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

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abstract

  • We investigated the effects of five different isoprostanes (8‐iso PGE1, 8‐iso PGE2, 8‐iso PGF1α, 8‐iso PGF2α and 8‐iso PGF2β) on vasomotor tone in human and porcine bronchial arterial tissues. In the human bronchial arteries, 8‐iso PGE2 and 8‐iso PGF2α 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 PGF2α 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. British Journal of Pharmacology (2003) 140, 759–763. doi:10.1038/sj.bjp.0705482

publication date

  • October 2003

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