title: CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats.
abstract: The present study was designed to evaluate the antihypertensive and cardiorenal protective effects of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, in Dahl salt-sensitive hypertensive rats (DS rats), and to compare the effects with spironolactone and eplerenone. DS rats were fed a control diet (0.3% NaCl) or high salt diet (8% NaCl) from 7 weeks of age. CS-3150 (0.25-2mg/kg), spironolactone (10-100mg/kg) or eplerenone (10-100mg/kg) were orally administered once a day to DS rats fed a high salt diet for 7 weeks. The high salt diet significantly increased systolic blood pressure, which was prevented by treatment with CS-3150 in a dose-dependent manner with no hyperkalemia (>5.5mEq/L). The antihypertensive effect of CS-3150 (0.5mg/kg) was equivalent to that of spironolactone (100mg/kg) and eplerenone (100mg/kg). CS-3150 also suppressed proteinuria and renal hypertrophy induced by the high salt diet. Histopathological examination of kidneys showed that CS-3150 markedly ameliorated glomerulosclerosis, tubular injury and tubulointerstitial fibrosis. In addition, CS-3150 inhibited left ventricular hypertrophy and elevation of plasma brain natriuretic peptide level. In contrast, the cardiorenal protective effects of spironolactone or eplerenone were partial, and the dose-dependency was not clear, especially in eplerenone-treated rats. These results indicate that chronic treatment with CS-3150 exerts antihypertensive and cardiorenal protective effects in a DS hypertensive rat model, and its potency is much superior to that of spironolactone or eplerenone. Thus, CS-3150 could be a promising agent for the treatment of hypertension and cardiorenal disorders.
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: arai.kiyoshi.ch@daiichisankyo.co.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Arai
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuruoka
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Homma
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D011188:Potassium / Q000097:blood; D011758:Pyrroles / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012449:Safety; D013450:Sulfones / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D000451:Mineralocorticoid Receptor Antagonists; D011758:Pyrroles; D018161:Receptors, Mineralocorticoid; D013450:Sulfones; D020097:Natriuretic Peptide, Brain; C000607547:esaxerenone; D011188:Potassium
keywords: Aldosterone; CS-3150; Mineralocorticoid receptor antagonist; Renal injury; Salt-sensitive hypertension