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Research ArticleArticle

Indapamide Lowers Blood Pressure by Increasing Production of Epoxyeicosatrienoic Acids in the Kidney

Fei Ma, Fan Lin, Chen Chen, Jennifer Cheng, Darryl C. Zeldin, Yan Wang and Dao Wen Wang
Molecular Pharmacology August 2013, 84 (2) 286-295; DOI: https://doi.org/10.1124/mol.113.085878
Fei Ma
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Fan Lin
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Chen Chen
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Jennifer Cheng
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Darryl C. Zeldin
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Yan Wang
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Dao Wen Wang
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China (F.M., F.L., C.C., Y.W., D.W.W.); and Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (J.C., D.C.Z.)
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Abstract

Diuretics are widely used in the treatment of hypertension, although the precise mechanisms remain unknown. Epoxyeicosatrienoic acids (EETs), cytochrome P450 (P450) epoxygenase metabolites of arachidonic acid, play critical roles in regulation of blood pressure. The present study was carried out to investigate whether EETs participate in the antihypertensive effect of thiazide diuretics [hydrochlorothiazide (HCTZ)] and thiazide-like diuretics (indapamide). Male spontaneously hypertensive rats (SHRs) were treated with indapamide or HCTZ for 8 weeks. Systolic blood pressure, measured via tail-cuff plethysmography and confirmed via intra-arterial measurements, was significantly decreased in indapamide- and HCTZ-treated SHRs compared with saline-treated SHRs. Indapamide increased kidney CYP2C23 expression, decreased soluble epoxide hydrolase expression, increased urinary and renovascular 11,12- and 14,15-EETs, and decreased production of 11,12- and 14,15-dihydroxyeicosatrienoic acids in SHRs. No effect on expression of CYP4A1 or CYP2J3, or on 20-hydroxyeicosatetraenoic acid production, was observed, suggesting indapamide specifically targets CYP2C23-derived EETs. Treatment of SHRs with HCTZ did not affect the levels of P450s or their metabolites. Increased cAMP activity and protein kinase A expression were observed in the renal microvessels of indapamide-treated SHRs. Indapamide ameliorated oxidative stress and inflammation in renal cortices by down-regulating the expression of p47phox, nuclear factor-κB, transforming growth factor-β1, and phosphorylated mitogen-activated protein kinase. Furthermore, the p47phox-lowering effect of indapamide in angiotensin II–treated rat mesangial cells was partially blocked by the presence of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) or CYP2C23 small interfering RNA. Together, these results indicate that the hypotensive effects of indapamide are mediated, at least in part, by the P450 epoxygenase system in SHRs, and provide novel insights into the blood pressure–lowering mechanisms of diuretics.

Footnotes

    • Received February 26, 2013.
    • Accepted May 30, 2013.
  • F.M. and F.L. contributed equally to this work.

  • This work was supported by the 973 Projects [2012CB517801 and 2012CB518004]; National Nature Science Foundation of China [31130031]; Key Project of The Ministry of Health of China; and the Intramural Research Program of the National Institutes of Health [National Institute of Environmental Health Sciences] [Grant Z01 ES025034].

  • dx.doi.org/10.1124/mol.113.085878.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 84 (2)
Molecular Pharmacology
Vol. 84, Issue 2
1 Aug 2013
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Research ArticleArticle

Indapamide, Hypertension, and EETs in Kidney

Fei Ma, Fan Lin, Chen Chen, Jennifer Cheng, Darryl C. Zeldin, Yan Wang and Dao Wen Wang
Molecular Pharmacology August 1, 2013, 84 (2) 286-295; DOI: https://doi.org/10.1124/mol.113.085878

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Research ArticleArticle

Indapamide, Hypertension, and EETs in Kidney

Fei Ma, Fan Lin, Chen Chen, Jennifer Cheng, Darryl C. Zeldin, Yan Wang and Dao Wen Wang
Molecular Pharmacology August 1, 2013, 84 (2) 286-295; DOI: https://doi.org/10.1124/mol.113.085878
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