Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin.
OBJECTIVE
Both ATV and SL reduce myocardial infarct size (IS) by enhancing expression and activity of NOS isoforms. We investigated whether atorvastatin (ATV) and sildenafil (SL) have synergistic effects on myocardial infarct size (IS) reduction and enhancing nitric oxide synthase (NOS) expression.


METHODS
Rats were randomized to nine groups: ATV-1 (1 mg/kg/d); ATV-10 (10 mg/kg/d); SL-0.7 (0.7 mg/kg); SL-1 (1 mg/kg); ATV-1 + SL-0.7; water alone (controls); 1400W (iNOS inhibitor; 1 mg/kg); ATV-10 + 1400W; and ATV-1 + SL-0.7 + 1400W. ATV was administered orally for 3 days. SL was administered intraperitoneally 18 h before surgery and 1400W intravenously 15 min before surgery. Rats either underwent 30 min ischemia-4 h reperfusion or the hearts were explanted for immunoblotting and enzyme activity tests without being exposed to ischemia.


RESULTS
IS (% risk area, mean +/- SEM) was smaller in the ATV-10 (13 +/- 1%), SL-1 (11 +/- 2%), SL-0.7 (18 +/- 2%) and ATV-1 + SL-0.7 (9 +/- 1%) groups as compared with controls (34 +/- 3%; P < 0.001), whereas ATV-1 had no effect (29 +/- 2%). ATV-1 + SL-0.7 (9 +/- 1%) reduced IS more than SL-0.7 alone (p = 0.012). 1400W abrogated the protective effect of ATV-10 (35 +/- 3%) and ATV-1 + SL-0.7 (34 +/- 1%). SL-0.7 and ATV-10 increased phosphorylated endothelial (P-eNOS; 210 +/- 2.5% and 220 +/- 8%) and inducible (iNOS; 151 +/- 1% and 154 +/- 1%) NOS expression, whereas ATV-1 did not. These changes were significantly enhanced by ATV-1 + SL-0.7 (P-eNOS, 256 +/- 2%, iNOS 195 +/- 1%). SL-1 increased P-eNOS (311 +/- 22%) and iNOS (185 +/- 1%) concentrations.


CONCLUSIONS
Combining low-dose ATV with SL augments the IS limiting effects through enhanced P-eNOS and iNOS expression.
Rosanio
Salvatore
S
The Department of Internal Medicine, Division of Cardiology, The University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA.
Ye
Yumei
Y
Atar
Shaul
S
Rahman
Atiar M
AM
Freeberg
Sheldon Y
SY
Huang
Ming-He
MH
Uretsky
Barry F
BF
Birnbaum
Yochai
Y
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D001596:Benzylamines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D015854:Up-Regulation
D000578:Amidines; D001596:Benzylamines; D002316:Cardiotonic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011758:Pyrroles; D013450:Sulfones; D000069059:Atorvastatin; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat