Oxidant- and lipid-induced pulmonary vasoconstriction mediated by arachidonic acid metabolites

Abstract

In experiments using isolated rabbit lungs perfused with Krebs-Henseleit buffer in a nonrecirculating manner, we found that administration of an organic peroxide, tert-butyl hydroperoxide (t-bu-OOH), or Intralipid, an esterified mixture of unsaturated fatty acids, caused a marked vasopressor response which was associated with increased levels of thromboxane in the effluent perfusate. The vasopressor response to t-bu-OOH was greater in the lungs of vitamin E-deficient animals, and this could be correlated with an attenuated ability to increase prostacyclin production in these lungs. Conversely, administration of Intralipid to normal lungs caused marked increases in prostacyclin and a smaller pressor response. The magnitude of the pressor response was strongly correlated with the ratio of thromboxane B2 to the prostacyclin metabolite. No release of these mediators was associated with pulmonary vasoconstriction caused by administration of angiotensin II. The pressor response could be completely blocked by administration of indomethacin. We propose that this activation of the cyclooxygenase pathway of arachidonic acid metabolism may be important in the pathophysiology of oxidant lung damage.

Evidence that in vivo constriction of cerebral arterioles by local application of tert-butyl hydroperoxide is mediated by release of endogenous thromboxane.

“…6 In the lung, thromboxane was thought to mediate the constriction that accompanied perfusion by TBHP. Other hydroperoxy compounds are reported to constrict a variety of vessels, including brain vessels, but no consideration has been given by others to a possible role of thromboxane in mediating these effects.…”

“…This data favored the hypothesis that, at least in the lung, the constrictor effect of TBHP was thromboxane-mediated. 6 We have carried the pharmacologic analysis much further. Our data show not only that a cyclooxygenase inhibitor, ASA, diminishes the effect of TBHP but also that constriction was diminished by OKY-046, a specific inhibitor of thromboxane synthetase, 4 and by SQ-29548, a selective antagonist of the thromboxane receptor.…”

“…However, Gurtner et al 6 found that tert-bnty\ hydroperoxide (TBHP) caused marked constriction of the perfused pulmonary vasculature, which was associated with the appearance of increased levels of thromboxane in the effluent. The elevated thromboxane level and the associated vasoconstriction were prevented by blocking cyclooxygenase, which was interpreted as indicating that TBHP stimulates cyclooxygenase-dependent arachidonate metabolism with a resultant increase in the production of eicosanoids like thromboxane.…”

“…The source of the thromboxane was thought to be lung "parenchyma" 6 ; however, the possibility of thromboxane released from vessel walls cannot be ruled out. Thromboxane can be made by blood vessel walls, 7 " 12 but this fact has not been emphasized in the literature because, under the published conditions of measurement, relatively little thromboxane is made compared with other eicosanoids, particularly the potent dilator prostacyclin.…”

Role of membrane associated serine esterase in the activation of phospholipase A2 by calcium ionophore (A23187) in pulmonary arterial smooth muscle cells

“…Production of AA is a crucial step in the generation of vasoactive mediators such as prostacyclin, prostaglandins, thromboxane and leukotrienes. The contribution of these AA metabolites in various patho-physiological conditions in the lung has been previously demonstrated [2][3][4]. Given the potency of these AA metabolites the rate limiting step for their production, i.e., the activity of PLA 2 must be tightly regulated.…”