Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BK
            <sub>Ca</sub>
            Channels

Archer, Stephen L.; Gragasin, Ferrante S.; Wu, Xi-Chen; Wang, Shaohua; McMurtry, Sean; Kim, Daniel H.; Platonov, Michael; Koshal, Arvind; Hashimoto, Kyoko; Campbell, William B.; Falck, John R.; Michelakis, Evangelos D.

doi:10.1161/01.cir.0000047278.28407.c2

Cited by 240 publications

(250 citation statements)

References 28 publications

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“…18 Indeed, mammary arteries removed from patients undergoing coronary artery bypass surgery express CYP 2C9, and inhibiting the enzyme abolishes the acetylcholine-and bradykinin-induced EDHF-mediated relaxation of these vessels. 3 The results of the present investigation, however, do not suggest that CYP 2C epoxygenase contributes to acetylcholine-induced vasodilatation of the forearm vasculature in patients with coronary artery disease. Indeed, instead of decreasing vasodilator responses to acetylcholine in patients treated with L-NMMA, sulfaphenazole increased blood flow.…”

Section: Fichtlscherer Et Alcontrasting

confidence: 85%

“…Preventing the generation of 11,12-EET by these arteries abolished the acetylcholine-and bradykinin-induced NO/prostaglandin I 2 -independent relaxation. 3 A similar CYP 2C9 -dependent vasodilator mechanism has also been reported in the skeletal muscle circulation of healthy subjects. 4 In addition to generating vasodilator EETs, CYP 2C9 also generates significant amounts of oxygen-derived free radicals, which compromise endothelium-dependent vasodilatation by scavenging NO.…”

supporting

confidence: 57%

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Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

et al. 2004

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Background-Nitric oxide (NO)-and prostacyclin-independent vasodilatation in several vascular beds has been linked to the activation of cytochrome P450 (CYP) epoxygenases expressed in endothelial cells. However, these enzymes, which generate vasodilator epoxyeicosatrienoic acids, may also produce oxygen-derived free radicals, which attenuate the bioavailability of NO. Here, we studied the involvement of CYP 2C9 in modulating endothelium-dependent and -independent changes in forearm blood flow (FBF) in healthy volunteers and in patients with manifest coronary artery disease. Methods and Results-The effects of sulfaphenazole, a selective inhibitor of CYP 2C9, on endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside, SNP) FBF responses were measured by venous occlusion plethysmography in 5 healthy subjects and in 16 patients with angiographically documented stable coronary artery disease. Sulfaphenazole did not modify FBF responses to acetylcholine or SNP in healthy subjects. In contrast, sulfaphenazole markedly and dose-dependently enhanced the FBF response to acetylcholine without affecting the response to SNP. Vitamin C also increased the FBF response to acetylcholine, but this effect was further potentiated by sulfaphenazole. In the presence of N -monomethyl-L-arginine, sulfaphenazole failed to significantly improve acetylcholine-induced vasodilatation. The oxidation of serum proteins was enhanced in patients with coronary artery disease, and this effect was significantly attenuated by sulfaphenazole. Conclusions-The CYP 2C9 inhibitor sulfaphenazole enhances endothelium-dependent vasodilator responses in patients with manifest coronary artery disease. This effect seems to be related to an increase in the bioavailability of NO, probably as a consequence of an attenuated generation of reactive oxygen species by CYP 2C9 in endothelial cells.

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Section: Fichtlscherer Et Alcontrasting

confidence: 85%

supporting

confidence: 57%

Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

et al. 2004

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“…The lack of effect of the cytochrome P450 epoxygenase inhibitors is in agreement with the nonsignificant effect of iberiotoxin, because EETs have been reported to exert their effects through activation of BK Ca channels on smooth muscle cells. 8 In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, K IR , and Na ϩ /K ϩ -ATPase by NO and (2) IK Ca and SK Ca channels. The latter are activated by a factor other than NO.…”

Section: Discussionmentioning

confidence: 88%

“…In addition, EETs might directly activate BK Ca channels on smooth muscle cells. 8 In the present study, we set out to verify the aforementioned concept in human coronary microarteries (HCMAs). Bradykinin has already been reported to hyperpolarize smooth muscle cells in human coronary arteries, 11 and this hyperpolarization could not be attributed to NO.…”

mentioning

confidence: 99%

Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries

Batenburg¹,

Garrelds²,

Kats³

et al. 2004

Hypertension

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Abstract-To investigate the mediators of bradykinin-induced vasorelaxation in human coronary microarteries (HCMAs), HCMAs (diameter Ϸ300 m) obtained from 42 heart valve donors (20 men and 22 women; age range, 3 to 65 years; mean age, 46 years) were mounted in Mulvany myographs. In the presence of the cyclooxygenase inhibitor indomethacin, bradykinin relaxed preconstricted HCMAs in a concentration-dependent manner. N G -nitro-L-arginine methyl ester and ODQ (inhibitors of nitric oxide [NO] synthase and guanylyl cyclase, respectively) and the NO scavenger hydroxocobalamin, either alone or in combination, shifted the bradykinin concentration-response curve to the right. Removal of H 2 O 2 (with catalase), inhibition of cytochrome P450 epoxygenase (with sulfaphenazole or clotrimazole) or gap junctions (with 18␣-glycyrrhetinic acid or carbenoxolone), and blockade of large-(BK Ca ) and small-(SK Ca ) conductance Ca 2ϩ -dependent K ϩ channels (with iberiotoxin and apamin), either alone or in addition to hydroxocobalamin, did not affect bradykinin. In contrast, complete blockade of bradykinin-induced relaxation was obtained when we combined the nonselective BK Ca and intermediate-conductance (IK Ca ) Ca 2ϩ -dependent K ϩ channel blocker charybdotoxin and apamin with hydroxocobalamin. Charybdotoxin plus apamin alone were without effect. Inhibition of inwardly rectifying K ϩ channels (K IR ) and Na ϩ /K ϩ -ATPase (with BaCl 2 and ouabain, respectively) shifted the bradykinin concentration-response curve 10-fold to the right but did not exert an additional effect in the presence of hydroxocobalamin. In conclusion, bradykinin-induced relaxation in HCMAs depends on (1) the activation of guanylyl cyclase, K IR , and Na ϩ /K ϩ -ATPase by NO and (2) IK Ca and SK Ca channels. The latter are activated by a factor other than NO. This factor is not a cytochrome P450 epoxygenase product or H 2 O 2 , nor does it depend on gap junctions or BK Ca channels. Key Words: bradykinin Ⅲ arteries Ⅲ endothelium-derived factors Ⅲ nitric oxide E ndothelium-dependent relaxation induced by bradykinin cannot fully be attributed to the release of nitric oxide (NO). In resistance-size vessels, a large proportion of endothelium-derived relaxation involves the release of endothelium-derived hyperpolarizing factors (EDHFs). 1 Putative EDHF candidates are prostacyclin, S-nitrosothiols, K ϩ , cytochrome P450 products of arachidonic acid (epoxyeicosatrienoic acids [EETs]), and H 2 O 2 , 2-8 and EDHF-dependent responses have been reported to involve large-, intermediate-, and/or small-conductance Ca 2ϩ -activated K ϩ channels (BK Ca , IK Ca , and SK Ca, respectively), inwardly rectifying K ϩ (K IR ) channels, Na ϩ /K ϩ -ATPase, and gap junctions. 4,5,8 -10 Busse et al 9 recently summarized all currently available data on EDHF and proposed that EDHF-mediated relaxation (ie, relaxation observed in the absence of NO) depends on the activation of endothelial IK Ca and SK Ca channels. 4 Such activation results in the release of K ϩ into the myoendothelial spac...

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“…EETs have been considered to be candidates of endothelium-derived hyperpolarizing factors in human coronary vessel bed (23,28). EETs are potent modulators of the cardiac Na ϩ channel (29), the L-type Ca 2ϩ channels (30), and the coronary arterial smooth muscle Ca 2ϩ -activated K ϩ channels (31,32).…”

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confidence: 99%

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

Lü

Hong

Lee

2005

Journal of Biological Chemistry

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We have previously reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent stereospecific activators of the cardiac K ATP channel. The epoxide group in EET is critical for reducing channel sensitivity to ATP, thereby activating the channel. This study is to identify the molecular sites on the K ATP channels for EET-mediated activation. We investigated the effects of EETs on Kir6.2⌬C26 with or without the coexpression of SUR2A and on Kir6. The cardiac ATP-sensitive K ϩ (K ATP ) 1 channels are biological sensors that respond to intracellular metabolic changes and play important roles in regulating cardiac functions (1). Although the role of the cardiac K ATP channels under normal physiological conditions remains unclear, it is crucial in ischemic preconditioning, and activation of K ATP channels occurs during cardiac ischemia and hypoxia, leading to reduced Ca 2ϩ influx and intracellular Ca 2ϩ overload (2). Some important insights were provided by studies using the Kir6.2 knock-out mice, which have compromised ability in modulating cardiac electrophysiological properties, contractility (3, 4), and in handling cardiac ischemia and stress (3,5,6). Recently, a form of human dilated cardiomyopathy was found to be associated with mutations of the cardiac K ATP channels (7).The cardiac K ATP channel is a heterooctamer containing four inward rectifier K ϩ channel (Kir6.2) and four sulfonylurea receptor (SUR2A) subunits. SUR contains two cytoplasmic nucleotide binding folds that were initially thought to be important for channel regulation by ATP (8). However, a truncation mutant of the Kir6.2 involving deletion of the C-terminal 26 residues (Kir6.2⌬C26) gives rise to channels that retain much of the ATP sensitivity in the absence of SUR (9). Also, mutations in the SUR produced only small effects on ATP inhibition of Kir6.2/SUR currents (10). Previous studies have demonstrated that both the N and C termini of Kir6.2 contribute to the site(s) that regulates ATP sensitivity, and they include Arg-50, Cys-166, Ile-167, Thr-171, Arg-176, Arg-177, Glu-179, Ile-182, Lys-185, Arg-192, Arg-201, and Gly-344 residues. Of these, Arg-50, Lys-185, and Arg-201 residues are particularly crucial for ATP sensitivity and are implicated for interaction with the ␣, ␤, and ␥ phosphates of ATP (11-13). However, the mechanism of Kir6.2 channel inhibition by ATP remains to be elucidated.Lipid metabolites are important modulators of the K ATP channels, and these include the long chain acyl-CoA esters (14), phosphatidylinositol 4,5-bisphosphate (PIP 2 ), phosphoinositides (15), L-palmitoylcarnitine (16), and epoxyeicosatrienoic acids (EETs) (17, 18). Arachidonic acid is converted by the cytochrome P450 epoxygenase into 4 EET regioisomers, 5.6-, 8,9-, 11,12-, and 14,15-EET (Fig. 1) (19). EETs are abundant endogenous constituents of the human and rat hearts, measured at 70 ng of total EETs per g of rat heart (20). 8,9-, 11,12-, and 14,15-EET contribute 39, 28, and 33%, respectively, ...

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Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BK _Ca Channels

Cited by 240 publications

References 28 publications

Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

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Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BK Ca Channels

Cited by 240 publications

References 28 publications

Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

Inhibition of Cytochrome P450 2C9 Improves Endothelium-Dependent, Nitric Oxide–Mediated Vasodilatation in Patients With Coronary Artery Disease

Mediators of Bradykinin-Induced Vasorelaxation in Human Coronary Microarteries

Molecular Determinants of Cardiac KATP Channel Activation by Epoxyeicosatrienoic Acids

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Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BK _Ca Channels