The cardioprotective effect of a statin and cilostazol combination : Relationship to akt and endothelial nitric oxide synthase activation

• Published in: Cardiovascular drugs and therapy 2007-10, Vol.21 (5), p.321-330
• Main Authors: MANICKAVASAGAM, Saraswathy, YE, Yumei, YU LIN, PEREZ-POLO, Regino J, HUANG, Ming-He, LUI, Charles Y, HUGHES, Michael G, MCADOO, David J, URETSKY, Barry F, BIRNBAUM, Yochai
• Format: Article
• Language: English
• Subjects: Adenosine - metabolism; Administration, Oral; Animals; Atorvastatin Calcium; Biological and medical sciences; Body Weight; Cardiovascular system; Cyclic AMP-Dependent Protein Kinases - drug effects; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelium, Vascular - enzymology; Heptanoic Acids - administration & dosage; Immunoblotting; Male; Medical sciences; Miscellaneous; Myocardium - metabolism; Nitric Oxide Synthase Type III - drug effects; Nitric Oxide Synthase Type III - metabolism; Organ Culture Techniques; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Pyrroles - administration & dosage; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - prevention & control; Risk Factors; Tetrazoles - administration & dosage; Treatment Outcome
• ISSN: 0920-3206; 1573-7241
• DOI: 10.1007/s10557-007-6036-0

Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction. Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride. Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 +/- 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 +/- 7%). ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.