TY - JOUR
T1 - Stable 5,6-epoxyeicosatrienoic acid analog relaxes coronary arteries through potassium channel activation
AU - Yang, Wenqi
AU - Gauthier, Kathryn M.
AU - Reddy, L. Manmohan
AU - Sangras, Bhavani
AU - Sharma, Kamalesh K.
AU - Nithipatikom, Kasem
AU - Falck, J R
AU - Campbell, William B.
PY - 2005/4
Y1 - 2005/4
N2 - 5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxadon. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 μmol/L) induced concentration-dependent relaxations, with maximal relaxation of 86±5% and EC50 of 1 μmol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 μmol/L; max relaxation 43±9%); the ATP-sensitive K+ channel inhibitor glybenclamide (10 μmol/L; max relaxation 49±6%); and the large conductance calcium-activated K+ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38±6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K+ to 20 mmol/L. Whole-cell outward K+ current was increased nearly 6-fold by PTPA (10 μmol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy) pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46±13% and 52±7%, respectively; EC50 1 μmol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether-containing prostaglandins that activate ATP-sensitive K+ channels and (2) activation of smooth muscle large conductance calcium-activated K+ channels. PDPAs only activate large conductance calcium-activated K+ channels.
AB - 5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxadon. However, investigations of its role in biological systems have been limited by its chemical instability. We developed a stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy)pentanoic acid (PTPA), in which the 5,6-epoxide was replaced with a 5-ether. PTPA obviates chemical and enzymatic hydrolysis. In bovine coronary artery rings precontracted with U46619, PTPA (1 nmol/L to 10 μmol/L) induced concentration-dependent relaxations, with maximal relaxation of 86±5% and EC50 of 1 μmol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 μmol/L; max relaxation 43±9%); the ATP-sensitive K+ channel inhibitor glybenclamide (10 μmol/L; max relaxation 49±6%); and the large conductance calcium-activated K+ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38±6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K+ to 20 mmol/L. Whole-cell outward K+ current was increased nearly 6-fold by PTPA (10 μmol/L), which was also blocked by iberiotoxin. Additionally, we synthesized 5-(pentadeca-6(Z),9(Z)-dienyloxy) pentanoic acid and 5-(pentadeca-3(Z),9(Z)-dienyloxy)pentanoic acid (PDPA), PTPA analogs that lack the 8,9 or 11,12 double bonds of arachidonic acid and therefore are not substrates for cyclooxygenase. The PDPAs caused concentration-dependent relaxations (max relaxations 46±13% and 52±7%, respectively; EC50 1 μmol/L), which were not altered by glybenclamide but blocked by iberiotoxin. These studies suggested that PTPA induces relaxation through 2 mechanisms: (1) cyclooxygenase-dependent metabolism to 5-ether-containing prostaglandins that activate ATP-sensitive K+ channels and (2) activation of smooth muscle large conductance calcium-activated K+ channels. PDPAs only activate large conductance calcium-activated K+ channels.
KW - Arachidonic acids
KW - Cyclooxygenase
KW - Endothelium-derived factors
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UR - http://www.scopus.com/inward/citedby.url?scp=15744402253&partnerID=8YFLogxK
U2 - 10.1161/01.HYP.0000153790.12735.f9
DO - 10.1161/01.HYP.0000153790.12735.f9
M3 - Article
C2 - 15699458
AN - SCOPUS:15744402253
SN - 0194-911X
VL - 45
SP - 681
EP - 686
JO - Hypertension
JF - Hypertension
IS - 4 SUPPL.
ER -