Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid

Rosolowsky, Mark; Campbell, William B.

doi:10.1152/ajpheart.1993.264.2.h327

Cited by 110 publications

(165 citation statements)

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“…The reasons for the discrepancy between these findings and those of the present study are not certain, but the differences could indicate that 'EDHF' is not the same in all tissues. Alternatively, the presence of indomethacin in the present study and its absence in earlier investigations (Pfister et al, 1991;Gebremedhin et al, 1992;Rosolowsky & Campbell, 1993) may be relevant, since indomethacin inhibits the relaxant effect of 5,6-EET (Carroll et al, 1990;Ellis et al, 1990). EETs may thus be metabolised to relaxant substances via cyclo-oxygenase giving rise to the false conclusion that EDHF is an EET.…”

Section: Discussionmentioning

confidence: 65%

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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1 The possibility that the endothelium-derived hyperpolarising factor (EDHF) in the rat hepatic artery is a cytochrome P450 mono-oxygenase metabolite of arachidonic acid was examined in the present study. In this preparation, acetylcholine elicits EDHF-mediated relaxations in the presence of the nitric oxide (NO) synthase and cyclo-oxygenase inhibitors No-nitro-L-arginine (L-NOARG) and indomethacin, respectively.2 17-Octadecynoic acid (17-ODYA, 50 gM), a suicide-substrate inhibitor of the cytochrome P450 mono-oxygenases responsible for the production of 5, 8, 11,[12][13][14], had no effect on acetylcholine-induced relaxations in the presence of L-NOARG (0.3 mM) plus indomethacin (10 gM). Furthermore, 5, 8, 11, Clotrimazole (3 gM) was without effect on these responses. The relaxant actions of the NO donor, 3-morpholino-sydnonimine, were unaffected by proadifen (10 gM). 5 The relaxant effects of the opener of ATP-sensitive potassium channels, levcromakalim, were abolished by proadifen (10 gM) and strongly attenuated by clotrimazole (3 gM). Proadifen (10 gM) also abolished the hyperpolarization induced by levcromakalim (1 gM). 6 The lack of effect of 17-ODYA on relaxations mediated by EDHF, together with the failure of extracellularly-applied EETs to produce relaxation, collectively suggest that EDHF is not an EET in the rat hepatic artery. It seems likely that inhibition of ion channels in the smooth muscle rather than reduced EDHF formation in the endothelium offers a better explanation for the actions of the cytochrome P450 inhibitors proadifen and clotrimazole.

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Section: Discussionmentioning

confidence: 65%

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Zygmunt

Edwards

Weston

et al. 1996

British J Pharmacology

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“…Bovine coronary artery endothelial cells metabolize arachidonic acid not only via cyclo-oxygenase and PGI2 synthase to PGI2, but also via the cytochrome P450 pathway to several regioisomeric epoxides (EETs). The relaxant effect of arachidonic acid in these arteries is only partially inhibited by treatment with indomethacin of SKF 525a, but completely abolished by the combined treatment with these agents, indicating that cytochrome P450-derived EETs mediate part of the dilator effect of arachidonic acid in this preparation (Rosolowsky & Campbell, 1993). Moreover, these EETs have been shown to activate large conductance Kc.…”

Section: Discussionmentioning

confidence: 89%

Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation

Bauersachs

Hecker

Busse

1994

British J Pharmacology

174

109

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1 In addition to nitric oxide (NO) and prostacyclin (PGI2) an endothelium-derived factor, which hyperpolarizes vascular smooth muscle cells via activation of K+ channels, contributes to the dilator effect of bradykinin in different vascular beds. Since this so-called endothelium-derived hyperpolarizing factor (EDHF) also seems to play an important role in the coronary circulation, we investigated its nature and mechanism of action in the rat isolated perfused heart (Langendorff preparation). 2 Bolus injections of bradykinin (1, 10, and 100 pmol) elicited a transient dose-dependent dilator response (e.g., 12 ± 2% decrease in coronary perfusion pressure (CPP) at 10 pmol bradykinin, n = 41).Administration of the cyclo-oxygenase inhibitor, diclofenac (1 f.M), augmented the bradykinin-induced dilation approximately twofold (n = 9 P<0.01). Combined treatment with the NO synthase inhibitor, N0-nitro-L-arginine (30 tiM) and diclofenac (1 pM) significantly reduced the duration, but increased the amplitude of the dilator response to bradykinin (27 ± 2% decrease in CPP, n = 24, P <0.01).3 The abolition of this N0-nitro-L-arginine/diclofenac-insensitive dilator response to bradykinin by tetrabutylammonium (0.3 mM), an inhibitor of Ca2+-dependent K+ channels (4 ± 1% decrease in CPP, n = 6, P < 0.01), supports the view that the dilator compound released in the coronary microcirculation is EDHF. 4 This EDHF-type dilation was reversibly inhibited by the phospholipase A2 inhibitor, quinacrine (3 pM, 9 ± 3% decrease in CPP, n = 6, P<0.01) and by the cytochrome P450 inhibitor SKF525a (3 fM, 6 ± 1% decrease in CPP, n = 6, P < 0.01). 5 Tetrabutylammonium, quinacrine or SKF 525a did not affect the endothelium-independent dilator response to sodium nitroprusside (1 nmol), indicating that these compounds did not affect smooth muscle relaxation in a non-specific manner. 6 These findings suggest that in the coronary microcirculation bradykinin stimulates the release of a cytochrome P450-derived arachidonic acid metabolite, which exhibits the characteristic features of EDHF.

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“…Tensions were recorded as described previously. 2,16 The thromboxane-mimetic U46619 (10 to 20 nmol/L) was administered to contract the vessels to 50% to 75% of KCl-induced contraction. Cumulative additions of 5,6-EET or 5,6-EET analogs were added to the chamber.…”

Section: Vascular Reactivity Of Bovine Coronary Arteriesmentioning

confidence: 99%

Stable 5,6-Epoxyeicosatrienoic Acid Analog Relaxes Coronary Arteries Through Potassium Channel Activation

et al. 2005

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Abstract-5,6-Epoxyeicosatrienoic acid (5,6-EET) is a cytochrome P450 epoxygenase metabolite of arachidonic acid that causes vasorelaxation. 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 mol/L) induced concentration-dependent relaxations, with maximal relaxation of 86Ϯ5% and EC 50 of 1 mol/L. The relaxations were inhibited by the cyclooxygenase inhibitor indomethacin (10 mol/L; max relaxation 43Ϯ9%); the ATP-sensitive K ϩ channel inhibitor glybenclamide (10 mol/L; max relaxation 49Ϯ6%); and the large conductance calcium-activated K ϩ channel inhibitor iberiotoxin (100 nmol/L; max relaxation 38Ϯ6%) and abolished by the combination of iberiotoxin with indomethacin or glybenclamide or increasing extracellular K ϩ to 20 mmol/L. Whole-cell outward K ϩ current was increased nearly 6-fold by PTPA (10 mol/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 46Ϯ13% and 52Ϯ7%, respectively; EC 50 1mol/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 ϩ channels and (2) Key Words: arachidonic acids Ⅲ cyclooxygenase Ⅲ endothelium-derived factors C ytochrome P450 epoxygenases metabolize arachidonic acid to 4 regioisomeric epoxyeicosatrienoic acids (EETs): 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET. 1 The EETs have a range of biological activities including vasodilation, 2,3 release of catecholamines 4 and hypothalamic hormones, 5 and alteration of sodium transport. 6 In some instances, the 4 EET regioisomers are equipotent in biological activity, 2 and in other instances, a particular regioisomer is active, whereas other isomers are inactive or less active. 7 EETs are metabolized by soluble epoxide hydrolase to dihydroxyeicosatrienoic acids (DHETs) 8 by ␤-oxidation to short-chain epoxides 9 or by incorporation into membrane phospholipids. 10 These pathways represent mechanisms of cellular inactivation and EET recycling. With the exception of 5,6-EET, the EETs are chemically stable in alkaline aqueous solution. 5,6-EET is hydrolyzed to 5,6-DHET and its ␦-lactone under neutral and acidic conditions. 11,12 In some studies, the methyl ester of 5,6-EET is used because of its improved chemical stability. The chemical instability has limited investigation of this EET regioiso...

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Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid

Cited by 110 publications

References 0 publications

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Effects of cytochrome P450 inhibitors on EDHF‐mediated relaxation in the rat hepatic artery

Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation

Stable 5,6-Epoxyeicosatrienoic Acid Analog Relaxes Coronary Arteries Through Potassium Channel Activation

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