Cytochrome P450 2C is an EDHF synthase in coronary arteries

Fißlthaler, Beate; Popp, Rüdiger; Kiss, Levente; Potente, Michael; Harder, David R.; Fleming, Ingrid; Busse, Rudi

doi:10.1038/46816

Cited by 830 publications

(535 citation statements)

References 19 publications

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“…Using a coronary vessel bioassay system, Gebremedhin et al [5]implicated a CYP450 metabolite as the mediator of the bradykinin-mediated activation of smooth muscle calcium-activated K + channels. Interestingly, transfection of porcine coronary arteries with a CYP2C8/34 antisense oligonucleotide decreased CYP2C protein levels and attenuated bradykinin-induced EDHF vasodilation [7]. Taken together, these studies provide strong evidence that a CYP450-derived epoxygenase metabolite is responsible for the EDHF component of the renal microvascular response to bradykinin.…”

Section: Discussionmentioning

confidence: 58%

“…Endothelium-derived EETs dilate blood vessels by activating vascular smooth muscle K + channels, resulting in membrane hyperpolarization [3, 4, 5]. Additionally, cytochrome P450 (CYP450) inhibitors and antisense oligonucleotides have been reported to block EDHF-mediated vasodilation in isolated blood vessels from several organs and species [4, 5, 6, 7]. …”

Section: Introductionmentioning

confidence: 99%

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Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin

Imig¹,

Falck²,

Wei³

et al. 2001

J Vasc Res

113

112

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In the kidney, epoxyeicosatrienoic acids (EETs) have been suggested to be endothelium-derived hyperpolarizing factors (EDHFs). The aim of the present study was to determine the contribution of EETs to the preglomerular vasodilation elicited by bradykinin. Sprague-Dawley rats were studied utilizing an in vitro perfused juxtamedullary nephron preparation. The afferent arteriolar diameter was determined and the diameter averaged 19 ± 1 µm (n = 26) at a renal perfusion pressure of 100 mm Hg. Addition of 1, 10 and 100 nM bradykinin to the perfusate dose-dependently increased afferent arteriolar diameter by 5 ± 1, 12 ± 2 and 17 ± 2%, respectively. The nitric oxide inhibitor N^ω-nitro-L-arginine reduced bradykinin-induced afferent arteriolar vasodilation by 50%, and the diameter increased by 9 ± 2% in response to 100 nM bradykinin. Epoxygenase inhibitors N-methylsulphonyl-6-(2-propargyloxyphenyl)hexanamide or miconazole greatly attenuated the nitric oxide-independent component of the vasodilation elicited by bradykinin. Cyclooxygenase (COX) inhibition attenuated the nitric oxide-independent vasodilation elicited by 1 nM bradykinin but did not significantly affect the vascular response to 100 nM bradykinin. Combined inhibition of nitric oxide, COX and epoxygenase pathways completely abolished bradykinin-mediated afferent arteriolar vasodilation. In additional studies, renal microvessels were isolated and incubated with bradykinin and samples were analyzed by NICI/GC/MS. Under control conditions, renal microvascular EET levels averaged 49 ± 9 pg/mg/20 min (n = 7). In the presence of bradykinin, EET levels were significantly higher and averaged 81 ± 11 pg/mg/20 min (n = 7). These data support the concept that EETs are EDHFs and contribute to the nitric oxide-independent afferent arteriolar vasodilation elicited by bradykinin.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin

Imig¹,

Falck²,

Wei³

et al. 2001

J Vasc Res

113

112

View full text Add to dashboard Cite

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“…The biochemical nature of the inhibitory interaction between NO and EDHF remains to be elucidated in detail, but there is evidence to suggest that it may involve a cGMP-dependent mechanism. Alternatively, NO itself may inhibit cytochrome P-450 2C and, therefore, the release of EET, which has been described as an EDHF [37, 38]. …”

Section: Discussionmentioning

confidence: 99%

Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries

et al. 2001

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An arteriograph was used to assess myogenic tone, smooth muscle contractility and the influence of endothelial function on mesenteric resistance artery reactivity in insulin-resistant mice (C57BL/KsJ-db/db) and age- and gender-matched wild-type mice. Increases in transmural pressure induced myogenic tone in arteries from both control and db/db mice. At 12 and 16 weeks of age, greater tone developed in diabetic than in control mice. In control, but not in db/db mice, pretreatment of arteries with L-NAME potentiated myogenic tone. Indomethacin and SQ29548 (PGH₂/TXA₂ receptor antagonist) had no efffect in control, but inhibited myogenic tone in db/db mice. Endothelium-dependent vasodilation induced by acetylcholine and bradykinin, was depressed in db/db mice and potentiated by SQ29548 and LY333531 (protein kinase C_β inhibitor). Messenger RNA expression levels for PKC_β were over-expressed 2.5-fold in db/db relative to those in control mice. However, expression levels of mRNA for eNOS, PKC_α, and PKC_ξ were similar in the db/db and control mice. Collectively, these results suggest that the greater myogenic tone in resistance arteries from diabetic mice may be attributable, to greater amounts of one or more vasoconstricting prostanoids. Our data indicate that in diabetic mice, basal and agonist-stimulated NO releases are depressed and NO-mediated vasorelaxation in these mice may be countered by an endogenous vasoconstrictive prostanoid. This prostanoid-induced vasoconstriction is mediated by a PKC_β-dependent mechanism. Therefore, heightened activation of PKC_β and release of a vasoconstrictor prostanoid could play a role in endothelial dysfunction associated with type II diabetes.

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“…Interestingly, a recent study by Fisslthaler et al [29]has shown that the induction of cytochrome P450 enzymes in native endothelial cells enhances EDHF-mediated relaxation and hyperpolarization to bradykinin. In addition, the report also demonstrated attenuated EDHF-mediated vascular responses in arteries transfected with cytochrome P450 antisense oligonucleotides [29].…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 Activity and Endothelial Dysfunction in Insulin Resistance

et al. 2000

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Impaired endothelium-dependent relaxation attributable to nitric oxide/prostacyclin-independent factor (endothelium-dependent hyperpolarizing factor; EDHF) has been demonstrated in the small mesenteric arteries of insulin-resistant rats. The purpose of this study was to determine if modulation of the cytochrome P450 enzyme system would restore EDHF-mediated relaxation in insulin-resistant rats. Sprague-Dawley rats were randomized to control (n = 32) or insulin-resistant (n = 32) groups. Each group was further randomized to treatment (n = 48) or placebo (n = 16). Miconazole (3 days) and phenobarbital (3 and 14 days) achieved cytochrome P450 inhibition and induction, respectively. Following drug treatment, mean arterial pressure was measured and vascular function was assessed in small mesenteric arteries in vitro. Specifically, acetylcholine-induced relaxation alone and in the presence of indomethacin plus N-nitro-L-arginine (LNNA) or KCl was determined. Miconazole reduced the maximal relaxation in response to acetylcholine in control rats. Similarly, in the presence of LNNA plus indomethacin, acetylcholine-induced relaxation was impaired in the miconazole-treated control group versus the placebo group, whereas relaxation in the presence of KCl was unchanged. Miconazole did not affect relaxation in insulin-resistant arteries. In contrast, 3- and 14-day treatment with phenobarbital significantly improved acetylcholine-induced relaxation in insulin-resistant arteries. Likewise, acetylcholine-mediated relaxation in the presence of LNNA plus indomethacin was also improved after phenobarbital treatment, while relaxation in the presence of KCl was unchanged. Phenobarbital treatment did not affect the control group. Miconazole treatment increased the mean arterial pressure in control rats, while 14-day phenobarbital treatment normalized the mean arterial pressure in insulin-resistant rats. Cytochrome P450 induction results in the restoration of EDHF-mediated relaxation in small mesenteric arteries and the normalization of mean arterial pressure in insulin-resistant rats. Thus, endothelial dysfunction secondary to insulin resistance can be reversed by the induction of cytochrome P450.

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Cytochrome P450 2C is an EDHF synthase in coronary arteries

Cited by 830 publications

References 19 publications

Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin

Epoxygenase Metabolites Contribute to Nitric Oxide-Independent Afferent Arteriolar Vasodilation in Response to Bradykinin

Influence of Type II Diabetes on Arterial Tone and Endothelial Function in Murine Mesenteric Resistance Arteries

Cytochrome P450 Activity and Endothelial Dysfunction in Insulin Resistance

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