Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle Academic Article uri icon

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abstract

  • We investigated the effects of five different isoprostanes (8-iso PGE1, 8-iso PGE2, 8-iso PGF1alpha, 8-iso PGF2alpha and 8-iso PGF2beta) on vasomotor tone in human and porcine bronchial arterial tissues. In the human bronchial arteries, 8-iso PGE2 and 8-iso PGF2alpha evoked powerful constrictions (magnitudes several fold greater than the responses to high millimolar KCl) with negative log concentration causing 50% excitation (EC50) values of 6.8 and 6.5, respectively; 8-iso PGE1 was less potent (EC50 not calculated, since a clear peak contraction was not obtained), while the other isoprostanes were largely ineffective. In the porcine arteries, on the other hand, all three F-ring isoprostanes as well as 8-iso PGE2 evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl-evoked response; 8-iso PGE2 and 8-iso PGF2alpha were the most potent, with negative log EC50 values of 6.5. We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8-iso PGE2, since this was the most potent of the isoprostanes we tested. These responses were largely reversed by the thromboxane A2-selective (TP) prostanoid receptor antagonist ICI 192605 (10-8 m; 4(Z)-6-[(2,4,5 cis)2-(2-chlorophenyl)-4-(2-hydroxy phenyl)1,3-dioxan-5-yl]hexenoic acid) as well as by the nonspecific tyrosine kinase inhibitor genistein (10-5 and 10-4 m), and were reversed approximately 50% by the Rho-kinase inhibitor Y27632 (10-5 m; (+)-(R)-trans-4-(1-aminoethyl)-N-(pyridyl) cyclohexanecarboxamide dihydrochloride). We conclude, therefore, that 8-iso PGE2 constricts bronchial vasculature through the activation of TP receptors, which in turn trigger tyrosine kinase and Rho-kinase activities, resulting in powerful vasoconstriction. These findings are highly relevant to lung transplantation and to exercise-induced asthma.

publication date

  • October 2003

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