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

Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) re gulates renal O-2 consumption. This mechanism is impaired in heart and kidn ey of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy -3-methylglutaryl-CoA reductase, increases eNOS expression in the endotheli um. Therefore, we studied whether simvastatin treatment could restore the r egulation of renal O-2 consumption by stimulators of NO production in dogs with CHF. Renal O-2 consumption was measured after stimulation of NO produc tion 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, b radykinin (10(-4) M), ramiprilat (10(-4) M), amlodipine (10(-5) M), and SNA P (10(-4) M) significantly reduced O2 consumption in the renal cortex (-31. 8 <plus/minus> 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%). Res ponses to bradykinin, ramiprilat, and amlodipine were significantly attenua ted in CHF but were partially or completely restored by simvastatin. Respon ses to SNAP were unaffected. These data demonstrate that treatment with sim vastatin improves renal production of NO in CHF, restoring the normal regul ation of renal O-2 consumption by NO.