TY - JOUR
T1 - 14,15-EET analogs
T2 - Characterization of structural requirements for agonist and antagonist activity in bovine coronary arteries
AU - Gauthier, Kathryn M.
AU - Falck, J R
AU - Reddy, L. Manmohan
AU - Campbell, William B.
N1 - Funding Information:
The authors thank Ms. Sarah Hittner, Mr. Erik Edwards and Ms. Christine Deeter for technical assistance and Mrs. Gretchen Barg for secretarial assistance. This work was supported by grants from the American Heart Association, Northland Affiliate, the National, Heart, Lung and Blood Institute, HL-51055, the National Institute of General Medical Sciences, GM-31278 and the Robert A. Welch Foundation.
PY - 2004/6
Y1 - 2004/6
N2 - Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties.
AB - Arachidonic acid metabolites contribute to the regulation of vascular tone and therefore tissue blood flow. The vascular endothelium metabolizes arachidonic acid by cytochrome P450 epoxygenases to epoxyeicosatrienoic acids or EETs. The placement of the epoxide group can occur on any of the double bonds of arachidonic acid resulting in four EET regioisomers; 5,6-, 8,9-, 11,12- and 14,15-EET. In the vasculature, EETs are key components of cellular signaling cascades that culminate in the activation of smooth muscle potassium channels to induce membrane hyperpolarization and vascular relaxation. In some vasculatures such as bovine coronary arteries, EET regioisomers are equipotent in inducing relaxations, while in other arteries, a specific EET regioisomer induces relaxation while others do not. Therefore, the position of the double bonds and/or the epoxide group may alter vascular agonist activity. This observation suggests that small alterations in the chemical structure of EETs can significantly impact vascular activity. To explore this hypothesis, we synthesized a series of EET analogs and characterized their vasodilator agonist and antagonist activity in bovine coronary arteries. In this chapter, we first review the mechanisms of EET-dependent relaxations in bovine coronary arteries to familiarize the reader with the role of EETs in these arteries. The second component is a synopsis of the functional characterization of the 14,15-EET analogs and the resulting description of structural components required for vascular dilator activity. Lastly, we discussed the characterization of three 14,15-EET analogs with specific EET-antagonist activity and compared this to the activity of similar 11,12-EET analogs. These studies have revealed that specific structural components of the 14,15-EET molecule are critical for dilator activity and that alteration of these components influences agonist activity and may confer antagonist properties.
KW - EDHF
KW - Endothelium
KW - Epoxyeicosatrienoic acid
KW - Vascular relaxation
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UR - http://www.scopus.com/inward/citedby.url?scp=1542512379&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2003.09.014
DO - 10.1016/j.phrs.2003.09.014
M3 - Article
C2 - 15026029
AN - SCOPUS:1542512379
SN - 1043-6618
VL - 49
SP - 515
EP - 524
JO - Pharmacological Research
JF - Pharmacological Research
IS - 6
ER -