Inhibition of inducible nitric oxide synthase attenuates platelet adhesion in subpleural arterioles caused by lung ischemia-reperfusion in rabbits.
Oxidative stress, induced by lung ischemia-reperfusion, leads to platelet and leukocyte activation and may contribute to decreased alveolar perfusion by platelet adhesion to the arteriolar wall. We investigated the hypothesis that ischemia-reperfusion injury increases inducible nitric oxide synthase (iNOS) activity and subsequent generation of reactive nitrogen species with P-selectin-dependent platelet-endothelial interactions and vasoconstriction during lung reperfusion. Subpleural arterioles, labeled platelets, and leukocytes were examined in anesthetized, open-chest rabbits by intravital fluorescence microscopy. Ischemia was caused by reversible occlusion of the right pulmonary artery for 1 or 2 h (1IR and 2IR groups). During 2 h of reperfusion, postischemic platelet rolling and adhesion were independent from leukocyte-arteriolar wall interactions and correlated with pulmonary arteriolar constriction in proportion to the length of ischemia. In rabbits treated with an iNOS inhibitor (1400W) before occlusion (2IR + 1400W group), platelet-arteriolar wall interactions and vasoconstriction were prevented. iNOS expression and activity in ischemic lung tissue were markedly greater than control and also were proportional to ischemia duration. NOS activity, immunochemically detected P-selectin, and nitrotyrosine expression in ischemic lung tissue from animals subjected to ischemia-reperfusion, as well as the plasma level of soluble P-selectin, were significantly higher than in nonischemic lungs and were inhibited by pretreatment with 1400W. These results show that platelet adhesion and arteriolar constriction during early reperfusion in the ventilated lung can result from increased iNOS activity and is highly correlated with reactive nitrogen species and P-selectin expression.
Ovechkin
Alexander V
AV
Dept. of Physiology, University of Louisville, Louisville, KY 40202, USA.
Lominadze
David
D
Sedoris
Kara C
KC
Gozal
Evelyne
E
Robinson
Tonya W
TW
Roberts
Andrew M
AM
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007097:Imines / Q000008:administration & dosage; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010973:Platelet Adhesiveness; D011652:Pulmonary Circulation; D011817:Rabbits; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
D007097:Imines; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D052247:Nitric Oxide Synthase Type II