Simvastatin upregulates coronary vascular endothelial nitric oxide production in
conscious dogs.
Mital, Seema, Xiaoping Zhang, Gong Zhao, Robert D. Bernstein, Carolyn J. Smith,
David L. Fulton, William C. Sessa, James K. Liao, and Thomas H. Hintze.
1Division of Pediatric Cardiology, Columbia University, College of Physicians and
Surgeons, New York, New York 10032; Departments of 2Physiology and 3Pathology,
New York Medical College, Valhalla, New York 10595; 4Department of Pharmacology,
Yale University School of Medicine, New Haven, Connecticut 06520; and 5Division of
Cardiology, Brigham and Women's Hospital, Boston, Massachusetts 02115
APStracts 7:0471H, 2000.
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«minus»1×day«minus»1) 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 muM (P < 0.05); baseline and agonist-stimulated NO production in isolated
coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen
consumption («mvo2») decreased from 6.8 ± 0.6 to 5.9 ± 0.4 ml/min (P < 0.05); NO-
dependent regulation of «mvo2» 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 «mvo2».
Received 22 September 1999; accepted in final form 5 June 2000
APS Manuscript Number H0914-9.
Article publication pending Am J Physiol Heart Circ Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 20 October 2000