Simvastatin reverses impaired regulation of renal oxygen consumption in congestive heart failure.
Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) regulates renal O(2) consumption. 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 O(2) consumption by stimulators of NO production in dogs with CHF. Renal O(2) consumption 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(-4) M), amlodipine (10(-5) M), and SNAP (10(-4) M) significantly reduced O(2) 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 O(2) consumption by NO.
Adler
S
S
Division of Nephrology, Department of Medicine, New York Medical College, Valhalla, New York 10532, USA. stephen@nymc.edu
Huang
H
H
Trochu
J N
JN
Xu
X
X
Gupta
S
S
Hintze
T H
TH
D017311:Amlodipine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D017311:Amlodipine; D009569:Nitric Oxide; C052549:ramiprilat; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D010396:Penicillamine; D017257:Ramipril; D001920:Bradykinin