1 We examined the e ects of several E-ring and F-ring isoprostanes on mechanical activity in pulmonary artery and vein. 2 8-iso PGE 2 and 8-iso PGF 2a were powerful spasmogens in human vasculature and in canine pulmonary vein. 8-iso PGE 1 and 8-iso PGF 2b also exhibited moderate spasmogenic activity in canine pulmonary vein; 8-iso PGF 1a , 8-iso PGF 1b , and 8-iso PGF 3a were generally ine ective. Canine pulmonary arteries did not exhibit excitatory responses to any of the isoprostanes. 3 The spasmogenic e ects of 8-iso PGE 2 were markedly attenuated by the TP-receptor blocker ICI 192605 and by the EP-receptor blocker AH 6809 (7log K B =8.4 and 5.7, respectively). PGE 2 was a very weak agonist (&100 fold less so than 8-iso PGE 2 ). 4 In the presence of ICI 192605 (10 76 M), 8-iso PGE 1 evoked modest dose-dependent relaxations in human and canine pulmonary vein, and in canine pulmonary artery, but not in the human pulmonary artery. The other isoprostanes were generally ine ective as vasodilators in the pulmonary vasculature of both species. 5 The spasmogenic e ects of 8-iso PGE 2 and 8-iso PGF 2a did not involve elevation of [Ca 2+ ] i . 6 8-iso PGE 2 -evoked contractions were blocked by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and HA 1077), but not by inhibitors of protein kinase C (calphostin C or chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). 7 The actions of 8-isoprostanes in the lungs are compound-, species-and tissue-dependent. Several isoprostanes evoke vasoconstriction: in the case of 8-iso PGE 2 , this involves activation of TPreceptors, tyrosine kinases and Rho kinases. 8-iso PGE 1 is also able to cause vasodilation. British Journal of Pharmacology (2001)

We compared the effects of two redox forms of nitric oxide, NO(+) [liberated by S-nitroso-N-acetyl-penicillamine (SNAP)] and NO. [liberated by 3-morpholinosydnonimine (SIN-1) in the presence of superoxide dismutase], on cytosolic concentration of Ca(2+) ([Ca(2+)](i); single cells) and tone (intact strips) obtained from human main stem bronchi and canine trachealis. SNAP evoked a rise in [Ca(2+)](i) that was unaffected by removing external Ca(2+) but was markedly reduced by depleting the internal Ca(2+) pool using cyclopiazonic acid (10(-5) M). Dithiothreitol (1 mM) also antagonized the Ca(2+) transient as well as the accompanying relaxation. SNAP attenuated responses to 15 and 30 mM KCl but not those to 60 mM KCl, suggesting the involvement of an electromechanical coupling mechanism rather than a direct effect on the contractile apparatus or on Ca(2+) channels. SNAP relaxations were sensitive to charybdotoxin (10(-7) M) or tetraethylammonium (30 mM) but not to 4-aminopyridine (1 mM). Neither SIN-1 nor 8-bromoguanosine 3',5'-cyclic monophosphate had any significant effect on resting [Ca(2+)](i), although both of these agents were able to completely reverse tone evoked by carbachol (10(-7) M). We conclude that NO(+) causes release of internal Ca(2+) in a cGMP-independent fashion, leading to activation of Ca(2+)-dependent K(+) channels and relaxation, whereas NO. relaxes the airways through a cGMP-dependent, Ca(2+)-independent pathway.