Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs

Statin drugs can upregulate endothelial nitric oxide (NO) synthase (eNOS) i n isolated endothelial cells independent of lipid-lowering effects. We inve stigated the effect of short-term simvastatin administration on coronary va scular 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).day(-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 coron ary vasodilation) and ACh-mediated coronary vasodilation were enhanced (P < 0.05). Response to endothelium-independent vasodilators, adenosine and nit roglycerin, was not potentiated. After simvastatin administration, plasma n itrate 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 (M (V) over dot O-2) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/ min (P < 0.05); NO-dependent regulation of M(V) over dot O-2 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 aorta s and coronary vascular endothelium. Short-term administration of simvastat in in dogs increases coronary endothelial NO production to enhance NO-depen dent coronary vasodilation and NO-mediated regulation of M(V) over dot O-2.