SAT-356 Differential Effects of Lipophilic and Hydrophilic Statins on Aldosterone Biosynthesis

Abstract

Statin therapy, which lowers LDL cholesterol, has a profound beneficial cardiovascular (CV) effect. However, some of statins’ CV benefits appear to be independent of decreases in LDL. We showed that statins reduce Aldosterone (ALDO) levels, a key hormone in cardiovascular function, and this effect was greater in lipophilic (e.g., Simvastatin) versus hydrophilic (e.g., Pravastatin) statins. The mechanism by which statins reduce ALDO production is unknown. Thus, the purpose of this study was to determine the effects of statins on the two key regulatory steps of ALDO biosynthesis. We hypothesized that Simvastatin, but not pravastatin, would inhibit the late, but not the early pathway of ALDO biosynthesis. Methods: Wistar rats (n=80, 30% female, 175-250 grams) were fed a 0.03% Na+ diet for 7 days with ad lib access to tap water. After euthanasia Zona Glomerulosa (ZG) cells were isolated from adrenal capsules. ZG cell incubates were studied for 1 hour under the following 8 conditions; Control, Angiotensin II (AngII, 10-7M), Fludrocortisone acetate (Fludro, 3µg), Simvastatin (SIMV, 100µM), Pravastatin (PRAV,100µM), Fludro+AngII, SIMV+AngII, and PRAV+AngII. To separately evaluate the early and late pathways we added Trilostane (TRIL), which inhibits 3β-OH-dehydrogenase enzyme, and a fixed dose of Corticosterone (CORT, 1µM) to the ZG cells. Under these conditions, Pregnenolone levels (PREG reflect early pathway activity and the ALDO/Corticosterone (ALDO/CORT) ratios reflect late pathway activity. Cells in each of the 8 conditions were incubated with and without TRIL (10µM) plus CORT, replicated in duplicate, and repeated 8 times. Results in ALDO and ALDO/CORT Ratio are presented as percent of maximum response (obtained after stimulation with AngII or in control conditions) while other data are in absolute measures, and analyzed by ANOVA and t-test. Results: In comparison to the maximum response caused by AngII (without TRIL); SIMV caused a reduction in aldosterone production while PRAV did not (72.1±26.6% vs 105±32.1%, p < 0.05). In the presence of TRIL, we observed that; 1) SIMV increased PREG in comparison to the control (696.63±98.15ng/dL vs 286.95±167.82ng/dL, p < 0.05) and to PRAV (696.63±98.15ng/dL vs. 291.57±290.39ng/dL, p < 0.05). However, 2) SIMV reduced the Aldo/Cort Ratio when compared to the Control, AngII, and Pravastatin conditions (53.3±5.3% vs 100%, 95.1±8.2%, 81.3±12.0%, p < 0.05 for SIMV vs all other conditions). Conclusions: These data show that SIMV and not PRAV decreases ALDO production. SIMV reduces ALDO by inhibiting the late pathway of ALDO biosynthesis. The SIMV-induced increase in PREG, is insufficient to overcome SIMV’s inhibition of the late pathway. These findings suggest that lipophilic statins have additional benefits (beyond HMG-CoA reductase inhibition) that influence the Renin-Angiotensin-Aldosterone System.