1. 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. 2. Porcine coronary arteries (PCAs) were mounted in organ baths, preconstricted, and exposed to BK or the ACE-resistant BK analogue Hyp(3)-Tyr(Me)(8)-BK (HT-BK) with or without the NOS inhibitor L-NAME (100 microM), the NO scavenger hydroxocobalamin (200 microM), the Ca(2+)-dependent K(+)-channel blockers charybdotoxin+apamin (both 100 nM), or the ACE inhibitor quinaprilat (10 microM). 3. BK and HT-BK dose-dependently relaxed preconstricted vessels (pEC(50) 8.0+/-0.1 and 8.5+/-0.2, respectively). pEC(50)'s were approximately 10 fold higher with quinaprilat, and approximately 10 fold lower with L-NAME or charybdotoxin+apamin. Complete blockade was obtained with hydroxocobalamin or L-NAME+ charybdotoxin+apamin. 4. 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. 5. 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. 6. 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 Ca(2+)-dependent K(+)-channels. ACE inhibitors potentiate BK independent of their effect on BK metabolism.

Angiotensin-Converting Enzyme Inhibitors/*pharmacology, Animals, Bradykinin/metabolism/*pharmacology, Coronary Vessels/*drug effects/physiology, Drug Interactions, Drug Resistance, Enzyme Inhibitors/pharmacology, In Vitro, NG-Nitroarginine Methyl Ester/*pharmacology, Nitric Oxide/*physiology, Swine, Vasodilation/*drug effects
dx.doi.org/10.1038/sj.bjp.0703555, hdl.handle.net/1765/12885
British Journal of Pharmacology
Erasmus MC: University Medical Center Rotterdam

Danser, A.H.J, Tom, B, de Vries, R.R.P, & Saxena, P.R. (2000). L-NAME-resistant bradykinin-induced relaxation in porcine coronary arteries is NO-dependent: effect of ACE inhibition. British Journal of Pharmacology, 195–202. doi:10.1038/sj.bjp.0703555