Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome

Chunhua Jin, Yejoo Jeon, Daniel T Kleven, Jennifer S. Pollock, John Jason White, David M. Pollock

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Experiments determined whether the combination of endothelin A (ETA) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl saltsensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone. All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-2'-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1+ cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ETAantagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.

Original languageEnglish (US)
Pages (from-to)467-473
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number2
DOIs
StatePublished - Nov 1 2014

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Chlorthalidone
Endothelins
Kidney
Wounds and Injuries
Drinking Water
Arterial Pressure
Fats
Inbred Dahl Rats
Receptors, Tumor Necrosis Factor, Type II
Sodium Chloride Symporter Inhibitors
Therapeutics
Podocytes
Telemetry
Proteinuria
Diuretics
Antihypertensive Agents
Rodentia
Salts
Cell Count
Macrophages

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. / Jin, Chunhua; Jeon, Yejoo; Kleven, Daniel T; Pollock, Jennifer S.; White, John Jason; Pollock, David M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 351, No. 2, 01.11.2014, p. 467-473.

Research output: Contribution to journalArticle

Jin, Chunhua ; Jeon, Yejoo ; Kleven, Daniel T ; Pollock, Jennifer S. ; White, John Jason ; Pollock, David M. / Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. In: Journal of Pharmacology and Experimental Therapeutics. 2014 ; Vol. 351, No. 2. pp. 467-473.
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