title: Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome.
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 salt-sensitive 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 ETA antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Jin
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
authors.forename: Yejoo
authors.initials: Y
authors.lastname: Jeon
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Kleven
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia.
authors.forename: John J
authors.initials: JJ
authors.lastname: White
authors.affiliation: Cardio-Renal Physiology and Medicine (C.J., J.S.P., D.M.P.), University of Alabama at Birmingham, Birmingham, Alabama; and Departments of Medicine (Y.J., J.J.W.) and Pathology (D.T.K.), Georgia Regents University, Augusta, Georgia dpollock@uab.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Pollock
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D062186:Arterial Pressure / Q000187:drug effects; D000077868:Atrasentan; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002752:Chlorthalidone / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000009:adverse effects
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000959:Antihypertensive Agents; D000077868:Atrasentan; D015815:Cell Adhesion Molecules; D002752:Chlorthalidone; D003849:Deoxyguanosine; D004232:Diuretics; D004338:Drug Combinations; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D008565:Membrane Proteins; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017673:Sodium Chloride, Dietary; C110936:Havcr1 protein, rat; C113267:nephrin