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Am J Physiol Renal Physiol (July 12, 2001). doi:10.1152/ajprenal.0138.2001
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Articles in PresS, published online ahead of print July 12, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.0138.2001
Submitted on May 4, 2001
Accepted on June 25, 2001

Simvastatin Reverses Impaired Regulation of Renal Oxygen Consumption in Congestive Heart Failure

Stephen Adler1*, Harer Huang1, Jean Noel Trochu2, Xiaobin Xu2, Shabnam Gupta1, and Thomas H Hintze2

1 Medicine, New York Medical College, Valhalla, NY, USA
2 Physiology, New York Medical College, Valhalla, NY, USA

* To whom correspondence should be addressed. E-mail: stephen{at}nymc.edu.

Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal oxygen (O2) consumption. This mechanism is impaired in heart and kidney of dogs with heart failure (CHF). Simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A 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 O2 consumption was measured following 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 days vs 29±1.2 days; P<0.01). In normal dogs, bradykinin (10-4 M), ramiprilat (10-4M), amlodipine (10-5M) and SNAP (10-4M) 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.






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