TY - JOUR
T1 - Comparison of vasodilatory properties of 14,15-EET analogs
T2 - Structural requirements for dilation
AU - Falck, J R
AU - Krishna, U. Murali
AU - Reddy, Y. Krishna
AU - Kumar, P. Srinagesh
AU - Reddy, K. Malla
AU - Hittner, Sarah B.
AU - Deeter, Christine
AU - Sharma, Kamalesh K.
AU - Gauthier, Kathryn M.
AU - Campbell, William B.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Epoxyeicosatrienoic acids (EETs) are endothelium-derived eicosanoids that activate potassium channels, hyperpolarize the membrane, and cause relaxation. We tested 19 analogs of 14,15-EET on vascular tone to determine the structural features required for activity. 14,15-EET relaxed bovine coronary arterial rings in a concentration-related manner (ED50 = 10-6 M). Changing the carboxyl to an alcohol eliminated dilator activity, whereas 14; 15-EET-methyl ester and 14,15-EET- methylsulfonimide retained full activity. Shortening the distance between the carboxyl and epoxy groups reduced the agonist potency and activity. Removal of all three double bonds decreased potency. An analog with a Δ8 double bond had full activity and potency. However, the analogs with only a Δ5 or Α11 double bond had reduced potency. Conversion of the epoxy oxygen to a sulfur or nitrogen resulted in loss of activity. 14(S),15(R)-EET was more potent than 14(R),15(S)-EET, and 14,15-(cis)-EET was more potent than 14,15-(trans)-EET. These studies indicate that the structural features of 14,15-EET required for relaxation of the bovine coronary artery include a carbon-1 acidic group, a Δ8 double bond, and a 14(S),15(R)-(cis)-epoxy group.
AB - Epoxyeicosatrienoic acids (EETs) are endothelium-derived eicosanoids that activate potassium channels, hyperpolarize the membrane, and cause relaxation. We tested 19 analogs of 14,15-EET on vascular tone to determine the structural features required for activity. 14,15-EET relaxed bovine coronary arterial rings in a concentration-related manner (ED50 = 10-6 M). Changing the carboxyl to an alcohol eliminated dilator activity, whereas 14; 15-EET-methyl ester and 14,15-EET- methylsulfonimide retained full activity. Shortening the distance between the carboxyl and epoxy groups reduced the agonist potency and activity. Removal of all three double bonds decreased potency. An analog with a Δ8 double bond had full activity and potency. However, the analogs with only a Δ5 or Α11 double bond had reduced potency. Conversion of the epoxy oxygen to a sulfur or nitrogen resulted in loss of activity. 14(S),15(R)-EET was more potent than 14(R),15(S)-EET, and 14,15-(cis)-EET was more potent than 14,15-(trans)-EET. These studies indicate that the structural features of 14,15-EET required for relaxation of the bovine coronary artery include a carbon-1 acidic group, a Δ8 double bond, and a 14(S),15(R)-(cis)-epoxy group.
KW - Arachidonic acid
KW - Cytochrome P-450
KW - Endothelium-derived hyperpolarizing factor
KW - Epoxyeicosatrienoic acid
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U2 - 10.1152/ajpheart.00831.2001
DO - 10.1152/ajpheart.00831.2001
M3 - Article
C2 - 12388250
AN - SCOPUS:0037232845
SN - 0363-6135
VL - 284
SP - H337-H349
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 1 53-1
ER -