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Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle
Author(s) -
Tazzeo Tracy,
Miller John,
Janssen Luke J
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705482
Subject(s) - isoprostanes , prostanoid , chemistry , thromboxane a2 , prostaglandin , endocrinology , rho associated protein kinase , medicine , vasoconstriction , contraction (grammar) , antagonist , thromboxane , receptor , signal transduction , arachidonic acid , biochemistry , enzyme , platelet
We investigated the effects of five different isoprostanes (8‐ iso PGE 1 , 8‐ iso PGE 2 , 8‐ iso PGF 1 α , 8‐ iso PGF 2 α and 8‐ iso PGF 2 β ) on vasomotor tone in human and porcine bronchial arterial tissues. In the human bronchial arteries, 8‐ iso PGE 2 and 8‐ iso PGF 2 α evoked powerful constrictions (magnitudes several fold greater than the responses to high millimolar KCl) with negative log concentration causing 50% excitation (EC 50 ) values of 6.8 and 6.5, respectively; 8‐ iso PGE 1 was less potent (EC 50 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 PGE 2 evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl‐evoked response; 8‐ iso PGE 2 and 8‐ iso PGF 2 α were the most potent, with negative log EC 50 values of 6.5. We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8‐ iso PGE 2 , since this was the most potent of the isoprostanes we tested. These responses were largely reversed by the thromboxane A 2 ‐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 PGE 2 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