CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats

• Published in: European journal of pharmacology Vol. 769; pp. 266 - 273
• Main Authors: Arai, Kiyoshi, Tsuruoka, Hiroyuki, Homma, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.12.2015
• Subjects: Aldosterone; Animals; Antihypertensive Agents - adverse effects; Antihypertensive Agents - pharmacology; Blood Pressure - drug effects; CS-3150; Cytoprotection - drug effects; Heart - drug effects; Heart - physiopathology; Hypertension - blood; Hypertension - pathology; Hypertension - physiopathology; Hypertension - prevention & control; Kidney - drug effects; Kidney - pathology; Male; Mineralocorticoid receptor antagonist; Mineralocorticoid Receptor Antagonists - adverse effects; Mineralocorticoid Receptor Antagonists - pharmacology; Natriuretic Peptide, Brain - blood; Organ Size - drug effects; Potassium - blood; Pyrroles - adverse effects; Pyrroles - pharmacology; Rats; Rats, Inbred Dahl; Receptors, Mineralocorticoid - metabolism; Renal injury; Safety; Salt-sensitive hypertension; Sulfones - adverse effects; Sulfones - pharmacology; Renal injury; Salt-sensitive hypertension; CS-3150; Aldosterone; Mineralocorticoid receptor antagonist
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.11.028

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.