Role of eicosanoids in hypoxic vasoconstriction in isolated lamb lungs

1987 ◽  
Vol 253 (3) ◽  
pp. H626-H633 ◽  
Author(s):  
J. U. Raj ◽  
P. Chen
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Receptor Blocker ◽  
Lipoxygenase Inhibitor ◽  
Thromboxane Receptor ◽  
Thromboxane Synthetase ◽  
Vasoconstrictor Response ◽  
Micron Diameter ◽  
Arterial Constriction

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

scholarly journals Involvement of thromboxane A2 in airway mucous cells in asthma-related cough

2002 ◽  
Vol 92 (2) ◽  
pp. 763-770 ◽  
Author(s):  
Anbo Xiang ◽  
Yoshiyuki Uchida ◽  
Akihiro Nomura ◽  
Hiroaki Iijima ◽  
Tohru Sakamoto ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Allergic Airway Inflammation ◽  
Thromboxane A2 ◽  
Lavage Fluid ◽  
Mucous Cells ◽  
Thromboxane Receptor ◽  
Neurokinin Receptor ◽  
Thromboxane Synthetase ◽  
Thromboxane Receptor Antagonist

The aim of this study was to elucidate the role of thromboxane A2 (TxA2) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10−5 M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA2 mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB2 in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA2 derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.

Contributions of thromboxane and leukotrienes to PAF-induced impairment of lung function in the rat

1994 ◽  
Vol 77 (1) ◽  
pp. 262-269 ◽  
Author(s):  
S. Uhlig ◽  
L. Wollin ◽  
A. Wendel
Keyword(s):  
Platelet Activating Factor ◽  
Inhibitory Effect ◽  
Rat Lung ◽  
Lipoxygenase Inhibitor ◽  
Edema Formation ◽  
Thromboxane Receptor ◽  
Pulmonary Vasoconstriction ◽  
Minor Part ◽  
Dual Inhibition

This study was carried out to further clarify the role of eicosanoids in platelet-activating factor (PAF)-induced pulmonary vasoconstriction, bronchoconstriction, and edema formation in the isolated perfused rat lung. Infusion of PAF into the isolated perfused rat lung caused vasoconstriction [mean effective concn (EC50) = 0.88 nmol], caused bronchoconstriction (EC50 = 0.71 nmol), and increased the capillary filtration coefficient (EC50 = 1.4 nmol). Two minutes after injection of 50 nmol PAF, a high thromboxane concentration (3,000 pg/ml) and a low peptidoleukotriene concentration (150 pg/ml) were found in the effluent perfusate. PAF-induced vaso- and bronchoconstriction were unaffected by the non-redox 5-lipoxygenase inhibitor ZM-230,487 but were markedly attenuated by inhibition of cyclooxygenase with acetylsalicylic acid or thromboxane-receptor antagonism with BM-13177. Dual inhibition of cyclooxygenase and 5-lipoxygenase had the most pronounced inhibitory effect on PAF-induced vaso- and bronchoconstriction. None of the inhibitors tested prevented the increase in vascular permeability. We conclude that thromboxane is the major vasoconstrictor and bronchoconstrictor induced by PAF, whereas leukotrienes contribute a significant but minor part in this system. PAF-induced microvascular permeability was not inhibited by blockade of arachidonate metabolism and therefore seems to be mediated by a mechanism independent of eicosanoids.

Macrophage 12(S)-HETE Enhances Angiotensin II–Induced Contraction by a BLT2 (Leukotriene B 4 Type-2 Receptor) and TP (Thromboxane Receptor)-Mediated Mechanism in Murine Arteries

Hypertension ◽  
2021 ◽  
Author(s):  
Tamas Kriska ◽  
Anja Herrnreiter ◽  
Sandra L. Pfister ◽  
Adeniyi Adebesin ◽  
John R. Falck ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ang Ii ◽  
Enhancing Effect ◽  
Thromboxane Receptor ◽  
Abdominal Aortic ◽  
Induced Hypertension ◽  
Arterial Constriction ◽  
Thromboxane Receptor Antagonist ◽  
Arterial Endothelial Cells

12/15-LO (12/15-lipoxygenase), encoded by Alox15 gene, metabolizes arachidonic acid to 12(S)-HETE (12-HETE). Macrophages are the major source of 12/15-LO among immune cells, and 12/15-LO plays a crucial role in development of hypertension. Global Alox15- or macrophage-deficient mice are resistant to Ang II (angiotensin II)–induced hypertension. This study tests the hypothesis that macrophage 12(S)-HETE contributes to Ang II–mediated arterial constriction and thus to development of Ang II–induced hypertension. Ang II constricted isolated abdominal aortic and mesenteric arterial rings. 12(S)-HETE (100 nmol/L) alone was without effect; however, it significantly enhanced Ang II–induced constriction. The presence of wild-type macrophages also enhanced the Ang II–induced constriction, while Alox15 −/− macrophages did not. Using this model, pretreatment of aortic rings with inhibitors, receptor agonists/antagonists, or removal of the endothelium, systematically uncovered an endothelium-mediated, Ang II receptor-2–mediated and superoxide-mediated enhancing effect of 12(S)-HETE on Ang II constrictions. The role of superoxide was confirmed using aortas from p47 phox−/− mice where 12(S)-HETE failed to enhance constriction to Ang II. In cultured arterial endothelial cells, 12(S)-HETE increased the production of superoxide, and 12(S)-HETE or Ang II increased the production of an isothromboxane-like metabolite. A TP (thromboxane receptor) antagonist inhibited 12(S)-HETE enhancement of Ang II constriction. Both Ang II–induced hypertension and the enhancing effect of 12(S)-HETE on Ang II contractions were eliminated by a BLT2 (leukotriene B 4 receptor-2) antagonist. These results outline a mechanism where the macrophage 12/15-LO pathway enhances the action of Ang II. 12(S)-HETE, acting on the BLT2, contributes to the hypertensive action of Ang II in part by promoting endothelial synthesis of a superoxide-derived TP agonist.

Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence

2001 ◽  
Vol 280 (5) ◽  
pp. L856-L865 ◽  
Author(s):  
Q. Liu ◽  
J. S. K. Sham ◽  
L. A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Bronchial Arteries ◽  
Pulmonary Vasoconstriction ◽  
Endothelial Denudation ◽  
Basal Release ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

To determine the role of endothelium in hypoxic pulmonary vasoconstriction (HPV), we measured vasomotor responses to hypoxia in isolated seventh-generation porcine pulmonary arteries < 300 μm in diameter with (E+) and without endothelium. In E+ pulmonary arteries, hypoxia decreased the vascular intraluminal diameter measured at a constant transmural pressure. These constrictions were complete in 30–40 min; maximum at Po 2 of 2 mmHg; half-maximal at Po 2 of 40 mmHg; blocked by exposure to Ca2+-free conditions, nifedipine, or ryanodine; and absent in E+ bronchial arteries of similar size. Hypoxic constrictions were unaltered by indomethacin, enhanced by indomethacin plus N G-nitro-l-arginine methyl ester, abolished by BQ-123 or endothelial denudation, and restored in endothelium-denuded pulmonary arteries pretreated with 10−10 M endothelin-1 (ET-1). Given previous demonstrations that hypoxia caused contractions in isolated pulmonary arterial myocytes and that ET-1 receptor antagonists inhibited HPV in intact animals, our results suggest that full in vivo expression of HPV requires basal release of ET-1 from the endothelium to facilitate mechanisms of hypoxic reactivity in pulmonary arterial smooth muscle.

Modulatory role of EDRF in hypoxic contraction of isolated porcine pulmonary arteries

1992 ◽  
Vol 262 (3) ◽  
pp. H691-H697 ◽  
Author(s):  
M. Ogata ◽  
M. Ohe ◽  
D. Katayose ◽  
T. Takishima
Keyword(s):  
Contractile Response ◽  
Isometric Force ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Pulmonary Vasoconstriction ◽  
Basal Release ◽  
Endothelium Derived Relaxing Factor ◽  
Endothelium Dependent Relaxation ◽  
Porcine Pulmonary Artery

To examine the hypothesis that suppression of basal release of endothelium-derived relaxing factor (EDRF) by hypoxia might be related to the mechanism of hypoxic pulmonary vasoconstriction, rings of porcine pulmonary artery (PA, 2 mm OD) were suspended in organ chambers and changes in isometric force were measured. Hypoxia significantly reduced endothelium-dependent relaxation induced by acetylcholine and augmented contractile response to phenylephrine. This augmentation by hypoxia was not seen in rings without endothelium. Contractile response to phenylephrine was also enhanced by removal of endothelium. With 15 min of hypoxia, PA contracted and guanosine 3',5'-cyclic monophosphate content decreased. Pretreatment with 10(-6) M methylene blue, 3 x 10(-7) M oxyhemoglobin, and 9.6 x 10(-5) M NG-monomethyl-L-arginine significantly enhanced hypoxic contraction. Furthermore, removal of endothelium also enhanced hypoxic contraction. These results suggest that suppression of basally released EDRF by hypoxia was not the cause of the contractile response to hypoxia and that EDRF modulates the hypoxic contraction of porcine PA in basal conditions at this diameter.

Role of peptidoleukotrienes in hypoxic pulmonary vasoconstriction in rats

1990 ◽  
Vol 259 (3) ◽  
pp. H751-H758 ◽  
Author(s):  
T. J. McDonnell ◽  
J. Y. Westcott ◽  
J. Czartolomna ◽  
N. F. Voelkel
Keyword(s):  
Lung Tissue ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Lavage Fluid ◽  
Lung Lavage ◽  
Physiological Salt Solution ◽  
Slight Reduction ◽  
Lipoxygenase Inhibitor ◽  
Pulmonary Vasoconstriction ◽  
Eicosanoid Production

The role of leukotrienes in the mechanism of hypoxic pulmonary vasoconstriction (HPV) is controversial. To determine whether leukotriene C4 (LTC4) was produced during HPV, LTC4 levels were measured in individual samples of lung tissue, lung bronchoalveolar lavage fluid (BALF), and blood perfusate in isolated perfused lungs ventilated with normoxic or hypoxic gas mixtures. HPV was not associated with increased LTC4 in lung tissue or increased LTE4 in blood perfusate. Consistent with previous studies demonstrating elevated levels of LTC4 in pooled BALF fluid from hypoxic lungs, individual lung BALF samples demonstrated an elevation of LTC4 during hypoxia. However, the process of lung lavage alone stimulated eicosanoid production, with LTC4, 6-ketoprostaglandin F1 alpha, and thromboxane B2 levels being higher in lavaged compared to non-lavaged lungs. In lungs to which the lipoxygenase inhibitor AA 861 was added to the perfusate, a reduction in the lung tissue LTC4 levels was observed without any or only a slight reduction in HPV. To evaluate the physiological effects of LTC4 in the airways, exogenous LTC4 (1-1,000 ng) was added to the airways of both blood- and physiological salt solution-perfused lungs without any effect on the pulmonary artery pressure or a response to hypoxia. These results do not support the hypothesis that leukotrienes mediate HPV in the rat.

scholarly journals ASIC1 contributes to pulmonary vascular smooth muscle store-operated Ca2+ entry

2009 ◽  
Vol 297 (2) ◽  
pp. L271-L285 ◽  
Author(s):  
Nikki L. Jernigan ◽  
Michael L. Paffett ◽  
Benjimen R. Walker ◽  
Thomas C. Resta
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Cyclopiazonic Acid ◽  
Fura 2 ◽  
Whole Cell Patch Clamp ◽  
Intracellular Ca ◽  
Arterial Constriction

Acid-sensing ion channels (ASIC) are voltage-insensitive, cationic channels that have recently been identified in vascular smooth muscle (VSM). It is possible that ASIC contribute to vascular reactivity via Na+ and Ca2+ conductance; however, their function in VSM is largely unknown. In pulmonary VSM, store-operated Ca2+ entry (SOCE) plays a significant role in vasoregulatory mechanisms such as hypoxic pulmonary vasoconstriction and receptor-mediated arterial constriction. Therefore, we hypothesized that ASIC contribute to SOCE in pulmonary VSM. We examined SOCE resulting from depletion of intracellular Ca2+ stores with cyclopiazonic acid in isolated small pulmonary arteries and primary cultured pulmonary arterial smooth muscle cells by measuring 1) changes in VSM [Ca2+]i using fura-2 indicator dye, 2) Mn2+ quenching of fura-2 fluorescence, and 3) store-operated Ca2+ and Na+ currents using conventional whole cell patch-clamp configuration in voltage-clamp mode. The role of ASIC was assessed by the use of the ASIC inhibitors, amiloride, benzamil, and psalmotoxin 1, or siRNA directed towards ASIC1, ASIC2, or ASIC3 isoforms. We found that store-operated VSM [Ca2+]i responses, Mn2+ influx, and inward cationic currents were attenuated by either pharmacological ASIC inhibition or treatment with ASIC1 siRNA. These data establish a unique role for ASIC1 in mediating SOCE in pulmonary VSM and provide new insight into mechanisms of VSM Ca2+ entry and pulmonary vasoregulation.

Endothelium-dependent relaxation in isolated human arteries and veins

1987 ◽  
Vol 73 (5) ◽  
pp. 547-552 ◽  
Author(s):  
S. Thom ◽  
A. Hughes ◽  
G. Martin ◽  
P. S. Sever
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Lipoxygenase Inhibitor ◽  
Human Arteries ◽  
Endothelium Dependent Relaxation

1. The role of the endothelium in mediating relaxation to acetylcholine, the calcium ionophore A23187, vasoactive intestinal peptide and peptide histidine methionine was studied using isolated human blood vessels. 2. Segments of renal, colic, pulmonary, uterine, transverse cervical, brachial, coronary and coeliac branch arteries, and saphenous veins, were obtained from surgical resection material for use in tissue bath studies. 3. Acetylcholine or A23187 produced endothelium-dependent relaxation in isolated vessels from all vascular beds studied. Coronary arteries, however, differed in their response to acetylcholine which produced predominantly a contractile response, either alone or after initial relaxation. 4. Vasoactive intestinal peptide and peptide histidine methionine produced endothelium-dependent relaxation in coeliac branch arteries. However, these peptides relaxed isolated pulmonary arteries independently of endothelium. 5. Endothelium-dependent relaxation in response to acetylcholine and A23187 was antagonized by nordihydroguaretic acid, a lipoxygenase inhibitor, and methylene blue and haemoglobin, inhibitors of soluble guanylate cyclase. In these respects the endothelium-dependent responses of human arteries to acetylcholine and A23187 resemble those described in other species.

Afferent arteriolar responses to ANG II involve activation of PLA2 and modulation by lipoxygenase and P-450 pathways

1997 ◽  
Vol 273 (2) ◽  
pp. F274-F282 ◽  
Author(s):  
J. D. Imig ◽  
P. C. Deichmann
Keyword(s):  
Arachidonic Acid ◽  
Vessel Diameter ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Lipoxygenase Inhibitor ◽  
Lipoxygenase Pathway ◽  
Vasoconstrictor Response ◽  
Vasoconstrictor Effect ◽  
Cytochrome P 450

Activation of angiotensin receptors activates phospholipase A2 (PLA2) in various tissues, resulting in the release of arachidonic acid and formation of vasoactive metabolites. The present study examined the role of the lipoxygenase and cytochrome P-450 pathways by evaluating the effects of PLA2, cyclooxygenase, lipoxygenase, and epoxygenase inhibition on the afferent arteriolar responses to angiotensin II (ANG II) and norepinephrine in the vitro perfused rat juxtamedullary nephron preparation. ANG II (0.01-100 nM) resulted in a dose-dependent afferent arteriolar vasoconstriction ranging from 3 +/- 1 to 32 +/- 2% (n = 47). Norepinephrine at 0.01, 0.1, and 1.0 microM also decreased afferent arteriolar diameter by 5 +/- 1, 17 +/- 1, and 34 +/- 2%, respectively (n = 43). In the presence of arachidonyl trifluoromethyl ketone (AACOCF3, 20 microM), a PLA2 inhibitor, afferent arteriolar vasoconstriction to ANG II (100 nM) was attenuated, and the diameter decreased by 23 +/- 4% (n = 7). The cyclooxygenase inhibitor, indomethacin (10 microM), and the cyclooxygenase-2 inhibitor, NS-398 (10 microM), did not affect the afferent arteriolar response to ANG II. The lipoxygenase inhibitor biacalein (1 microM) attenuated the afferent arteriolar response to ANG II, and vessel diameter decreased by 11 +/- 5% (n = 6) in response to 100 nM ANG II. On the other hand, miconazole (1 microM), a selective epoxygenase inhibitor, enhanced the afferent arteriolar vasoconstriction to 100 nM ANG II. 17-Octadecynoic acid (17-ODYA, 1 microM), an inhibitor of hydroxylase and epoxygenase metabolism of arachidonic acid, also increased the responsiveness of the afferent arteriole. PLA2, lipoxygenase, or cytochrome P-450 inhibition had no effect on the afferent arteriolar vasoconstriction to norepinephrine. The afferent arteriolar vasoconstrictor response to norepinephrine (0.1 microM) was enhanced by indomethacin or NS-398, and diameter decreased by 25 +/- 3% and 28 +/- 4%, respectively. Results of this study suggest that metabolites of the cyclooxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of norepinephrine. Furthermore, these data suggest that activation of PLA2 is involved in part of the afferent arteriolar response to ANG II and that metabolites of the lipoxygenase pathway augment and metabolites of the epoxygenase pathway attenuate the afferent arteriolar vasoconstrictor effect of ANG II.

Do Thromboxane-Sensitive Receptors Mediate Platelet Aggregation In The Rat?

1981 ◽  
Author(s):  
G G Duncan ◽  
G M Smith
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Thromboxane Receptor ◽  
Competitive Antagonism ◽  
Conflicting Evidence ◽  
Thromboxane Synthetase ◽  
Thromboxane Receptor Antagonist ◽  
Induced Aggregation

Evidence has been produced to suggest that platelets of rabbits and humans contain receptors sensitive to thromboxane A2 (TxA2) and that inhibition of platelet aggregation can be achieved by preventing the conversion of the cyclo endoperoxides to TxA2 or by competitive antagonism of TxA2 at these TxA2-sensitive receptors. Conflicting evidence has been published on the possible role of TxA2 in the rat and this communication will attempt to explain the effects of agonists and inhibitors in rats and rabbits.Platelet aggregation was measured in vivo by continuously measuring the circulating platelet count using the Technicon Auto-counter. Collagen, PGH2 and the synthetic prostanoids U446l9 and U44069 were studied in rats and collagen and PGH2 were also studied in rabbits. The effects of cyclo-oxygenase inhibitors, thromboxane synthetase inhibitors and thromboxane receptor antagonists on aggregation produced by collagen and PGH2 were studied. Collagen, U44069 and PGH2 produced a dose-dependent fall in platelet count in rats. U46619 was inactive at nontoxic doses. Cyclo-oxygenase inhibitors partially inhibited collagen-induced aggregation in both rats and rabbits. 1-n-butylimidazole (25 mg/kg) and phthalazinol (1 mg/kg) (reported to be a thromboxane receptor antagonist) both inhibited aggregation produced by collagen and PGH2 in the rabbit but they did not affect aggregation produced by collagen in the rat.The activity of the cyclo-oxygenase inhibitors suggests that collagen-induced aggregation is partially mediated by products of arachidonic acid in rats and rabbits but evidence that the conversion of PGH2 to TxA2 is necessary for aggregation to be produced in rats by this pathway could not be obtained.

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