Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs

Morganroth, Melvin L.; Stenmark, Kurt R.; Zirrolli, Joseph A.; Mauldin, Richard E.; Mathias, Melvin M.; Reeves, John Τ.; Murphy, Robert C.; Voelkel, Norbert F.

doi:10.1016/0090-6980(84)90040-6

Cited by 51 publications

(16 citation statements)

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“…Previous studies have suggested that LT may mediate the pulmonary vasoconstriction seen in patients with persistent pulmonary hypertension syndrome (19) and with the adult respiratory distress syndrome (20,2 l), and in laboratory animals during hypoxia (15). The results of our present study suggest that LTD4 produces more pulmonary vasoconstriction than LTC4.…”

Section: Discussionsupporting

confidence: 54%

“…( Recent studies have shown that LT cause in vitro contraction of smooth muscle in a variety of tissues including trachea (1-4), lung (1, [3][4][5], uterus (4,6), gastrointestinal tract (4,6,7), and blood vessels (1, 3,4, 8-1 1). LT may also play an important role in in vivo vascular smooth muscle contraction (12)(13)(14)(15)(16)(17)(18). This hypothesis is supported by the finding that the LT receptor antagonist FPL57231 (Fisons, plc, Loughborough, UK) attenuates hypoxia-induced pulmonary vasoconstriction in several animal species (13,14,17).…”

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confidence: 99%

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The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

1987

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ABSTRACT. Leukotriene (LT) C4 or D4 may mediate pulmonary hypertension induced by hypoxia. LT have also been isolated from patients with persistent pulmonary hypertension of the newborn syndrome and the adult respiratory distress syndrome. To compare the effects of LTC4 and D4 on the pulmonary and systemic circulations, we performed dos4response studies on spontaneously breathing newborn lambs. To determine whether the hemodynamic effects of LT are mediated through a-adrenergic stimulation, some lambs were pretreated with the a-adrenergic antagonist phentolamine mesylate before LT injection. These results were com~ared to the effects of retreatment with the LT receptor &tagonist F~~5 7 2 3 i .To determine whether the LT-induced decrease in cardiac output was mediated by the decrease in heart rate, other lambs had their heart rate maintained by left atrial pacing. We found that LTC4 and D4 increased systemic arterial pressure and decreased cardiac output and heart rate. However, LTD,, but not LTC4, increased pulmonary arterial pressure. The hemodynamic effects of LTC4 and LTD4 were completely blocked by FPL57231 but not by phentolamine mesylate. Maintenance of heart rate by left atrial pacing did not alter the LT-induced decrease in cardiac output. We conclude that LTC4 and D4 have similar effects on the systemic circulation. However, LTD4 produces more pulmonary vasoconstriction. Because FPL57231 did block the pulmonary vasoconstriction caused by LT, LT antagonists may be useful in treating patients with pulmonary hypertension. (Pediatr Res 21: 176-182, 1987 animal species (13,14,17). Clinically, LT have been isolated from the lung lavage fluid of patients with either the persistent pulmonary hypertension of the newborn syndrome (19) or the adult respiratory distress syndrome (20, 2 1).The specific LT that cause pulmonary vasoconstriction and other types of smooth muscle contraction are L T C and LTD4, both C-6 peptide derivatives of LTA4. L T C is converted to LTD4 through peptidolysis (6). Several previous studies have shown LTD4 to be a potent in vivo pulmonary vasoconstrictor (1 2, 18,22,23). Evidence suggests that LTC4 is also a pulmonary vasoconstrictor (3, 1 1, 16, 24). If LT do mediate the pulmonary vasoconstriction seen in some disease states, then LTC4 and LTD4 may play equal roles, or one may predominate.In this study, we first wanted to determine whether L T C and LTD4 produce equal pulmonary and systemic circulatory effects. We therefore performed dose-response studies of L T C and LTD4 on spontaneously breathing newborn lambs.It is possible that the pulmonary and systemic vasoconstriction produced by LT are mediated through other substances. To investigate whether the hemodynamic effects of LT are mediated through LT receptor stimulation or a-adrenergic stimulation (25), we treated some lambs with FPL57231, a LT receptor antagonist, or phentolamine mesylate, an a-adrenergic antagonist, before injecting LT.Although previous studies had suggested that LT decrease cardiac output without affecting hear...

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

1987

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“…Diethylcarbamazine has previously been shown to reduce the antigen-induced release of SRS-A from guinea-pig chopped lung (Piper & Temple, 1981). Diethylcarbamazine, at concentrations similar to those used in the present study, has been reported to inhibit the release of leukotrienes rat perfused lungs induced by Paf, arachidonic acid or hypoxia (Voelkel et al, 1982;Morganroth et al, 1984). LTB4 release from Paf-challenged hearts was identified by co-elution ofir LTB4 with [3H]-LTB4 added to the cardiac effluents before purification and isolation on r.p.-h.p.l.c.…”

Section: Paf-induced Release Ofcyclo-oxygenase and Lipoxygenase Productsmentioning

confidence: 65%

Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet‐activating factor is mediated by leukotriene C₄

Piper

Stewart

1986

British J Pharmacology

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1 Platelet-activating factor (Paf, 0.04-4.50 nmol) dose-dependently induced coronary vasoconstriction and decreased cardiac contractility in rat, isolated perfused hearts and concomitantly released leukotriene-like bioactivity into the cardiac effluent.2 Platelet-activating factor (0.9 nmol) induced an increase in 6-keto-prostaglandin Fl (6-keto-PGFI.), PGF2., PGE2 and thromboxane B2 (TXB2) measured by radioimmunoassay (RIA) of cardiac effluents following partial purification using C18 Sep-Paks. 3 The leukotriene-like bioactivity released by Paf was identified as leukotriene C4 (LTC4) using a combination of isolation on reverse phase-h.p.l.c. (r.p.h.p.l.c.) and quantitation by RIA. In addition, LTB4 was also identified by r.p.h.p.l.c. and the levels, determined by RIA, were within the range having biological activity. 4 The release ofcyclo-oxygenase products by Pafwas prevented by indomethacin (2.8 pM), markedly attenuated by diethylcarbamazine (7.7mM) but unaffected by FPL 55712 (1.9 pM)-pretreatment. Furthermore, LTC4 (50 pmol) did not increase the release of the cyclo-oxygenase products measured. 5 The release of LTB4 and LTC4 appeared to be unaffected by indomethacin pretreatment whereas diethylcarbamazine-pretreatment markedly inhibited release. 6 The coronary vasoconstriction induced by Paf (0.9 nmol) was attenuated by pretreatment with indomethacin or diethylcarbamazine, whereas FPL 55712 caused a marked inhibition of the response. In contrast, the decrease in cardiac contractility was prevented by indomethacin or diethylcarbamazine and unaffected by FPL 55712 pretreatment. 7 It is concluded that LTC4 may be largely responsible for the coronary vasoconstriction induced by Paf with cyclo-oxygenase products having a possible modulatory role whereas the latter appear to be involved in the Paf-induced decrease in cardiac contractility.

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“…In fetal lambs, U60257 increases pulmonary blood flow similarly to FPL5723 1. U60257 blocks hypoxic pulmonary vasoconstriction and leukotriene C4 production in isolated perfused rat lungs without effect on antiotensin 11-induced pulmonary hypertension (4,30). In our study, U60257 had no effect on baseline vascular pressure or cardiac output.…”

Section: Discussionmentioning

confidence: 53%

“…Metabolites of arachidonic acid may mediate the pulmonary vasoconstriction seen in utero (1,2) and during alveolar hypoxia (3)(4)(5)(6). They may also be important mediators of the hemodynamic changes occumng in the adult respiratory distress syndrome (7), endotoxic shock (8)(9)(10)(11)(12)(13)(14), and the syndrome of persistent pulmonary hypertension of the newborn (15).…”

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Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

1989

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ABSTRACT. Leukotrienes C4 and Dd and thromboxane A2 are potent vasoconstrictors that may mediate pulmonary vasoconstriction in many clinical situations. There is a complex interaction among leukotrienes and thromboxane A2, because inhibition of thromboxane synthesis prevents some of the hemodynamic effects of exogenous leukotrienes. Similarly, if leukotrienes mediate thromboxane A*-induced pulmonary vasoconstriction, then leukotriene antagonists should attenuate the effects of a thromboxane A2-mimetic such as U46619. First, dose response curves for the hemodynamic effects of U46619 were performed on seven spontaneously breathing newborn lambs. Then a putative leukotriene receptor antagonist, FPL57231,l mg/ kg/min, or a putative leukotriene synthesis antagonist, U60257, 30 mg/kg, was given before infusing U46619 (1 pg/kg/min). U46619 caused significant dose-dependent increases in pulmonary and systemic arterial pressures (p < Metabolites of arachidonic acid may mediate the pulmonary vasoconstriction seen in utero (1,2) and during alveolar hypoxia (3-6). They may also be important mediators of the hemodynamic changes occumng in the adult respiratory distress syndrome (7), endotoxic shock (8-14), and the syndrome of persistent pulmonary hypertension of the newborn (15). The most potent pulmonary vasoconstricting metabolites of arachidonic acid are the peptidoleukotrienes (leukotrienes C4 and D4) (16-IS), formed via the lipooxygenase pathway, and thromboxane A2 (8, 10, 1 1, 13, 14), formed via the cyclooxygenase pathway. There is a complex interaction among these leukotrienes and thromboxane Az. TO date, the evidence suggests that leukotriene C4 and D4 stimulate the production of thromboxane A2 (16, 18-2 1). These studies would imply that thromboxane A2 is involved in leukotriene-induced pulmonary vasoconstriction. The pur- Supported by Grants HL 355 18 and HL 24056 from the National Heart, Lung and Blood Institute and by a Grant-in-Aid from the American Lung Association. 8pose of the present study was to investigate the other possibility: that thromboxane A2 stimulates the production or release of leukotrienes. Because of the instability of thromboxane A2 and the limited potency of its stable measurable metabolite, thromboxane Bz, we used the specific thromboxane Az-mimetic, U46619 (Upjohn Co., Kalamazoo, MI) (22-29). In newborn lambs, after characterizing the pulmonary and systemic hemodynamic effects of U466 19 by performing dose-response studies, we attempted to block or attenuate the hemodynamic response to U466 19 using FPL5723 1, a putative leukotriene receptor antagonist (Fisons plc, Loughborough, England) (2, 5, 16) and U60257, a putative leukotriene synthesis inhibitor (Upjohn) (1, 6, 30-34). MATERIALS AND METHODS Surgical Preparations.Under local anesthesia with 1 % lidocaine hydrochloride, seven newborn lambs at 1 to 3 d of age had polyvinyl catheters placed into a hind leg artery and vein and advanced to the descending aorta and inferior vena cava, respectively. General anesthesia was then induced by ha...

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Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs

Cited by 51 publications

References 12 publications

The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet‐activating factor is mediated by leukotriene C₄

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

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Leukotriene C4 production during hypoxic pulmonary vasoconstriction in isolated rat lungs

Cited by 51 publications

References 12 publications

The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet‐activating factor is mediated by leukotriene C4

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

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Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet‐activating factor is mediated by leukotriene C₄