piriprost and Hypoxia

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

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

Several lines of evidence suggest that leukotrienes may be mediators of hypoxic pulmonary vasoconstriction (HPV). However, the effect of leukotriene inhibition on HPV remains controversial. The present study investigated the effect of leukotriene synthesis inhibition and receptor blockade on HPV in the halothane-anesthetized sheep. After initial baseline measurements, the pulmonary pressor response to 15 min of global hypoxia (FIO2 = 0.13) was measured. A second set of baseline measurements was obtained and the sheep then received the combined cyclooxygenase/lipoxygenase inhibitor BW755C, the selective lipoxygenase inhibitor U60257, or the leukotriene receptor antagonist LY171883. Hemodynamic measurements were obtained after drug administration and during a subsequent hypoxic challenge (FIO2 = 0.13). Initial hypoxic challenge increased pulmonary artery pressure 68% and increased pulmonary vascular resistance 104%. Pulmonary hemodynamics after recovery from hypoxia were similar to initial baseline values. Drug administration had no significant hemodynamic effect. Hypoxic challenge after drug administration resulted in a pulmonary pressor response identical to the initial hypoxic challenge. Because leukotriene synthesis inhibition and receptor blockade did not alter the response to hypoxia, we conclude that leukotrienes are not obligatory mediators of HPV. A critical review of the literature supports a modulatory rather than an obligatory role for leukotrienes in HPV.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Acetophenones; Anesthesia, Inhalation; Animals; Autacoids; Epoprostenol; Halothane; Hemodynamics; Hypoxia; Leukotriene Antagonists; Leukotrienes; Lung; Male; Receptors, Immunologic; Receptors, Leukotriene; Sheep; Tetrazoles; Vasoconstriction

Because leukotrienes may mediate hypoxic pulmonary vasoconstriction (HPV), we examined the influence of two lipoxygenase inhibitors on HPV in anesthetized pigs. HPV was induced by ventilation with a hypoxic gas mixture (FIO2 at 0.095), resulting in a fall in PaO2 to 23 +/- 2 mm Hg and a rise in pulmonary vascular resistance from 285 +/- 15 to 595 +/- 30 dyne/s/cm-5. After infusion of either U-60,257B (50 mg/kg, n = 13) or BW 755c (20 mg/kg, n = 8), the responses to repeated hypoxic challenges were recorded. After U-60,257B infusion the hypoxic pressor response was eliminated at 10 and 30 min and remained significantly (p less than 0.01) attenuated at 50 min. The pulmonary pressor response to angiotensin II infusion (0.2 micrograms/kg/min) was also ablated, whereas the systemic response was unchanged. In contrast, after BW 755c infusion there was a modest but sustained augmentation of HPV, maximum at 30 min (pulmonary vascular resistance, 158 +/- 23% control, p less than 0.01), and no alteration of the responses to angiotensin II. BW 755c inhibited the A23187-induced release of leukotrienes, but not histamine, from isolated porcine lung cells (IC50, 6.3 x 10(-5) M), whereas U-60,257B inhibited the release of both leukotriene (IC50, 1.1 x 10(-4) M) and histamine. These findings indicate that reduction of HPV by lipoxygenase inhibitors is not necessarily a consequence of inhibition of leukotriene synthesis.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Angiotensin II; Animals; Calcimycin; Epoprostenol; Female; Histamine Release; Hypoxia; Lipoxygenase Inhibitors; Lung; Male; Pulmonary Circulation; Pyrazoles; SRS-A; Swine; Vascular Resistance; Vasoconstriction

Arachidonic acid metabolites, notably leukotrienes (LTs), have been postulated to play a role in hypoxic pulmonary vasoconstriction. In the present study, we examined the contribution of arachidonic acid metabolites, via the cyclooxygenase, 5-lipoxygenase and cytochrome P-450 monooxygenase pathways, to the hypoxia (25 +/- 3 torr)- and anoxia (0 +/- 2 torr)-induced contractions of isolated pulmonary venules. Neither the cyclooxygenase inhibitors indomethacin (5 microM) or ibuprofen (10 microM) nor the 5-lipoxygenase inhibitors nordihydroguaiaretic acid (5 microM) or U 60257B (10 microM) affected the contractile responses. Similarly, the LT receptor antagonists FPL 57231 (3 microM) or LY 163443 (1 microM), at concentrations that inhibited LT-induced venular contractions, did not significantly affect the responses to hypoxia or anoxia. In fact, anoxia suppressed spontaneous LT release from the venules. The cytochrome P-450 inhibitor SKF-525A (500 microM) nonselectively depressed venular contractions induced by decreased PO2 and pharmacological agents. Induction of the cytochrome P-450 monooxygenase system with beta-naphthoflavone did not alter venular contractions induced by hypoxia or anoxia. Contractions of isolated guinea pig pulmonary venules elicited by decreased PO2 are not mediated by 5-lipoxygenase or cyclooxygenase metabolites. Furthermore, the data do not support a role for cytochrome P-450 metabolites of endogenous substrates in these contractions.

Topics: Acetophenones; Animals; Benzoflavones; beta-Naphthoflavone; Calcimycin; Chromones; Cytochrome P-450 Enzyme System; Epoprostenol; Guinea Pigs; Hypoxia; Leukotrienes; Lipoxygenase; Lipoxygenase Inhibitors; Lung; Masoprocol; Muscle Contraction; Muscles; Prostaglandin-Endoperoxide Synthases; Pyridines; Veins; Venules

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

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

A novel leukotriene synthesis inhibitor, piriprost (U-60,257) was characterized in three quantitated assays of secretion in the canine in vivo trachea. The normal baseline secretion rate was inhibited in a dose-related fashion when the inhibitor was given via the cranial thyroid artery (decrease compared to control dogs: 27 +/- 3.11% at 0.1 mg, n = 3, p less than 0.05; 56 +/- 4.85% at 0.5 mg, n = 3, p less than 0.01; 61.5 +/- 6.8% at 1.0 mg, n = 14, p less than 0.001). Hypoxia gas mixtures (8% O2 and 92% N2 4 min) delivered into the lung caused a mean increase in secretion of 160 +/- 11.2% (p less than 0.05). When the leukotriene inhibitor (1.0 mg) was given into the close arterial segment before hypoxia, this increased secretion response was blocked (160 +/- 11.2 to 40 +/- 16.7%; p less than 0.05). Finally, arachidonic acid caused a potent and long-lasting enhancement in secretion (179 +/- 9.0% of control; p less than 0.01) that was partially blocked by 5 mg/kg indomethacin 30 min before (90 +/- 12.7% of arachidonic acid; p less than 0.01), and when 1.0 mg U-60,257 preceded the arachidonic acid, an additional inhibition of 50% of the indomethacin inhibition was seen (p less than 0.01; n = 14). These findings are consistent with the hypothesis that canine secretion is modulated by arachidonic acid metabolites that act as agonists for secretion both by the cyclooxygenase and lipoxygenase pathways.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Dogs; Epoprostenol; Hypoxia; Indomethacin; Mucus