Abstract 175: Aldosterone Synthase Inhibition Prolongs Survival And Ameliorates Cardiac And Renal Dysfunction In An Angiotensin II-dependent Hypertensive Rat Model
Angiotensin II (Ang II) contributes to end-organ damage directly and also indirectly via stimulating aldosterone production. The present study evaluated the contribution of aldosterone to mortality/moribundity and cardiorenal injury in an Ang II-dependent model of hypertension (“double-transgenic rat”, dTGR). Aldosterone synthesis was blocked by pharmacologic inhibition of CYP11B2 (aldosterone synthase, AS) with FAD286 (FAD). FAD (1–100 mg/kg/day in drinking water from 3 to 8 weeks of age; n=10/group) dose-dependently prolonged median and 20% survival in dTGRs (Figure⇓). The optimal survival dose of FAD (30 mg/kg/day) was further evaluated in 7-week-old dTGRs (n=8), which were compared with age-matched untreated dTGRs (n=8) and untreated Sprague-Dawley (SD) rats (n=6). FAD improved cardiac systolic and diastolic function (echocardiography), attenuated cardiac hypertrophy and renal dysfunction, lowered plasma aldosterone concentration and urinary aldosterone excretion, but did not alter arterial pressure (Table⇓). Our results indicate that selective disruption of aldosterone biosynthesis prolongs survival and ameliorates organ damage.
This observation supports the concept that aldosterone is an independent cardiorenal risk factor and that AS inhibition may be a useful therapeutic approach.