Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle
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We investigated the effects of five different isoprostanes (8‐isoPGE1, 8‐isoPGE2, 8‐isoPGF1α, 8‐isoPGF2αand 8‐isoPGF2β) on vasomotor tone in human and porcine bronchial arterial tissues.In the human bronchial arteries, 8‐isoPGE2and 8‐isoPGF2αevoked 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‐isoPGE1was less potent (EC50not 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‐isoPGE2evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl‐evoked response; 8‐isoPGE2and 8‐isoPGF2αwere the most potent, with negative log EC50values of 6.5.We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8‐isoPGE2, 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 (10−8M; 4(Z)‐6‐[(2,4,5cis)2‐(2‐chlorophenyl)‐4‐(2‐hydroxy phenyl)1,3‐dioxan‐5‐yl]hexenoic acid) as well as by the nonspecific tyrosine kinase inhibitor genistein (10−5and 10−4M), and were reversed approximately 50% by the Rho‐kinase inhibitor Y27632 (10−5M; (+)‐(R)‐trans‐4‐(1‐aminoethyl)‐N‐(pyridyl) cyclohexanecarboxamide dihydrochloride).We conclude, therefore, that 8‐isoPGE2constricts 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
