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(Hypertension. 2004;43:488.)
© 2004 American Heart Association, Inc.

Scientific Contribution

Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries

Wendy W. Batenburg; Ingrid M. Garrelds; Jorge P. van Kats; Pramod R. Saxena; A. H. Jan Danser

From the Departments of Pharmacology (W.W.B., I.M.G., P.R.S., A.H.J.D.) and Thoracic Surgery and Heart Valve Bank (J.P.v.K.), Erasmus Medical Center, Rotterdam, The Netherlands.

Correspondence to Prof Dr A.H.J. Danser, Department of Pharmacology, Room EE1418b, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail a.danser{at}erasmusmc.nl

To investigate the mediators of bradykinin-induced vasorelaxation in human coronary microarteries (HCMAs), HCMAs (diameter 300 µm) 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 18-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.

Key Words: bradykinin • arteries • endothelium-derived factors • nitric oxide

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