Role of Thromboxane and Prostacyclin in Pulmonary Vasomotor Changes after Endotoxin in Dogs

Hales, Charles A.; Sonne, Luciana; Peterson, Myron B.; Kong, Derek Kai; Miller, Matthew A.; Watkins, W. D.

doi:10.1172/jci110281

Cited by 139 publications

(31 citation statements)

References 31 publications

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“…Infusion of endotoxin into dogs or sheep raises pulmonary vascular resistances (30)(31)(32)(33)(34). This effect apparently involves arachidonate products since the resulting pulmonary vasoconstriction can be blocked by cyclooxygenase inhibitors (35).…”

Section: Resultsmentioning

confidence: 99%

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Tate¹,

Morris²,

Schroeder³

et al. 1984

J. Clin. Invest.

207

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Abstract. Generation of reactive oxygen metabolites, thromboxane increases, and vasoconstriction have been implicated in the pathogenesis of acute edematous lung injury, such as that seen in patients with the Adult Respiratory Distress Syndrome (ARDS), but their interactions are unknown. We hypothesized that reactive 02 products would stimulate arachidonic acid metabolism in lungs and that vasoactive products of arachidonate, such as the potent vasoconstrictor thromboxane A2, might then mediate 02-metabolite-induced pulmonary vasoconstriction. We found that 02 metabolites generated by injection of purine plus xanthine oxidase caused increases in mean pulmonary artery perfusion pressures (27±4 mmHg) in isolated perfused lungs. In addition, purine plus xanthine oxidase also caused 30-fold increases in perfusate levels ofthromboxane B2 (the stable metabolite ofthromboxane A2) compared with only twofold increases in 6-keto-PGFia (the stable metabolite of prostacyclin). Moreover, prior addition of catalase inhibited both vasoconstriction and the thromboxane B2 production seen in isolated lungs following injection of purine plus xanthine oxidase. Similarly, pretreatment with cyclooxygenase inhibitors, either aspirin or indomethacin, also completely blocked thromboxane generation and markedly attenuated pressor responses usually seen after purine plus xanthine oxidase (increase in mean pulmonary artery perfusion pressures, 4.4±1.5 mmHg). Furthermore, imDr. Tate is a recipient of a Clinician-Scientist Award from the American Heart Association. Address correspondence and reprint requests to Dr.Tate, Pulmonary Division, Department of Medicine, Box 4000, Denver General Hospital, Denver, CO 80204.Received for publication 6 July 1983 and in revised form 26 April 1984. idazole, a thromboxane synthetase inhibitor, also decreased 02-metabolite-induced thromboxane generation and vasoconstriction. These results suggested that thromboxane generation might participate in 02-metaboliteinduced vasoconstriction. However, since a significant correlation between thromboxane levels and the degree ofvasoconstriction could not be demonstrated, and since addition of superoxide dismutase reduced thromboxane generation but did not affect the intensity of vasoconstriction, it is possible that thromboxane is not the only vasoactive mediator in this model. We conclude that exposing lungs to 02 metabolites results in thromboxane generation and that thromboxane is a major mediator of oxidant-induced vasoconstriction.

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Section: Resultsmentioning

confidence: 99%

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Tate¹,

Morris²,

Schroeder³

et al. 1984

J. Clin. Invest.

207

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“…Nevertheless, our data in awake rats with the two structurally independent PAF receptor antagonists suggest that PAF may act in the pulmonary circulation by blunting the hypoxic pressor reactivity in endotoxin-treated rats. Previous experiments demonstrated that inhibition of cyclooxygenase preserved hypoxic vasoconstriction in anesthetized dogs (49,50) but not in unanesthetized sheep (51), suggesting that vasodilator prostaglandins can not fully explain the endotoxin-induced alteration in pulmonary vasoreactivity. Although our observations do not resolve the discrepancy between the earlier dog and the more recent sheep studies, one might speculate that PAF could act in part via stimulation of vasodilator prostaglandin production (13), which might be species-specific (52).…”

Section: Discussionmentioning

confidence: 99%

Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

Chang¹,

Feddersen²,

Henson³

et al. 1987

J. Clin. Invest.

343

119

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Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3±1.3 to 13.7±2.0 ng/ml (P < 0.01) and lung PAF from 32.3±4.9 to 312.3±19.6 ng (P < 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia.

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“…2021 Cross reactivities and sensitivity limits of these antibodies and reagent sources have been described. 20 …”

Section: Radloimmunoassay Techniquesmentioning

confidence: 99%

Inhibition of thromboxane A2 production does not improve post-ischemic brain hypoperfusion in the dog.

Prough

Kong²,

Watkins³

et al. 1986

Stroke

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SUMMARY In a canine model of global brain ischemia, six dogs received a selective thromboxane A 2 synthetase inhibitor, UK 38,485 (dazmagrel) before the ischemic event; six received a saline placebo. Cerebral blood flow (CBF), systolic and diastolic arterial pressure, cardiac output, pH, PaCO 2 , PaO 2 , and arterial and jugular-vein thromboxane B 2 (a stable metabolite of thromboxane Aj) and 6-keto PGF ln (a stable metabolite of prostacyclin) were measured at baseline, after release of aortic and venae caval occlusion and at intervals up to 120 min thereafter. Treated animals showed nearly complete post-ischemic inhibition of thromboxane B 2 production; control animals showed increases in jugular venous thromboxane B 2 . Arterial and jugular venous levels of 6-keto PGF, a were significantly higher in treated animals at most post-ischemic intervals. CBF in both groups was similar to baseline values at tune 0, then declined similarly in both groups by 30 min to ^35% of baseline values where it remained thereafter. There were no significant differences in other variables at any interval. We conclude that inhibition of thromboxane A 2 production does not alter post-ischemic brain hypoperfusion.

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Role of Thromboxane and Prostacyclin in Pulmonary Vasomotor Changes after Endotoxin in Dogs

Cited by 139 publications

References 31 publications

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs.

Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

Inhibition of thromboxane A2 production does not improve post-ischemic brain hypoperfusion in the dog.

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