Signal transduction pathways involved in kinin B2 receptor-mediated vasodilation in the rat isolated perfused kidney

1 The signal transduction pathways involved in kinin B-2 receptor-related vasodilation were investigated in rat isolated perfused kidneys. During prostaglandin F-2 alpha or KCl-induced constriction, the vasodilator response to a selective B2 receptor agonist, Tyr(Me)(8)bradykinin (Tyr(Me)(BK)-B-8), was assessed. 2 Tyr(Me)(BK)-B-8 produced a concentration- and endothelium-dependent relaxation that was decreased by about 30-40% after inhibition of nitric oxide (NO) synthase by N-G-nitro-L-arginine (L-NOARG) or of cyclo-oxygenase by indomethacin; a greater decrease (about 40-50%) was observed after concomitant inhibition of the two pathways. 3 High extracellular K+ diminished Tyr(Me)(BK)-B-8-induced relaxation by about 75% suggesting a major contribution of endothelium-derived hyperpolarization. The residual response was almost completely suppressed by NO synthase and cyclo-oxygenase inhibition. The K+ channel inhibitors, tetrabutylammonium (non-specific) and charybdotoxin (specific for Ca2+-activated K+ channel), suppressed Tyr(Me)8BK-induced relaxation resistant to L-NOARG and indomethacin. 4 Inhibition of cytochrome P450 (clotrimazole or 7-ethoxyressoruim) decreased the NO/prostanoids-independent relaxation to Tyr(Me)(BK)-B-8 by more than 60%, while inhibition of the cannabinoid CB1 receptor (SR 141716A) had only a moderate effect. 5 Acetylcholine induced a concentration-dependent relaxation with characteristics nearly similar to the response to Tyr(Me)(BK)-B-8. In contrast, the relaxation elicited by sodium nitroprusside was potentiated in the absence of NO (L-NOARG or removal of endothelium) but remained unchanged otherwise. 6 These results indicate that the activation of kinin B-2 receptors in the rat isolated kidney elicits an endothelium-dependent vasorelaxation, mainly dependent on the activation of charybdotoxin-sensitive Ca2+-activated K+ channels. In addition, cytochrome P450 derivatives appear to be involved.