In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 294, No. 3 ( 2008-03), p. H1467-H1472
Abstract:
Previous studies indicate that 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA), an endothelium-derived hyperpolarizing factor in the rabbit aorta, mediates a portion of the relaxation response to acetylcholine by sequential metabolism of arachidonic acid by 15-lipoxygenase, hydroperoxide isomerase, and epoxide hydrolase. To determine the stereochemical configuration of the endothelial 11,12,15-THETA, its activity and chromatographic migration were compared with activity and migration of eight chemically synthesized stereoisomers of 11,12,15( S)-THETA. Of the eight isomers, only 11( R),12( S),15( S)-trihydroxyeicosa-5( Z),8( Z),13( E)-trienoic acid comigrated with the biological 11,12,15-THETA on reverse- and normal-phase HPLC and gas chromatography. The same THETA isomer (10 −7 –10 −4 M) relaxed the rabbit aorta in a concentration-related manner (maximum relaxation = 69 ± 5%). These relaxations were blocked by apamin (10 −7 M), an inhibitor of small-conductance Ca 2+ -activated K + channels. In comparison, 11( S),12( R),15( S),5( Z),8( Z),13( E)-THETA (10 −4 M) relaxed the aorta by 22%. The other six stereoisomers were inactive in this assay. With use of the whole cell patch-clamp technique, it was shown that 10 −4 M 11( R),12( S),15( S),5( Z),8( Z),13( E)-THETA increased outward K + current in isolated aortic smooth muscle cells by 119 ± 36% at +60 mV, whereas 10 −4 M 11( R),12( R),15( S),5( Z),8( Z),13( E)-THETA increased outward K + current by only 20 ± 2%. The 11( R),12( S),15( S),5( Z),8( Z),13( E)-THETA-stimulated increase in K + current was blocked by pretreatment with apamin. These studies suggest that 11( R),12( S),15( S)-trihydroxyeicosa-5( Z),8( Z),13( E)-trienoic acid is the active stereoisomer produced by the rabbit aorta. It relaxes smooth muscle by activating K + channels. The specific structural and stereochemical requirements for K + channel activation suggest that a specific binding site or receptor of 11,12,15-THETA is involved in these actions.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.01052.2007
Language:
English
Publisher:
American Physiological Society
Publication Date:
2008
detail.hit.zdb_id:
1477308-9
SSG:
12
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