasodilation were minimal. Furthermore, hypoxia itself did not alter the responses to ACh in 2D lungs. In contrast, SNP caused greater vasodilation in 2D than in 1M lungs regardless of baseline PVR. These data and studies suggest that whereas high PVR enhances EDNO synthesis, responsiveness to ENDO decreases as synthesis of ENDO increases in developing lungs studied under basal conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Age Factors; Animals; Animals, Newborn; Blood Gas Analysis; Endothelium, Vascular; Hypoxia; Infusions, Intravenous; Nitric Oxide; Nitroprusside; Perfusion; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Pulmonary Gas Exchange; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents; 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

Nitric oxide (NO) is a potent endogenous vasodilator. Its role in the normal and stressed pulmonary circulation is unclear. To better understand the importance of endogenous NO in normal physiological responses, we studied the effects of altered NO availability on the change in pulmonary vascular tone that accompanies exercise. In paired studies we measured blood flow and pressures in the pulmonary circulation at rest and during treadmill exercise at a speed of 4 mph with and without (a) N omega-nitro-L-arginine, 20 mg/kg intravenously, a selective inhibitor of NO synthase; (b) L-arginine, 200 mg/kg intravenously, substrate for NO synthase; (c) combination of the inhibitor and substrate; and (d) inhalation of NO > 30 ppm, to determine if endogenous release of NO elicits maximal vasodilation. In addition, we sought to determine the site of NO effect in the pulmonary circulation by preconstriction with either U-44619 or hypoxia (fraction of inspired O2 = 0.12) using a distal wedged pulmonary catheter technique. NO synthase inhibition raised pulmonary vascular tone equally at rest and exercise. L-Arginine reversed the effects of NO synthase inhibition but had no independent effect. NO inhalation did not reduce pulmonary vascular tone at rest or enhance the usual reduction in pulmonary vascular resistance with exercise. The effect of NO synthase inhibition was in pulmonary vessels upstream from small veins, suggesting that endogenous NO dilates primarily small arteries and veins at rest. We conclude that, in sheep, endogenous NO has a basal vasodilator function that persists during, but is not enhanced by, exercise.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Hemodynamics; Hypoxia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Physical Conditioning, Animal; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Sheep; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Chronic hypoxic exposure elicits pulmonary vascular remodeling and may alter normal pulmonary endothelial function. We examined the vasodilatory response to the receptor-mediated endothelium-dependent dilator arginine vasopressin (AVP), the non-receptor-mediated endothelium-dependent dilator A-23187, and the nitric oxide (NO) donor sodium nitroprusside in lungs isolated from control or chronically hypoxic rats. Lungs were isolated from male Sprague-Dawley rats and perfused with a physiological saline solution containing 4% albumin. Arterial and venous pressures were monitored and microvascular pressure was estimated by double occlusion, allowing assessment of segmental resistances. After equilibration, lungs were constricted with the thromboxane mimetic U-46619. Upon development of a stable pressor response, lungs were dilated with one of the above agents. A series of doses of AVP was administered to separate groups of lungs from control or chronically hypoxic rats. Lungs from chronically hypoxic rats exhibited an augmented dilatory response to AVP compared with control lungs, and this effect was due to enhanced dilation of precapillary segments. The total and segmental vasodilatory responses to A-23187 and sodium nitroprusside were not different between the two groups of lungs, suggesting that chronic hypoxia did not upregulate the enzyme NO synthase or enhance the vascular smooth muscle responsiveness to NO. Thus our data suggest that the augmented total and pulmonary arterial dilation to AVP after chronic hypoxia is most likely due to altered receptor-mediated processes of the hormone.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Amino Acid Oxidoreductases; Animals; Arginine Vasopressin; Calcimycin; Capillary Resistance; Dose-Response Relationship, Drug; Hypoxia; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Perfusion; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin; Thromboxane A2; Vasodilation

The possible involvement of ATP-sensitive K+ channels (KATP) in hypoxic relaxation of isolated porcine coronary arteries was investigated. Tubular segments taken from the left anterior descending artery were suspended in myographs for recording of isometric contractile force. Hypoxia (pO2 = 20.3 mm Hg +/- 0.5) produced a greater relaxation in preparations contracted by 30 mM K+ (49.7% +/- 7.2) compared with 124 mM K+ (19.9% +/- 2.2) which is compatible with the involvement of K+ channel activation in the mechanism of hypoxic relaxation. In a normal glucose-containing Krebs solution the KATP blocker glibenclamide (1 microM) failed to influence the hypoxic relaxation of preparations contracted by the thromboxane A2 analogue U-46619. Under conditions created to inhibit non-oxidative ATP production from glycolysis using a glucose-free Krebs solution containing 2-deoxyglucose (10 mM), the hypoxic relaxation was enhanced from 54.5% +/- 5.0 to 77.2% +/- 4.4. Under these conditions glibenclamide (1 microM) significantly inhibited the hypoxic relaxant response from 77.2% +/- 4.2 to 55.2% +/- 4.4 and prolonged the time until half-maximal relaxation from 5.5 min +/- 0.6 to 8.1 min +/- 0.6. A low concentration of the KATP opener levcromakalim (30 nM) failed to significantly potentiate the hypoxic relaxation. The adenosine receptor blocker theophylline (1 microM) or removal of the endothelium showed no effect on the hypoxic relaxation. In normal glucose-containing Krebs solution, indomethacin (10 microM) caused a small but significant inhibition of the hypoxic relaxation from 54.5% +/- 5.0 to 41.6% +/- 3.6.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Triphosphate; Animals; Benzopyrans; Coronary Vessels; Cromakalim; Deoxyglucose; Endothelium, Vascular; Glyburide; Glycolysis; Hypoxia; In Vitro Techniques; Indomethacin; Isometric Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Prostaglandin Endoperoxides, Synthetic; Pyrroles; Swine; Theophylline; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

The thromboxane mimetic U46619 (11 alpha,9 alpha-epoxymethano PGH2) increased 45Ca2+ uptake in sheep coronary artery rings. A larger increase occurred in endothelium-denuded than in endothelium-inact rings (increase in 45Ca2+ uptake: endothelium intact = 9.6 +/- 3.8, endothelium-denuded = 33.2 +/- 8.1 nmol g-1), in agreement with the increase in U46619 contraction produced by endothelium denudation. Hypoxia (PO2 = 4 mm Hg) inhibited both the U46619 contraction (at the U46619 EC50, contraction under oxygenated conditions = 158 +/- 35, under hypoxic conditions = 105 +/- 40 g cm-2) and the U46619-stimulated 45Ca2+ uptake. It is concluded that inhibition, by hypoxia, of the U46619 contractile effect on sheep coronary artery rings may be in part due to inhibition of U46619-stimulated 45Ca2+ uptake.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium; Calcium Radioisotopes; Coronary Vessels; Endothelium, Vascular; Hypoxia; In Vitro Techniques; Isometric Contraction; Muscle, Smooth, Vascular; Oxygen Consumption; Prostaglandin Endoperoxides, Synthetic; Sheep; Thromboxane A2; Vasodilator Agents

Topics: Animals; Arachidonic Acids; Disease Models, Animal; Dogs; Embolism, Fat; Epoprostenol; Female; Hypoxia; Indomethacin; Lung; Lung Injury; Male; Methacrylates; Microcirculation; Oleic Acid; Oleic Acids; Pulmonary Circulation; Pulmonary Embolism; Respiratory Distress Syndrome; Thromboxane A2; Vasoconstriction; Vasodilation

Coronary artery contractility is well known to be modulated by oxygen partial pressure. Both smooth muscle and the endothelium contribute to coronary artery oxygen sensitivity. Mechanisms underlying endothelium-dependent effects of oxygen include the sensitivity of the nitric oxide/endothelium-derived relaxing factor (EDRF), hydrogen peroxide, and eicosanoid pathways. In the present study, we characterize a novel endothelium-dependent component of porcine coronary artery oxygen sensitivity that is independent of these known pathways. Porcine coronary arteries were stimulated with either KCl or U46619. Hypoxia elicited a transient increase in force that was much greater in endothelium-intact arteries. This effect was abolished by nitric oxide/EDRF pathway inhibitors NG-monomethyl-L-arginine and N-nitro-L-arginine. In the steady state, hypoxia reduced isometric force to a similar degree in both intact and denuded arteries. Reoxygenation elicited a rapid and transient relaxation only in intact arteries. In contrast, this endothelium-dependent relaxation was not inhibited by nitric oxide/EDRF pathway inhibitors nor inhibitors of other potential oxygen-sensitive pathways, such as indomethacin, aminotriazole, superoxide dismutase, catalase, propranolol, or ouabain. The reoxygenation relaxation was, however, sensitive to very low levels of oxygen and was inhibited by cyanide and rotenone, suggesting an involvement of mitochondrial metabolism. Interestingly, the relaxation response to reoxygenation, similar to that for substance P, could be restored in denuded arteries by coupling with an endothelium-intact donor artery. This "sandwich" experiment suggests that the endothelium dependence is mediated by a transmissible factor. Our results indicate that a novel class of endothelium-dependent factors may contribute to coronary artery responses to changes in oxygen partial pressure.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine; Coronary Vessels; Endothelium, Vascular; Hypoxia; Oxygen; Partial Pressure; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Swine; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

To investigate dilator effects of endothelins (ETs) on the pulmonary circulation and possible changes induced by chronic hypoxia, we examined vascular responses to ET-1 and ET-3 as well as ET binding to receptor subtypes ETA and ETB in the lungs from rats exposed to either room air (controls), hypoxia (10% O2) for 3 wk (3 WH), or 3 WH followed by recovery to room air (3 WH+R). In controls, both ETA and ETB receptor binding was present in smooth muscle of airways and vessels. Infusion of ET-1 or ET-3 (3-100 pM) to isolated perfused lungs preconstricted by U-46619 produced dose-dependent vasodilation with a greater potency of ET-3 (P < 0.01). The vasodilator responses to ET-1 and ET-3 were potentiated by the cyclooxygenase blocker meclofenamate (3 x 10(-6) M) or by the thromboxane synthetase inhibitor R-68070. In meclofenamate-treated lungs, the vasodilator responses to ET-1 and ET-3 remained unaffected by the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (5 x 10(-4) M) or by the guanylate cyclase inhibitor, methylene blue (10(-4) M). Conversely, the K+ channel blockers glibenclamide (10(-4) M) and tetraethylammonium (10(-4) M) attenuated the vasodilator responses to both ET-1 and ET-3. The selective ETA receptor antagonist BQ-123 did not alter ET-induced vasodilation, whereas it attenuated ET-induced vasoconstriction. Vasodilation to both ET-1 and ET-3 was abolished in lungs from 3 WH rats (P < 0.01) but was fully restored in lungs from 3 WH+R rats. Pulmonary vasodilation induced by the K+ channel opener pinacidil, which was suppressed by glibenclamide, did not differ between controls and 3 WH rat lungs. We found no change in ETA and ETB receptor binding from pulmonary vessels in H rat lungs compared with controls. In conclusion, endothelin-induced pulmonary vasodilation which may involve activation of K+ channels is abolished during chronic hypoxia. This abolition does not appear to be related to alterations in ET-receptor subtypes or to unresponsiveness of K+ channels in the pulmonary circulation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine; Autoradiography; Dose-Response Relationship, Drug; Endothelins; Glyburide; Guanidines; Hypoxia; In Vitro Techniques; Iodine Radioisotopes; Lung; Male; Meclofenamic Acid; Nitroarginine; Pentanoic Acids; Pinacidil; Potassium Channel Blockers; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pyridines; Rats; Rats, Wistar; Receptors, Endothelin; Tetraethylammonium; Tetraethylammonium Compounds; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To assess the potential role of vasoactive cardiac eicosanoids in the modulation of coronary flow, we measure thromboxane(TX)B2, 6-keto-prostaglandin(PG)F1 alpha, PGE2 and sulphido-peptide leukotrienes (LTC4, D4, E4) in the coronary effluent of isolated perfused rat heart in both baseline and post-ischaemic conditions. Leukotrienes were undetectable. The order of production rate for the other eicosanoids was 6-keto-PGF1 alpha > TXB2 > PGE2. Production of such substances was increased about seven-fold over control after 5 min. global ischaemia; experiments with hypoxia showed that this was due to an actual increase in synthesis and not to a washout effect. A platelet source for TXB2 was excluded by 111In platelet labelling experiments. We assessed relative sensitivity to inhibition of cardiac TX synthesis relative to production of 6-keto-PGF1 alpha to inhibition by aspirin, ibuprofen, diclofenac and the specific thromboxane synthase inhibitor OKY-046. Aspirin, ibuprofen and diclofenac decreased 6-keto-PGF1 alpha production at a concentration always greater than required for a similar extent of TX inhibition. On the other hand a selective inhibition (> 90%) of TX was observed in the presence of OKY-046. Regression analysis of various 6-keto-PGF1 alpha/TXB2 ratios, as obtained in these different conditions, vs coronary flow, showed no correlation in baseline conditions, but a significant positive correlation (r = 0.59, P < 0.01) for post-ischaemic values. These data suggest a role for cardiac eicosanoids, including a non-platelet, cardiac-derived TX, in modulating the hyperaemic response in the isolated rat heart.

Topics: Animals; Blood Platelets; Coronary Circulation; Eicosanoids; Heart; Heart Rate; Hyperemia; Hypoxia; In Vitro Techniques; Indium Radioisotopes; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Thromboxane A2; Thromboxanes

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

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

The effect of hypoxia on splanchnic angiotensin II (AII)-stimulated prostaglandin (PG) release was examined in male rats. The superior mesenteric artery was cannulated and perfused in vitro with physiologic buffer at a pO2 of 460 or 60 torr. Splanchnic vessels were perfused isolated (SV) or in continuity with the small intestine (SV + SI). AII (10-300 ng) was infused as bolus injections. Quantitative analysis of SV + SI effluent by bioassay indicated the predominant PG released was PGI2. Quantitative analysis by radioimmunoassay confirmed PGI2 as the major PG released from the SV and SV + SI following AII stimulation. Relative hypoxia significantly decreased AII-stimulated release of PGI2 from the SV, and only modestly from the SV + SI. These data demonstrate two splanchnic sources of AII-stimulated vasodilator PG synthesis, the SV and SV + SI, with the SV more sensitive to relative hypoxia. Diminished release of splanchnic vascular (SV) vasodilator PGI2 may be of importance in AII-mediated splanchnic vasoconstriction seen in hypoxia and shock.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Biological Assay; Dinoprostone; Epoprostenol; Hypoxia; In Vitro Techniques; Male; Mesenteric Arteries; Muscle, Smooth; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane A2

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; Coronary Vessels; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Dogs; Epoprostenol; Female; Hypoxia; In Vitro Techniques; Male; Norepinephrine; Phentolamine; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Vasodilation

Thromboxane A2 (TxA2) is an arachidonic acid metabolite which causes severe pulmonary vasoconstriction (PV) and may mediate the PV produced by platelet-activating factor (PAF-acether) and leukotriene D4 (LTD4). To determine the role of TxA2 receptors on PAF-acether, LTD4, and hypoxia-induced PV, we administered PAF-acether 0.1 nmol/kg, the TxA2 analog U-46619 0.2 micrograms/kg/min, LTD4 3.0 micrograms/kg, or acute hypoxia (FiO2 = 0.12 for 3 min) before and during the infusion of the selective TxA2 receptor blocker SQ 29,548 50 micrograms/kg/min or vehicle into 27 open-chest, anesthetized newborn piglets, measuring pulmonary and systemic arterial pressures, cardiac index, and right and left ventricular pressures and dimensions. Mean pulmonary arterial pressure rose and cardiac index fell in response to PAF-acether (14 +/- 1 to 32 +/- 2 mm Hg and 91 +/- 5 to 15 +/- 5 mL/kg/min, both p less than 0.01), U-46619 (11 +/- 1 to 28 +/- 2 mm Hg and 93 +/- 10 to 36 +/- 9 mL/kg/min, both p less than 0.01), and LTD4 (13 +/- 3 to 22 +/- 2 mm Hg and 85 +/- 12 to 29 +/- 9 mL/kg/min, both p less than 0.05). Acute hypoxia increased PAP (12 +/- 1 to 26 +/- 2 mm Hg, p less than 0.01) but did not alter cardiac index. Infusion of SQ 29,548 prevented PAF-acether and U-46619-induced increases in pulmonary arterial pressure (13 +/- 1 to 14 +/- 1 mm Hg and 12 +/- 1 to 12 +/- 1 mm Hg) and decreases in cardiac index (70 +/- 4 to 70 +/- 3 mL/kg/min and 94 +/- 14 to 92 +/- 12 mL/kg/min) but failed to alter the response to LTD4 or hypoxia. Vehicle had no effect. We conclude that TxA2 receptors are not involved in LTD4 or hypoxia-induced PV but play an important role in the PV produced by PAF-acether and U-46619.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Female; Hemodynamics; Hydrazines; Hypoxia; Lung; Male; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Swine; Thromboxane A2; Vasoconstriction

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetophenones; Animals; Animals, Newborn; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypoxia; Lipids; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; SRS-A; Swine; Tetrazoles; Thromboxane A2; Vasoconstriction

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

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

This study investigated the effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (ketoprofen) on hypoxic pulmonary vasoconstriction in conscious adult sheep in order to evaluate the physiological role of thromboxane and other cyclooxygenase products. In addition, we studied the effects of histamine H1 (chlorpheniramine) and H2 antagonists (cimetidine) on hypoxic pulmonary vascular tone. Hypoxia caused a 37% rise in pulmonary arterial pressure (p less than 0.05) and a 36% increase in pulmonary vascular resistance (p less than 0.05). Pretreatment with intravenous OKY-046 10 mg/kg or ketoprofen 2 mg/kg had no effect on normoxic pulmonary vascular tone and inhibited the increase in plasma TXB2 concentration during hypoxia without affecting the pulmonary pressor response to hypoxia. Cimetidine produced an increase in hypoxic pulmonary vascular tone when individual members of the group were compared, but there was no statistically significant difference when the group was compared to the control study. Chlorpheniramine had no effect on hypoxic pulmonary tone. These data suggest that hypoxic pulmonary vasoconstriction is not mediated by release of TXA2, that hypoxic vascular tone is not modulated by cyclooxygenase products, and that the histamine H2 receptor may play a modulating role in hypoxic pulmonary vasoconstriction in conscious adult sheep.

Topics: Acrylates; Animals; Consciousness; Female; Hypoxia; Ketoprofen; Lung; Male; Methacrylates; Phenylpropionates; Receptors, Histamine H2; Sheep; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

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

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

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

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

Topics: Blood Platelets; Humans; Hypoxia; In Vitro Techniques; Platelet Aggregation; Thromboxane A2; Vascular Diseases

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

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

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

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Epoprostenol; Hemodynamics; Hypoxia; Ibuprofen; Imidazoles; Lung; Lymph; Meclofenamic Acid; Physical Exertion; Pulmonary Artery; Sheep; Thromboxane A2; Vascular Resistance

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

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

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

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

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Topics: Acrylates; Animals; Animals, Newborn; Arachidonic Acid; Arachidonic Acids; Fetus; Hypoxia; Lung; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Circulation; Respiration, Artificial; Sheep; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Vasoconstriction

We characterized and quantified products of exogenous arachidonic acid metabolism by neonatal lamb lungs perfused with Krebs solution and determined effects of alveolar hypoxia upon this metabolism. The predominant metabolite was PGI2 (62.4 +/- 5.8 (SEM)% of the total prostanoids (PGs) produced). An additional 23.1 +/- 6.7% was metabolized PGI2. PGE2 (1.7 +/- 3.0%) was produced also. Little thromboxane B2 (TXB2) (3.3 +/- 1.7%) was synthesized by these platelet-free lungs. Although the pulmonary vasoconstrictor response to arachidonic acid infusion reached a plateau in 71 +/- 19 seconds, the PG efflux was greater 8-15 minutes after beginning arachidonic acid infusion (3066 +/- 1353 ng/min) than 1-8 minutes into the infusion (899 +/- 343 ng/min). Reduction of FIO2 from 20% to 3% O2 which produces vasoconstriction in the absence of exogenous arachidonic acid, did not alter the PG profile nor quantity produced. With respect to the neonatal lamb pulmonary vasculature perfused with Krebs solution, we conclude: 1) exogenous arachidonic acid ultimately is metabolized predominantly to PGI2, 2) arachidonic acid-induced pulmonary vasoconstriction is not caused by TXA2, 3) short term hypoxia does not alter the conversion of excess arachidonic acid to PGs, and 4) a lag between intrapulmonary PG synthesis and pulmonary venous efflux may occur.

Topics: Animals; Animals, Newborn; Arachidonic Acid; Arachidonic Acids; Bicarbonates; Buffers; Epoprostenol; Hypoxia; Lung; Prostaglandins; Sheep; Thromboxane A2; Vasoconstriction

Products of the arachidonate cascade are known to be released from pulmonary tissue in normal and abnormal states, contributing to the regulation of pulmonary vascular resistance. To what extent hypoxic pulmonary vasoconstriction is affected by prostaglandin imbalances is still controversial. To evaluate PG and TX release, we measured plasma levels of TXA2, PGI2, PGF2a, and 13,14-dihydro-15-keto-PGF2a in healthy pigs undergoing normobaric hypoxic ventilation. Plasma levels of TXA2, PGI2, and PGF2a did not change during 10 minutes of hypoxia, whereas 13,14-dihydro-15-keto-PGF2a, the stable metabolite of PGF2a, was significantly elevated after 2, 5 and 10 minutes. Hemodynamic parameters showed an increase in heart rate and pulmonary vascular resistance. Our results suggest that alveolar hypoxia releases PGF2a from lung tissue, being rapidly metabolized to 13,14-dihydro-15-keto-PGF2a and that prostaglandins, at least in part, contribute to hypoxic pulmonary vasoconstriction.

Topics: Anesthesia, General; Animals; Hypoxia; Male; Prostaglandins; Pulmonary Circulation; Swine; Thromboxane A2; Thromboxanes; Vascular Resistance; Vasoconstriction

Plasma thromboxane A2, a vasoconstrictor, and plasma prostacyclin (epoprostenol), a vasodilator, were assessed by double-antibody radioimmunological assay of their respective stable circulating metabolites, thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha, in 9 patients with severe diffuse pulmonary fibrosis (DPF), who were known to become hypo-oxaemic during exercise, and in 9 healthy volunteers. In the 7 patients with the most severe DPF, mean arterial PO2 fell from 68 mm Hg at rest to 51 mm Hg at peak aerobic exercise, and mean TxB2 increased to twice the value at rest. The 9 controls remained oxygen saturated throughout exercise; their mean TxB2 did not change during aerobic exercise, but during anaerobic exercise increased to twice the value at rest, and increased further during recovery. There were no significant changes in 6-keto-prostaglandin F1 alpha in either group. The selective release of TxB2 during aerobic exercise in hypo-oxaemic patients suggests that thromboxane mediates hypoxic pulmonary vasoconstriction. Its release in normal man during anaerobic exercise may reflect a more general response to the metabolic changes of tissue hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aerobiosis; Anaerobiosis; Epoprostenol; Female; Humans; Hypoxia; Male; Physical Exertion; Prostaglandins; Pulmonary Fibrosis; Respiratory Function Tests; Thromboxane A2; Thromboxanes

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

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

A reduced oxygen supply to the heart causes coronary vasodilatation in the first instance. But if the hypoxia is severe or prolonged, the dilatation passes off and coronary vasospasm develops leading to a vicious circle with a further reduction of myocardial oxygenation. The spasm is associated with increased outflow of prostaglandin (PG)-like material and can be prevented or reversed by inhibitors of PG synthesis such as indomethacin or antagonists of PG action such as chloroquine. The spasm does not appear to be caused by thromboxane (TX) A2 since selective inhibitors of TXA2 synthesis enhance the hypoxic spasm and by themselves can cause spasm even in oxygenated hearts. The mechanism may be related to loss of negative feedback control of the PG pathway by TXA2. Oxygen may enhance TXA2 production and reduce formation of vasoconstrictor PGs, while smoking, because of the formation of carboxyhaemoglobin, may have the opposite effect. Oestradiol and testosterone do not influence the hypoxic spasm but progesterone at physiological concentrations blocks it completely. Progesterone may be the protective female hormone and the increased susceptibility to myocardial infarction in women on oral contraceptives may be related to reduced formation of endogenous progesterone.. The role of coronary vasospasm in many heart attacks has been reported. The paper presents a quite different mechanism, overproduction of prostaglandins (PGs), as the major factor in producing both the spasm and disorders of the rhythm which often accompany it. Coronary vasodilatation is caused by a reduced oxygen supply to the heart. If the hypoxia is severe or prolonged, coronary vasospasm results, leading to a further reduction of myocardial oxygenation. Increased outflow of PG-like material is related with the spasm, which can be prevented or reversed by infusion of inhibitors of PG synthesis (e.g., indomethacin) or of antagonists of PG action (chloroquine). The mechanism of the spasm may be associated with loss of negative feedback control of PG pathway by TXA2 (thromboxane). Oxygen may stimulate TXA2 production and reduce formation of vasoconstrictor PGs; the opposite effect is achieved with smoking due to formation of carboxyhaemoglobin. Estradiol and testosterone have no effect on hypoxic spasms; progesterone at physiological concentration blocks it entirely. Increased susceptibility to myocardial infarction of women on oral contraceptives is associated with reduced formation of endogenous progesterone, possibly the protective female hormone.

Topics: Coronary Circulation; Coronary Disease; Estradiol; Female; Humans; Hypoxia; Progesterone; Prostaglandins; Smoking; Testosterone; Thromboxane A2; Thromboxanes

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