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L ‐NAME‐resistant bradykinin‐induced relaxation in porcine coronary arteries is NO‐dependent: effect of ACE inhibition
Author(s) -
Danser A H Jan,
Tom Beril,
De Vries René,
Saxena Pramod R
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703555
Subject(s) - apamin , charybdotoxin , hydroxocobalamin , bradykinin , chemistry , bk channel , pharmacology , vasodilation , medicine , endocrinology , nitric oxide , biochemistry , receptor , calcium , membrane potential , organic chemistry , cyanocobalamin , vitamin b12
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 Hyp 3 ‐Tyr(Me) 8 ‐BK (HT‐BK) with or without the NOS inhibitor L ‐NAME (100 μ M ), the NO scavenger hydroxocobalamin (200 μ M ), the Ca 2+ ‐dependent K + ‐channel blockers charybdotoxin+apamin (both 100 n M ), or the ACE inhibitor quinaprilat (10 μ M ). 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 &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 n M 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 m M ) 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 Ca 2+ ‐dependent K + ‐channels. ACE inhibitors potentiate BK independent of their effect on BK metabolism.British Journal of Pharmacology (2000) 131 , 195–202; doi: 10.1038/sj.bjp.0703555