Simvastatin reverses impaired regulation of renal oxygen consumption in congestive heart failure

Abstract

First published July 12, 2001; 10.1152/ajprenal.00138.2001.—Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O2consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, increases eNOS expression in the endothelium. Therefore, we studied whether simvastatin treatment could restore the regulation of renal O2 consumption by stimulators of NO production in dogs with CHF. Renal O2consumption was measured after stimulation of NO production with bradykinin, ramiprilat, or amlodipine or the NO donor S-nitroso- N-acetylpenicillamine (SNAP). Simvastatin delayed the time to euthanasia in dogs with CHF (35 ± 1.0 vs. 29 ± 1.2 days; P < 0.01). In normal dogs, bradykinin (10−4 M), ramiprilat (10−4M), amlodipine (10−5 M), and SNAP (10−4 M) significantly reduced O2 consumption in the renal cortex (−31.8 ± 0.9, −30.3 ± 1.1, −30.1 ± 2.0, −46.9 ± 1.0%) and renal medulla (−29.7 ± 2.1, −33.0 ± 2.7, −30.8 ± 2.2, −46.8 ± 1.1%). Responses to bradykinin, ramiprilat, and amlodipine were significantly attenuated in CHF but were partially or completely restored by simvastatin. Responses to SNAP were unaffected. These data demonstrate that treatment with simvastatin improves renal production of NO in CHF, restoring the normal regulation of renal O2 consumption by NO.