Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinasein human and canine pulmonary vascular smooth muscles

1 We examined the effects of several E-ring and F-ring isoprostanes on mech anical activity in pulmonary artery and vein. 2 8-iso PGE(2) and 8-iso PGF(2 alpha) were powerful spasmogens in human vas culature and in canine pulmonary vein. 8-iso PGE(1) and 8-iso PGF(2 beta) a lso exhibited moderate spasmogenic activity in canine pulmonary vein; 8-iso PGF(1 alpha), 8-iso PGF(1 beta), and 8-iso PGF(3 alpha) were generally ine ffective. Canine pulmonary arteries did not exhibit excitatory responses to any of the isoprostanes. 3 The spasmogenic effects of 8-iso PGE(2) were markedly attenuated by the T P-receptor blocker ICI 192605 and by the EP-receptor blocker AH 6509 (-log K-B=8.4 and 5.7, respectively). PGE(2) was a very weak agonist (approximate to 100 fold less so than 8-iso PGE(2)). 4 In the presence of ICI 192605 (10(-6) M), 8-iso PGE(1) evoked modest dose -dependent relaxations in human and canine pulmonary vein, and in canine pu lmonary artery, but not in the human pulmonary artery. The other isoprostan es were generally ineffective as vasodilators in the pulmonary vasculature of both species. 5 The spasmogenic effects of 8-iso PGE(2) and 8-iso PGF(2 alpha) did not in volve elevation of [Ca2+](1). 6 8-iso PGE(2)-evoked contractions were blocked by inhibitors of tyrosine k inase (genistein) and Rho kinase (Y 27632 and HA 1077), but not by inhibito rs of protein kinase C (calphostin C or chelerythrine), mitogen-activated p rotein kinase kinase CPD 98059) or p38-kinase (SB 203580). 7 The actions of 8-isoprostanes in the lungs are compound-, species- and ti ssue-dependent. Several isoprostanes evoke vasoconstriction: in the case of 8-iso PGE(2), this involves activation of TP-receptors, tyrosine kinases a nd Rho kinases. 8-iso PGE(1) is also able to cause vasodilation.