Simvastatin upregulates coronary vascular endothelial nitric oxide production in conscious dogs.
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). 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 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 (NO(x)) levels increased from 5.22 +/- 1.2 to 7. 79 +/- 1.3 microM (P < 0.05); baseline and agonist-stimulated NO production in isolated coronary microvessels were augmented (P < 0.05); resting in vivo myocardial oxygen consumption (MVO(2)) decreased from 6.8 +/- 0.6 to 5.9 +/- 0.4 ml/min (P < 0.05); NO-dependent regulation of MVO(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 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 MVO(2).
Mital
S
S
Division of Pediatric Cardiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Zhang
X
X
Zhao
G
G
Bernstein
R D
RD
Smith
C J
CJ
Fulton
D L
DL
Sessa
W C
WC
Liao
J K
JK
Hintze
T H
TH
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D003243:Consciousness; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D008833:Microcirculation / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D019821:Simvastatin / Q000494:pharmacology*; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014702:Veratrine / Q000494:pharmacology
D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D009573:Nitrites; D012333:RNA, Messenger; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D014702:Veratrine; D005996:Nitroglycerin; D000241:Adenosine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester