Postischemic anti-inflammatory effects of bradykinin preconditioning.
We sought to determine the mechanisms whereby brief administration of bradykinin (bradykinin preconditioning, BK-PC) before prolonged ischemia followed by reperfusion (I/R) prevents postischemic microvascular dysfunction. Intravital videomicroscopic approaches were used to quantify I/R-induced leukocyte/endothelial cell adhesive interactions and microvascular barrier disruption in single postcapillary venules of the rat mesentery. I/R increased the number of rolling, adherent, and emigrated leukocytes and enhanced venular albumin leakage, effects that were prevented by BK-PC. The anti-inflammatory effects of BK-PC were largely prevented by concomitant administration of a B(2)-receptor antagonist but not by coincident B(1) receptor blockade, nitric oxide (NO) synthase inhibition, or cyclooxygenase blockade. However, NO synthase blockade during reperfusion after prolonged ischemia was effective in attenuating the anti-inflammatory effects of BK-PC. Pan protein kinase C (PKC) inhibition antagonized the beneficial effects of BK-PC but only when administered during prolonged ischemia. In contrast, specific inhibition of the conventional PKC isotypes failed to alter the effectiveness of BK-PC. These results indicate that bradykinin can be used to pharmacologically precondition single mesenteric postcapillary venules to resist I/R-induced leukocyte recruitment and microvascular barrier dysfunction by a mechanism that involves B(2) receptor-dependent activation of nonconventional PKC isotypes and subsequent formation of NO.
Shigematsu
S
S
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, School of Medicine in Shreveport, Shreveport, Louisiana 71130, USA.
Ishida
S
S
Gute
D C
DC
Korthuis
R J
RJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000502:physiology; D065168:Bradykinin Receptor Antagonists; D002196:Capillaries; D002448:Cell Adhesion; D002634:Chemotaxis, Leukocyte; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019194:Ischemic Preconditioning; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008643:Mesentery / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D019323:omega-N-Methylarginine; C065679:icatibant; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D011493:Protein Kinase C; D001920:Bradykinin