L‐NAME‐resistant bradykinin‐induced relaxation in porcine coronary arteries is NO‐dependent: effect of ACE inhibition

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Abstract
NO synthase (NOS) inhibitors partially block bradykinin (BK)-mediated vasorelaxation. Here we investigated whether this is due to incomplete NOS inhibition and/or NO release from storage sites. We also studied the mechanism behind ACE inhibitor-mediated BK potentiation. Porcine coronary arteries (PCAs) were mounted in organ baths, preconstricted, and exposed to BK or the ACE-resistant BK analogue Hyp3-Tyr(Me)8-BK (HT-BK) with or without the NOS inhibitor L-NAME (100 μM), the NO scavenger hydroxocobalamin (200 μM), the Ca2+-dependent K+-channel blockers charybdotoxin+apamin (both 100 nM), or the ACE inhibitor quinaprilat (10 μM). BK and HT-BK dose-dependently relaxed preconstricted vessels (pEC50 8.0±0.1 and 8.5±0.2, respectively). pEC50's were &10 fold higher with quinaprilat, and &10 fold lower with L-NAME or charybdotoxin+apamin. Complete blockade was obtained with hydroxocobalamin or L-NAME+ charybdotoxin+apamin. Repeated exposure to 100 nM BK or HT-BK, to deplete NO storage sites, produced progressively smaller vasorelaxant responses. With L-NAME, the decrease in response occurred much more rapidly. L-Arginine (10 mM) reversed the effect of L-NAME. Adding quinaprilat to the bath following repeated exposure (with or without L-NAME), at the time BK and HT-BK no longer induced relaxation, fully restored vasorelaxation, while quinaprilat alone had no effect. Quinaprilat also relaxed vessels that, due to pretreatment with hydroxocobalamin or L-NAME+charybdotoxin+apamin, previously had not responded to BK. In conclusion, L-NAME-resistant BK-induced relaxation in PCAs depends on NO from storage sites, and is mediated via stimulation of guanylyl cyclase and/or Ca2+-dependent K+-channels. ACE inhibitors potentiate BK independent of their effect on BK metabolism.