Antihypertensive and cardiorenal protective effects of SM-368229, a novel mineralocorticoid receptor antagonist, in aldosterone/salt-treated rats.
The purpose of this study was to evaluate the effects of SM-368229, a novel mineralocorticoid receptor (MR) antagonist, on the blood pressure and cardiorenal injury markers in aldosterone/salt-treated hypertensive rats, in comparison to those of spironolactone (SPI). Uninephrectomized rats, given 1% NaCl to drink, were infused with aldosterone (0.75 μg/h, s.c.). In experiment 1, SM-368229 (10, 30 mg/kg) or SPI (100 mg/kg) were administered for 14 days immediately after aldosterone/salt loading. In experiment 2, SM-368229 (10 mg/kg) or SPI (100 mg/kg) were administered for 10 days after 10 days of aldosterone/salt loading. In both experiments, SM-368229 prevented the increase in systolic blood pressure, heart/kidney weights, and urinary protein/N-acetyl-β-D- glucosaminidase excretion caused by aldosterone infusion. In real-time polymerase chain reaction analysis, SM-368229 abolished aldosterone-induced gene expression levels for inflammatory, fibrosis and oxidative stress markers in hearts and kidneys. The antihypertensive effect of SM-368229 (30 mg/kg) was superior to that of SPI, and the antihypertensive and cardiorenal protective effects of SM-368229 (10 mg/kg) were similar to those of SPI (100 mg/kg) in both experiments. These results clearly demonstrated that SM-368229 strongly attenuated the progression of hypertension and exerted cardiorenal protection in aldosterone/salt-treated hypertensive rats.
Pharmacology, Dainippon Sumitomo Pharma Co., Osaka, Japan.
Tetsuro
T
Nariai
Katsuya
K
Fujita
Masaya
M
Mori
Seiji
S
Katayama
Seiji
S
Hori
Kazuki
K
Matsui
D000118:Acetylglucosaminidase / Q000652:urine; D000450:Aldosterone; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000652:urine; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D048588:Benzoxazines; D015415:Biomarkers; D000451:Mineralocorticoid Receptor Antagonists; C561881:N-4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylthiophene-2-sulfonamide; D013449:Sulfonamides; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; D000118:Acetylglucosaminidase