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Apamin‐sensitive, non‐nitric oxide (NO) endothelium‐dependent relaxations to bradykinin in the bovine isolated coronary artery: no role for cytochrome P 450 and K +
Author(s) -
Drummond Grant R,
Selemidis Stavros,
Cocks Thomas M
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.0703107
Subject(s) - apamin , bradykinin , chemistry , ouabain , nitric oxide , endothelium derived hyperpolarizing factor , endocrinology , medicine , potassium channel , charybdotoxin , biochemistry , sodium , receptor , organic chemistry
Since cytochrome P 450 ‐derived metabolites of arachidonic acid and K + have been implicated in endothelium‐derived hyperpolarizing factor (EDHF)‐dependent responses, the aim of this study was to determine whether such factors contribute to non‐nitric oxide (NO), endothelium‐dependent relaxation to bradykinin (BK) in bovine isolated coronary artery. In rings of artery contracted with U46619 and treated with indomethacin (3 μ M ) and N G ‐nitro‐ L ‐arginine ( L ‐NOARG; 100 μ M ), relaxation to BK (0.01 n M ‐0.3 μ M ) was blocked by ∼60% after inhibition of K + channels with either high extracellular K + (high [K + ] o ; 15–67 m M ) or apamin (0.3 μ M ). Ouabain (1 μ M ), an inhibitor of Na + /K + ‐ATPase, decreased the sensitivity to BK without affecting the maximum response. In L ‐NOARG‐treated rings, ouabain had no further effect on the relaxation to BK. An inhibitor of inward‐rectifying K + channels, Ba 2+ (30 μ M ), had no effect on relaxations to BK in the absence or presence of either L ‐NOARG or ouabain. KCl (2.5–10 m M ) elicited small relaxations (∼20%) that were abolished by nifedipine (0.3 μ M ) and ouabain. Both the high [K + ] o /apamin‐sensitive relaxation to BK, and the relaxation to the K ATP channel‐opener, levcromakalim (0.6 μ M ), were unaffected by the cytochrome P 450 inhibitor, 7‐ethoxyresorufin (10 μ M ), or by co‐treatment with a phospholipase A 2 inhibitor, arachidonyl trifluoromethyl ketone (AACOCF 3 ; 3 μ M ) and a diacylglycerol (DAG)‐lipase inhibitor, 1,6‐bis‐(cyclohexyloximinocarbonylamino)‐hexane (RHC 80267; 30 μ M ). The non‐NO/high [K + ] o ‐insensitive, ∼40% relaxation to BK was, however, abolished by these treatments. Therefore, neither cytochrome P 450 ‐derived metabolites of arachidonic acid nor K + appear to mediate the EDHF‐like relaxation to BK (i.e the non‐NO, high [K + ] o /apamin‐sensitive component) in bovine coronary arteries. Cytochrome P 450 ‐derived metabolites may be released at higher BK concentrations to act in parallel with NO and the high [K + ] o /apamin‐sensitive mechanism.British Journal of Pharmacology (2000) 129 , 811–819; doi: 10.1038/sj.bjp.0703107