Free radicals generated by xanthine/xanthine oxidase system augment nitric oxide synthase (NOS) and cyclooxygenase (COX)-independent component of bradykinin-induced vasodilatation in the isolated guinea pig heart.

Recently, we have reported that bradykinin (Bk)-induced vasodilation was selectively potentiated by a low concentration of reactive oxygen species (ROS) generated by xanthine/xanthine oxidase system (XOX) in the coronary circulation of the isolated guinea pig heart. In an attempt to identify a mechanism of Bk response that is amplified by XOX, we analyze here the involvement of B1/B2 receptors and the participation ofNOS/COX pathways in the Bk responses before and after intracoronary infusion of XOX in the isolated guinea pig heart. Bk (0.3-3 pmoles) and acetylcholine (Ach) (100-300 pmoles) induced a dose-dependent coronary vasodilation. In the presence of a non-selective nitric oxide synthase (NOS) inhibitor L-NAME (10 -4 M) and non-selective cyclooxygenase inhibitor indomethacin (5 × 10 -5 M), vasodilation induced by Bk or Ach was inhibited. XOX infusion into the coronary circulation augmented Bk-induced vasodilation by approximately 100-300%. This effect was sustained and was observed at least Ih after XOX infusion. In contrast to Bk response, vasodilation induced by Ach was not modified by XOX infusion. Surprisingly, in the presence ofL-NAME+indomethacin, Bk-induced response was still amplified by XOX. In relative terms, this effect was even more pronounced. Again, under these experimental conditions, the response to Ach remained largely unchanged. In the presence ofB2 receptor antagonist,icatibant(100 nM), Ach-induced vasodilation was unaffected, while Bk-induced vasodilaton was abolished before and after XOX. In conclusion, in the isolated guinea pig heart low concentration of exogenous ROS generated by XOX system resulted in a sustained augmentation of Bk-induced coronary vasodilatation that cannot be explained by the up-regulation of Bl receptors, or the amplification of activity ofNOS-cGMP or COX pathways. The chemical identity of NOS/COX-independent component of Bk response that is up-regulated by XOX remains to be determined. EDHF is the most likely candidate.