Mediators of bradykinin-induced vasorelaxation in human coronary microarteries.
To investigate the mediators of bradykinin-induced vasorelaxation in human coronary microarteries (HCMAs), HCMAs (diameter approximately 300 microm) obtained from 42 heart valve donors (20 men and 22 women; age range, 3 to 65 years; mean age, 46 years) were mounted in Mulvany myographs. In the presence of the cyclooxygenase inhibitor indomethacin, bradykinin relaxed preconstricted HCMAs in a concentration-dependent manner. N(G)-nitro-L-arginine methyl ester and ODQ (inhibitors of nitric oxide [NO] synthase and guanylyl cyclase, respectively) and the NO scavenger hydroxocobalamin, either alone or in combination, shifted the bradykinin concentration-response curve to the right. Removal of H2O2 (with catalase), inhibition of cytochrome P450 epoxygenase (with sulfaphenazole or clotrimazole) or gap junctions (with 18alpha-glycyrrhetinic acid or carbenoxolone), and blockade of large- (BK(Ca)) and small- (SK(Ca)) conductance Ca2+-dependent K+ channels (with iberiotoxin and apamin), either alone or in addition to hydroxocobalamin, did not affect bradykinin. In contrast, complete blockade of bradykinin-induced relaxation was obtained when we combined the nonselective BK(Ca) and intermediate-conductance (IK(Ca)) Ca2+-dependent K+ channel blocker charybdotoxin and apamin with hydroxocobalamin. Charybdotoxin plus apamin alone were without effect. Inhibition of inwardly rectifying K+ channels (K(IR)) and Na+/K+-ATPase (with BaCl2 and ouabain, respectively) shifted the bradykinin concentration-response curve 10-fold to the right but did not exert an additional effect in the presence of hydroxocobalamin. In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, K(IR), and Na(+)/K(+)-ATPase by NO and (2) IK(Ca) and SK(Ca) channels. The latter are activated by a factor other than NO. This factor is not a cytochrome P450 epoxygenase product or H2O2, nor does it depend on gap junctions or BK(Ca) channels.
|Keywords||*Vasodilation, 8,11,14-Eicosatrienoic Acid/metabolism, Adolescent, Adult, Aged, Arterioles/drug effects/metabolism/physiology, Bradykinin/*pharmacology, Child, Child, Preschool, Coronary Vessels/anatomy & histology/metabolism/*physiology, Culture Techniques, Cyclic GMP/metabolism, Female, Gap Junctions/physiology, Humans, Hydrogen Peroxide/metabolism, In Vitro, Male, Middle Aged, Nitric Oxide/physiology, Potassium Channels/physiology|
|Persistent URL||dx.doi.org/10.1161/01.HYP.0000110904.95771.26, hdl.handle.net/1765/13283|
Batenburg, W.W., Garrelds, I.M., van Kats, J.P., Saxena, P.R., & Danser, A.H.J.. (2004). Mediators of bradykinin-induced vasorelaxation in human coronary microarteries.. Hypertension, 43(2 II), 488–492. doi:10.1161/01.HYP.0000110904.95771.26