title: Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle.
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.
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001981:Bronchial Arteries / Q000187:drug effects* / Q000502:physiology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D028421:Isoprostanes / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011458:Prostaglandins E / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: C492917:8-isoprostaglandin F1alpha; C492918:8-isoprostaglandin PGF2beta; D000577:Amides; D004146:Dioxanes; D028441:F2-Isoprostanes; D028421:Isoprostanes; D011458:Prostaglandins E; D011461:Prostaglandins F, Synthetic; D011725:Pyridines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; C057498:ICI 192605; C108830:Y 27632; C019443:isoprostaglandin E1; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D019833:Genistein; D000527:Alprostadil; D015232:Dinoprostone; C011987:8-isoprostaglandin E2