Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin

Salvatore Rosanio, Yumei Ye, Shaul Atar, Atiar M. Rahman, Sheldon Y. Freeberg, Ming He Huang, Barry F. Uretsky, Yochai Birnbaum

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Method: 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.

Original languageEnglish (US)
Pages (from-to)27-36
Number of pages10
JournalCardiovascular Drugs and Therapy
Volume20
Issue number1
DOIs
StatePublished - Feb 2006

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Reperfusion Injury
Nitric Oxide Synthase
Atorvastatin Calcium
Sildenafil Citrate
Ischemia
Myocardial Infarction
Immunoblotting

Keywords

  • Atorvastatin
  • Infarct size
  • Ischemia-reperfusion injury
  • Nitric oxide synthase
  • Sildenafil

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin. / Rosanio, Salvatore; Ye, Yumei; Atar, Shaul; Rahman, Atiar M.; Freeberg, Sheldon Y.; Huang, Ming He; Uretsky, Barry F.; Birnbaum, Yochai.

In: Cardiovascular Drugs and Therapy, Vol. 20, No. 1, 02.2006, p. 27-36.

Research output: Contribution to journalArticle

Rosanio, Salvatore ; Ye, Yumei ; Atar, Shaul ; Rahman, Atiar M. ; Freeberg, Sheldon Y. ; Huang, Ming He ; Uretsky, Barry F. ; Birnbaum, Yochai. / Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin. In: Cardiovascular Drugs and Therapy. 2006 ; Vol. 20, No. 1. pp. 27-36.
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title = "Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin",
abstract = "Purpose: 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. Method: 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.",
keywords = "Atorvastatin, Infarct size, Ischemia-reperfusion injury, Nitric oxide synthase, Sildenafil",
author = "Salvatore Rosanio and Yumei Ye and Shaul Atar and Rahman, {Atiar M.} and Freeberg, {Sheldon Y.} and Huang, {Ming He} and Uretsky, {Barry F.} and Yochai Birnbaum",
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T1 - Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin

AU - Rosanio, Salvatore

AU - Ye, Yumei

AU - Atar, Shaul

AU - Rahman, Atiar M.

AU - Freeberg, Sheldon Y.

AU - Huang, Ming He

AU - Uretsky, Barry F.

AU - Birnbaum, Yochai

PY - 2006/2

Y1 - 2006/2

N2 - Purpose: 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. Method: 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.

AB - Purpose: 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. Method: 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.

KW - Atorvastatin

KW - Infarct size

KW - Ischemia-reperfusion injury

KW - Nitric oxide synthase

KW - Sildenafil

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