title: CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats.
abstract: The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury.
authors.affiliation: End-Organ Disease Laboratories (K.A., N.U., T.H.), Rare Disease and LCM Laboratories (Y.M.), and Venture Science Laboratories (H.T.), Daiichi Sankyo Co., Ltd., Tokyo, Japan arai.kiyoshi.ch@daiichisankyo.co.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Arai
authors.affiliation: End-Organ Disease Laboratories (K.A., N.U., T.H.), Rare Disease and LCM Laboratories (Y.M.), and Venture Science Laboratories (H.T.), Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: End-Organ Disease Laboratories (K.A., N.U., T.H.), Rare Disease and LCM Laboratories (Y.M.), and Venture Science Laboratories (H.T.), Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ubukata
authors.affiliation: End-Organ Disease Laboratories (K.A., N.U., T.H.), Rare Disease and LCM Laboratories (Y.M.), and Venture Science Laboratories (H.T.), Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuruoka
authors.affiliation: End-Organ Disease Laboratories (K.A., N.U., T.H.), Rare Disease and LCM Laboratories (Y.M.), and Venture Science Laboratories (H.T.), Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Homma
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D064791:Desoxycorticosterone Acetate / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D011758:Pyrroles; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D013450:Sulfones; D064791:Desoxycorticosterone Acetate; C000607547:esaxerenone