L-NAME-resistant bradykinin-induced relaxation in porcine coronary arteries is NO-dependent: effect of ACE inhibition.
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.
Danser
A H
AH
Department of Pharmacology, Erasmus University Rotterdam, Rotterdam, The Netherlands. danser@farma.fgg.eur.nl
Tom
B
B
de Vries
R
R
Saxena
P R
PR
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester