The
mineralocorticoid receptor (MR) antagonists
PF-03882845 and
eplerenone were evaluated for renal protection against
aldosterone-mediated renal disease in uninephrectomized Sprague-Dawley (SD) rats maintained on a high
salt diet and receiving
aldosterone by osmotic mini-pump for 27 days. Serum K(+) and the urinary
albumin to
creatinine ratio (UACR) were assessed following 14 and 27 days of treatment.
Aldosterone induced renal
fibrosis as evidenced by increases in UACR,
collagen IV staining in kidney cortex, and expression of pro-fibrotic genes relative to
sham-operated controls not receiving
aldosterone. While both
PF-03882845 and
eplerenone elevated serum K(+) levels with similar potencies,
PF-03882845 was more potent than
eplerenone in suppressing the rise in UACR.
PF-03882845 prevented the increase in
collagen IV staining at 5, 15 and 50 mg/kg BID while
eplerenone was effective only at the highest dose tested (450 mg/kg BID). All doses of
PF-03882845 suppressed
aldosterone-induced increases in
collagen IV,
transforming growth factor-β 1 (Tgf-β 1),
interleukin-6 (Il-6), intermolecular adhesion molecule-1 (Icam-1) and
osteopontin gene expression in kidney while
eplerenone was only effective at the highest dose. The therapeutic index (TI), calculated as the ratio of the EC50 for increasing serum K(+) to the EC50 for UACR lowering, was 83.8 for
PF-03882845 and 1.47 for
eplerenone. Thus, the TI of
PF-03882845 against
hyperkalemia was 57-fold superior to that of
eplerenone indicating that
PF-03882845 may present significantly less risk for
hyperkalemia compared to
eplerenone.