Postischemic anti-inflammatory effects of bradykinin preconditioning

Postischemic anti-inflammatory effects of bradykinin preconditioning. Am J Physiol Heart Circ Physiol 280: H441-H454, 2001.--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.sub.2]-receptor antagonist but not by coincident [B.sub.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.sub.2] receptor-dependent activation of nonconventional PKC isotypes and subsequent formation of NO. ischemic preconditioning; leukocyte adhesion; leukocyte emigration; venular albumin leakage; protein kinase C; bradykinin [B.sub.2] receptors