The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation.
BACKGROUND
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.


OBJECTIVE
CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction.


METHODS
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.


RESULTS
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%).


CONCLUSIONS
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.
Manickavasagam
Saraswathy
S
The Division of Cardiology, University of Texas Medical Branch, Galveston, TX 77555-0553, USA.
Ye
Yumei
Y
Lin
Yu
Y
Perez-Polo
Regino J
RJ
Huang
Ming-He
MH
Lui
Charles Y
CY
Hughes
Michael G
MG
McAdoo
David J
DJ
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D000241:Adenosine / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D001835:Body Weight; D000077407:Cilostazol; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000201:enzymology*; D006538:Heptanoic Acids / Q000008:administration & dosage*; D015151:Immunoblotting; D008297:Male; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D012307:Risk Factors; D013777:Tetrazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
D006538:Heptanoic Acids; D011758:Pyrroles; D013777:Tetrazoles; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine; D000077407:Cilostazol