Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinase in human and canine pulmonary vascular smooth muscles.
1. We examined the effects 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(2 alpha) were powerful spasmogens in human vasculature and in canine pulmonary vein. 8-iso PGE(1) and 8-iso PGF(2 beta) also exhibited moderate spasmogenic activity in canine pulmonary vein; 8-iso PGF(1 alpha), 8-iso PGF(1beta), and 8-iso PGF(3 alpha) were generally ineffective. 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 TP-receptor blocker ICI 192605 and by the EP-receptor blocker AH 6809 (-log K(B)=8.4 and 5.7, respectively). PGE(2) was a very weak agonist ( approximately 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 pulmonary artery, but not in the human pulmonary artery. The other isoprostanes 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 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 TP-receptors, tyrosine kinases and Rho kinases. 8-iso PGE(1) is also able to cause vasodilation.
Janssen
L J
LJ
Asthma Research Group, Father Sean O'Sullivan Research Centre, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. janssen1@fhs.csu.mcmaster.ca
Premji
M
M
Netherton
S
S
Coruzzi
J
J
Lu-Chao
H
H
Cox
P G
PG
D000818:Animals; D002118:Calcium / Q000502:physiology; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D011448:Prostaglandin Antagonists; D011459:Prostaglandins E, Synthetic; D011461:Prostaglandins F, Synthetic; D011465:Prostaglandins, Synthetic; D014662:Vasoconstrictor Agents; D010770:Phosphotransferases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium