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Articles in PresS, published online ahead of print April 11, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00826.2001
Submitted on September 20, 2001
Accepted on April 9, 2002
1 Cardiology Section, Southern Arizona Veterans Administration Health Care System and University of Arizona Sarver Heart Center, Tucson, AZ, USA
* To whom correspondence should be addressed. E-mail: mohgaballa{at}aol.com.
Congestive heart failure (CHF) after myocardial infarction (MI) is associated with diminished endothelial nitric oxide (NO)-mediated vasorelaxation. The 3-hydroxy-3 methylglutaryl CoA reductase inhibitors have been shown to modulate vascular tone, independent of their effects on lipid lowering. We hypothesized that simvastatin restores NO-dependent vasorelaxation with CHF. We found that incubation of normal rat aorta with (0.1) mM simvastatin for 24 hours enhanced acetylcholine (ACh)-mediated vasorelaxation (P<0.05). Moreover, simvastatin increased (P<0.05) endothelial nitric oxide synthase (eNOS) protein content by over 200% (82.0±14.0 vs 21.6±7.9%, II/µg). In cultured endothelial cells, simvastatin (10 and 20 µM) increased eNOS levels by 114.7±39.9 and 212.0±75.0% II/µg protein, respectively (both P<0.05), (n=8). Oral gavage with 20 mg/kg/day simvastatin for three weeks in the rat coronary artery ligation model of CHF, decreased (P<0.05) mean arterial pressure (105 ± 5.75 vs 96.5 ± 10.8mmHg) and left ventricular (LV) dP/dt (4288 ± 672, vs 4091 ± 1064 mmHg/sec, N=6). Simvastatin reduced (P<0.05) basal vasoconstriction and improved acetylcholine (ACh)-mediated vasorelaxation in CHF arterial rings. Inhibition of NO generation by NG-nitro-L-arginine methyl ester (L-NAME, 100 µM) abolished the ACh-induced vasorelaxation in all rats. In conclusion, chronic treatment of CHF with simvastatin restores endothelial NO-dependent dysfunction and upregulated eNOS protein content in arterial tissue.
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