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.
Batenburg
Wendy W
WW
Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
Garrelds
Ingrid M
IM
van Kats
Jorge P
JP
Saxena
Pramod R
PR
Danser
A H Jan
AH
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D003331:Coronary Vessels / Q000033:anatomy & histology / Q000378:metabolism / Q000502:physiology*; D046508:Culture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D017629:Gap Junctions / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D014664:Vasodilation
D015221:Potassium Channels; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D015126:8,11,14-Eicosatrienoic Acid; D006152:Cyclic GMP; D001920:Bradykinin