© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts
aLaboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, "G. d'Annunzio" University of Chieti, Ospedale S. Camillo de Lellis, Via Forlanini, 50, 66100 Chieti, Italy
bDepartment of Biomorphology, Biology Section, "G. d'Annunzio" University of Chieti, Chieti, Italy
* Corresponding author. Tel.: +39-0871-41512; fax: +39-0871-402817 rdecater{at}ifc.cnr.it
Objective: We tested the hypothesis of beneficial effects of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin in a model of ischemia–reperfusion, and investigated potential mechanisms. Methods: Isolated working rat hearts were subjected to 15 min global ischemia and 22–180 min reperfusion in the presence or absence of simvastatin (10–100 µM). We evaluated creatinephosphokinase and nitrite levels in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcribed polymerase chain reaction and Western blotting) in the presence or absence of the transcriptional inhibitor actinomycin-D. Results: Simvastatin (25 µM) significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. Protection became less evident at 50 µM and reverted to increased damage at 100 µM. At 25 µM, simvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, probably due to a post-transcriptional regulation since unaltered by animal pretreatment with actinomycin D. Simvastatin also significantly decreased iNOS mRNA and protein, as well as nitrite production after ischemia–reperfusion. The addition of the NOS inhibitor N
-nitro-L-arginine methylester (L-NAME, 30 µM) to 25 µM simvastatin-treated hearts significantly reduced cardioprotection against ischemia–reperfusion. Conclusions: In this model, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant simvastatin concentration reduces ischemia–reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by cholesterol-independent, NO-dependent mechanisms.
KEYWORDS Endothelial function; Nitric oxide; Ischemia; Myocytes; Reperfusion; Statins
1 Present address: Department of Internal Medicine, University of Genoa, Genoa, Italy.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Gao, W. Wang, and I. H. Zucker Simvastatin Inhibits Central Sympathetic Outflow in Heart Failure by a Nitric-Oxide Synthase Mechanism J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 278 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Kocsis, J. Pipis, V. Fekete, A. Kovacs-Simon, L. Odendaal, E. Molnar, Z. Giricz, T. Janaky, J. van Rooyen, T. Csont, et al. Lovastatin interferes with the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2406 - H2409. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Di Nardo Di Maio, Z. Lohinai, C. D'Arcangelo, P. E. De Fazio, L. Speranza, M.A. De Lutiis, A. Patruno, A. Grilli, and M. Felaco Nitric Oxide Synthase in Healthy and Inflamed Human Dental Pulp Journal of Dental Research, April 1, 2004; 83(4): 312 - 316. [Abstract] [Full Text] [PDF]
|
|