Bradykinin prevents postischemic leukocyte adhesion and emigration and attenuates microvascular barrier disruption.
Although a number of recent reports indicate that bradykinin attenuates ischemia- reperfusion (I/R)-induced tissue injury, the mechanisms underlying its protective actions are not fully understood. However, because bradykinin induces endothelial nitric oxide (NO) production and NO donors have been shown to attenuate postischemic leukocyte adhesion, endothelial barrier disruption, and tissue injury, we hypothesized that bradykinin may act to reduce I/R-induced tissue injury by preventing leukocyte recruitment and preserving microvascular barrier function. To address this postulate, we used intravital videomicroscopic approaches to quantify leukocyte-endothelial cell interactions and microvascular barrier function in single postcapillary venules in the rat mesentery. Reperfusion after 20 min of ischemia significantly decreased wall shear rate and leukocyte rolling velocity, increased the number of rolling, adherent, and emigrated leukocytes, and disrupted the microvascular barrier as evidenced by enhanced venular albumin leakage. Superfusion of the mesentery with bradykinin (10 nM) during I/R significantly reduced these deleterious effects of I/R. Although these inhibitory effects of bradykinin were not affected by cyclooxygenase blockade with indomethacin (10 microM), coadministration with NO synthase (N(omega)-nitro-L-arginine methyl ester, 10 microM) or bradykinin B(2)-receptor (HOE-140, 1 microM) antagonists abolished the protective actions of bradykinin. Plasma NO concentration was measured in the mesenteric vein and was significantly decreased after I/R, an effect that was prevented by bradykinin treatment. These results indicate that bradykinin attenuates I/R-induced leukocyte recruitment and microvascular dysfunction by a mechanism that involves bradykinin B(2)-receptor-dependent NO production.
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, School of Medicine in Shreveport, Shreveport, Louisiana 71130, USA.
S
S
Shigematsu
S
S
Ishida
D C
DC
Gute
R J
RJ
Korthuis
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood*; D014699:Venules / Q000187:drug effects / Q000502:physiology
D065168:Bradykinin Receptor Antagonists; C065679:icatibant; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester