title: Endothelin A receptor antagonist, atrasentan, attenuates renal and cardiac dysfunction in Dahl salt-hypertensive rats in a blood pressure independent manner.
abstract: Proteinuria is a hallmark of chronic kidney disease (CKD) and cardiovascular disease (CVD), and a good predictor of clinical outcome. Selective endothelin A (ETA) receptor antagonist used with renin-angiotensin system (RAS) inhibitors prevents development of proteinuria in CKD. However, whether the improvement in proteinuria would have beneficial effects on CVD, independent of RAS inhibition, is not well understood. In this study, we investigated whether atrasentan, an ETA receptor antagonist, has renal and cardiovascular effects independent of RAS inhibition. Male Dahl salt sensitive (DSS) rats, at six weeks of age, received water with or without different doses of atrasentan and/or enalapril under high salt (HS) diet or normal diet (ND) for 6 weeks. At the end of 12th week, atrasentan at a moderate dose significantly attenuated proteinuria and serum creatinine without reducing mean arterial pressure (MAP), thereby preventing cardiac hypertrophy and improving cardiac function. ACE inhibitor enalapril at a dose that did not significantly lowered BP, attenuated cardiac hypertrophy while moderately improving cardiac function without reducing proteinuria and serum creatinine level. Nonetheless, combined therapy of atrasentan and enalapril that does not altering BP exerted additional cardioprotective effect. Based on these findings, we conclude that BP independent monotherapy of ETA receptor antagonist attenuates the progression of CKD and significantly mitigates CVD independent of RAS inhibition.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America; Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Samad
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ui Kyoung
authors.initials: UK
authors.lastname: Kim
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Kang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America; Department of BIN Fusion Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
mesh_terms: D000818:Animals; D000077868:Atrasentan; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D015870:Gene Expression; D006331:Heart Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D006984:Hypertrophy; D007677:Kidney Function Tests; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010656:Phenylephrine / Q000009:adverse effects / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
chemical_list: D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D000077868:Atrasentan