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1 Division of Pediatric Cardiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032; Departments of 2 Physiology and 3 Pathology, New York Medical College, Valhalla, New York 10595; 4 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520; and 5 Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts 02115
Statin drugs can upregulate
endothelial nitric oxide (NO) synthase (eNOS) in isolated endothelial
cells independent of lipid-lowering effects. We investigated the effect
of short-term simvastatin administration on coronary vascular eNOS and
NO production in conscious dogs and canine tissues. Mongrel dogs were
instrumented under general anesthesia to measure coronary blood flow
(CBF). Simvastatin (20 mg · kg
1 · day1) was
administered orally for 2 wk; afterward, resting CBF was found to be
higher compared with control (P < 0.05) and
veratrine- (activator of reflex cholinergic NO-dependent coronary
vasodilation) and ACh-mediated coronary vasodilation were enhanced
(P < 0.05). Response to endothelium-independent
vasodilators, adenosine and nitroglycerin, was not potentiated. After
simvastatin administration, plasma nitrate and nitrite
(NOx) levels increased from 5.22 ± 1.2 to 7.79 ± 1.3 µM (P < 0.05); baseline and
agonist-stimulated NO production in isolated coronary microvessels were
augmented (P < 0.05); resting in vivo myocardial
oxygen consumption (M
O2) decreased from
6.8 ± 0.6 to 5.9 ± 0.4 ml/min (P < 0.05);
NO-dependent regulation of MO2 in
response to NO agonists was augmented in isolated myocardial segments
(P < 0.05); and eNOS protein increased 29% and eNOS
mRNA decreased 50% in aortas and coronary vascular endothelium.
Short-term administration of simvastatin in dogs increases coronary
endothelial NO production to enhance NO-dependent coronary vasodilation
and NO-mediated regulation of MO2.
statins; coronary vasodilation; myocardial oxygen consumption
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