Nitric oxide/cytochrome P450 interactions in cyclosporin A-induced effects in the rat

Blanton, Ahmad; Nsaif, Rami H; Hercule, Hantz C.; Oyekan, Adebayo

doi:10.1097/01.hjh.0000242412.88653.f2

Cited by 19 publications

(7 citation statements)

References 29 publications

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“…The expression Cyp2c29 was downregulated in MS-PPOH-treated mouse aortae compared with controls. It has been reported that at the concentration used, MS-PPOH has no effect on pathways other than the CYP patheway (5,39,40). EDHF stimulates hyperpolarization of smooth muscle cells and thus induces vasodilation (16).…”

Section: Discussionmentioning

confidence: 95%

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

Nayeem¹,

Poloyac²,

Falck³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

113

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We hypothesized that A2A adenosine receptor (A2A AR) activation causes vasorelaxation through cytochrome P-450 (CYP) epoxygenases and endothelium-derived hyperpolarizing factors, whereas lack of A2A AR activation promotes vasoconstriction through Cyp4a in the mouse aorta. Adenosine 5'-N-ethylcarboxamide (NECA; 10(-6) M), an adenosine analog, caused relaxation in wild-type A2A AR (A2A AR+/+; +33.99 +/- 4.70%, P < 0.05) versus contraction in A2A AR knockout (A2A AR(-/-); -27.52 +/- 4.11%) mouse aortae. An A2A AR-specific antagonist (SCH-58261; 1 microM) changed the NECA (10(-6) M) relaxation response to contraction (-35.82 +/- 4.69%, P < 0.05) in A2A AR+/+ aortae, whereas no effect was noted in A2A AR(-/-) aortae. Significant contraction was seen in the absence of the endothelium in A2A AR+/+ (-2.58 +/- 2.25%) aortae compared with endothelium-intact aortae. An endothelial nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester; 100 microM) and a cyclooxygenase inhibitor (indomethacin; 10 microM) failed to block NECA-induced relaxation in A2A AR+/+ aortae. A selective inhibitor of CYP epoxygenases (methylsulfonyl-propargyloxyphenylhexanamide; 10 microM) changed NECA-mediated relaxation (-22.74 +/- 5.11% at 10(-6) M) and CGS-21680-mediated relaxation (-18.54 +/- 6.06% at 10(-6) M) to contraction in A2A AR+/+ aortae, whereas no response was noted in A2A AR(-/-) aortae. Furthermore, an epoxyeicosatrienoic acid (EET) antagonist [14,15-epoxyeicosa-5(Z)-enoic acid; 10 microM] was able to block NECA-induced relaxation in A2A AR+/+ aortae, whereas omega-hydroxylase inhibitors (10 microM dibromo-dodecenyl-methylsulfimide and 10 microM HET-0016) changed contraction into relaxation in A2A AR(-/-) aorta. Cyp2c29 protein was upregulated in A2A AR+/+ aortae, whereas Cyp4a was upregulated in A2A AR(-/-) aortae. Higher levels of dihydroxyeicosatrienoic acids (DHETs; 14,15-DHET, 11,12-DHET, and 8,9-DHET, P < 0.05) were found in A2A AR+/+ versus A2A AR(-/-) aortae. EET levels were not significantly different between A2A AR+/+ and A2A AR(-/-) aortae. It is concluded that CYP epoxygenases play an important role in A2A AR-mediated relaxation, and the deletion of the A2A AR leads to contraction through Cyp4a.

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Section: Discussionmentioning

confidence: 95%

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

Nayeem¹,

Poloyac²,

Falck³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

113

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“…Our data suggest that the endothelium-dependent CGS 21680-induced vascular relaxation is mediated by CYP epoxygenases and EETs in HS mouse aorta. Notably, at the concentration used in the current study, MS-PPOH and 14,15-EEZE do not have any effect on pathways other than the CYP pathway (4,25,26).…”

Section: Discussionmentioning

confidence: 99%

High-salt diet enhances mouse aortic relaxation through adenosine A_2Areceptor via CYP epoxygenases

Nayeem¹,

Ponnoth²,

Boegehold³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Nayeem MA, Ponnoth DS, Boegehold MA, Zeldin DC, Falck JR, Mustafa SJ. High-salt diet enhances mouse aortic relaxation through adenosine A 2A receptor via CYP epoxygenases. Am J Physiol Regul Integr Comp Physiol 296: R567-R574, 2009. First published December 24, 2008 doi:10.1152/ajpregu.90798.2008.-We hypothesize that A 2A adenosine receptors (A2A AR) promote aortic relaxation in mice through cytochrome P450 (CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4 -5 wks were used. Concentration-response curves (10 Ϫ11 -10 Ϫ5 M) for 5Ј-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine analog) and CGS 21680 ( Ϫ7 M of NECA, significant relaxation in HS (ϩ22.58 Ϯ 3.12%) was observed compared with contraction in NS (Ϫ10.62 Ϯ 6.27%, P Ͻ 0.05). ZM 241385 changed the NECA response to contraction (P Ͻ 0.05) in HS. At 10 Ϫ7 M of CGS 21680, significant relaxation in HS (ϩ32.04 Ϯ 3.08%) was observed compared with NS (ϩ10.45 Ϯ 1.34%, P Ͻ 0.05). SCH 58261, L-NAME, MS-PPOH, and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction (P Ͻ 0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation (P Ͻ 0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS and NS vs. nontreated HS group (P Ͼ 0.05). CYP2C29 protein was 55% and 74% upregulated in HS vs. NS (P Ͻ 0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% upregulated in NS vs. HS (P Ͻ 0.05) mice aorta and kidneys, respectively. A1 AR was downregulated, whereas A2A AR was upregulated in HS compared with NS. These data suggest that HS may activate CYP2C29 via A2A AR, causing relaxation, whereas NS may contribute to the upregulation of CYP4A causing contraction.vasodilation; vasoconstriction SEVERAL LINES OF EVIDENCE suggest that adenosine is cardioprotective (29 -31). This nucleoside is present in nearly every tissue and organ (17, 29 -31) and is involved in modulation of various physiological activities (31-34, 40). Furthermore, the production of adenosine is also increased under stressful conditions such as hypoxia, ischemia, and inflammation and in response to pathological events (27, 38).The regulation of vascular tone by adenosine involves activation of four receptor subtypes: A 1 , A 2A , A 2B , and A 3 . Adenosine A 1 and A 2A receptors are widely distributed throughout the peripheral vasculature (24,45,46). Adenosine-induced vasodilation is primarily caused by the activation of A 2A receptors in the coronary and renal arteries and other vessels (1,2,15,28,43).There is a correlation between adenosine and salt intake; switching rats from a normal-salt (NS) diet to a high-salt (HS) diet leads to increased adenosine levels in the renal cortex and medulla and increased urinary adenosine levels (41). Through the activation of A 2A receptors, this increase in renal adenosine concentration could possibly contribute to a reduction in macula densa-mediated re...

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“…These include: rats treated with an adenovirus to upregulate the expression of CYP4A2 in the endothelium (55); spontaneously hypertensive rats (SHR) (96, 167–169); androgen-induced hypertensive rats (57, 58); rats treated with the immunosuppressant drug cyclosporine A which induces CYP4A expression (170); and CYP4A12 transgenic and CYP4A14 KO mice in which the production of 20-HETE is elevated (41, 171, 172). In androgen-induced hypertensive rats, the expression of the gp-91 and gp-47 phox subunits of NADPH oxidase and the production of ROS are elevated (57).…”

Section: 20-hete In the Control Of Vascular Functionmentioning

confidence: 99%

Molecular mechanisms in differentiated thyroid cancer

2016

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Cytochrome P450s enzymes catalyze the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid and hydroxyeicosatetraeonic acid (HETEs). 20-HETE is a vasoconstrictor that depolarizes vascular smooth muscle cells by blocking K+ channels. EETs serve as endothelial derived hyperpolarizing factors. Inhibition of the formation of 20-HETE impairs the myogenic response and autoregulation of renal and cerebral blood flow. Changes in the formation of EETs and 20-HETE have been reported in hypertension and drugs that target these pathways alter blood pressure in animal models. Sequence variants in CYP4A11 and CYP4F2 that produce 20-HETE, UDP-glucuronosyl transferase involved in the biotransformation of 20-HETE and soluble epoxide hydrolase that inactivates EETs are associated with hypertension in human studies. 20-HETE contributes to the regulation of vascular hypertrophy, restenosis, angiogenesis and inflammation. It also promotes endothelial dysfunction and contributes to cerebral vasospasm and ischemia-reperfusion injury in the brain, kidney and heart. This review will focus on the role of 20-HETE in vascular dysfunction, inflammation, ischemic and hemorrhagic stroke and cardiac and renal ischemia reperfusion injury.

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Nitric oxide/cytochrome P450 interactions in cyclosporin A-induced effects in the rat

Abstract: These data suggest that cyclosporin A-induced nephrotoxicity can be accounted for by reduced NO production and a consequent increase in 20-HETE. The cyclosporin A-induced nephrotoxicity is thus an ideal model for evaluating NO/CYP450 interactions.

Cited by 19 publications

References 29 publications

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

High-salt diet enhances mouse aortic relaxation through adenosine A_2Areceptor via CYP epoxygenases

Molecular mechanisms in differentiated thyroid cancer

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Nitric oxide/cytochrome P450 interactions in cyclosporin A-induced effects in the rat

Abstract: These data suggest that cyclosporin A-induced nephrotoxicity can be accounted for by reduced NO production and a consequent increase in 20-HETE. The cyclosporin A-induced nephrotoxicity is thus an ideal model for evaluating NO/CYP450 interactions.

Cited by 19 publications

References 29 publications

Role of CYP epoxygenases in A2AAR-mediated relaxation using A2AAR-null and wild-type mice

Role of CYP epoxygenases in A2AAR-mediated relaxation using A2AAR-null and wild-type mice

High-salt diet enhances mouse aortic relaxation through adenosine A2Areceptor via CYP epoxygenases

Molecular mechanisms in differentiated thyroid cancer

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Product

Resources

About

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

Role of CYP epoxygenases in A_2AAR-mediated relaxation using A_2AAR-null and wild-type mice

High-salt diet enhances mouse aortic relaxation through adenosine A_2Areceptor via CYP epoxygenases