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Am J Physiol Heart Circ Physiol 293: H813-H818, 2007. First published April 6, 2007; doi:10.1152/ajpheart.00210.2007
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Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination

Yumei Ye,1 Yu Lin,1 Regino Perez-Polo,2 Ming-He Huang,1 Michael G. Hughes,3 David J. McAdoo,3 Saraswathy Manickavasagam,1 Barry F. Uretsky,1 and Yochai Birnbaum1,2

1Division of Cardiology and Departments of 2Biochemistry and Molecular Biology and 3Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas

Submitted 16 February 2007 ; accepted in final form 3 April 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Atorvastatin (ATV) limits infarct size (IS) by activating Akt and ecto-5-nucleotidase, which generates adenosine. Activated Akt and adenosine activate endothelial nitric oxide synthase (eNOS). When given orally, high doses (10 mg/kg) are needed to achieve full protection. We determined whether dipyridamole (DIP), by preventing the reuptake of adenosine, has a synergistic effect with ATV in reducing myocardial IS. In this study, rats received 3-days of the following: water, ATV (2 mg·kg–1·day–1), DIP (6 mg·kg–1·day–1), or ATV + DIP. In addition, rats received 3-days of the following: aminophylline (Ami; 10 mg·kg–1·day–1) or Ami + ATV + DIP. Rats underwent 30 min of myocardial ischemia followed by 4 h of reperfusion (IS protocol), or hearts were explanted for immunoblotting. As a result, IS in the controls was 34.0 ± 2.8% of the area at risk. ATV (33.1 ± 2.1%) and DIP (30.5 ± 1.5%) did not affect IS, whereas ATV + DIP reduced IS (12.2 ± 0.5%; P < 0.001 vs. each of the other groups). There was no difference in IS between the Ami alone (48.1 ± 0.8%) and the Ami + ATV + DIP (45.8 ± 2.9%) group (P = 0.422), suggesting that Ami completely blocked the protective effect. Myocardial adenosine level in the controls was 30.6 ± 3.6 pg/µl. ATV (51.0 ± 4.9 pg/µl) and DIP (51.5 ± 6.8 pg/µl) caused a small increase in adenosine levels, whereas ATV + DIP caused a greater increase in adenosine levels (66.4 ± 3.1 pg/µl). ATV and DIP alone did not affect myocardial Ser473 phosphorylated-Akt and Ser1177 phosphorylated-eNOS levels, whereas ATV + DIP significantly increased them. In conclusion, low-dose ATV and DIP had synergistic effects in reducing myocardial IS and activation of Akt and eNOS. This combination may have a potential benefit in augmenting the eNOS-mediated pleiotropic effects of statins.

adenosine; Akt; infarct size; nitric oxide synthase

SEVERAL EXPERIMENTAL STUDIES have shown that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), administered either before myocardial ischemia (3, 6, 10, 23, 24, 34–36, 43, 44, 48, 50–53) or immediately after reperfusion (5, 12, 50), reduce myocardial infarct size (IS). It has been shown that statins activate phosphatidylinositol-3-kinase (5, 12, 19, 50) with subsequent activation of both Akt (5, 11, 12, 18, 19, 27, 30, 35, 38, 50, 53) and ecto-5-nucleotidase, which generates adenosine (9, 35, 46). Both Akt (5, 18, 27) and adenosine (15, 29, 39, 40, 47) activate endothelial nitric oxide synthase (eNOS). eNOS activation is essential for this protective effect, since nonspecific nitric oxide synthase inhibitors blunt the IS-limiting effect of statins (6, 51) and since statins do not reduce IS in eNOS–/– mice (5, 23, 52). Inhibition of the adenosine receptors, on the other hand, also abrogates the IS-limiting effects of statins (28, 35). We recently showed that adenosine is needed for phosphorylation of Akt by 3-phosphoinositide-dependent kinase-1 and subsequent phosphorylation of eNOS (54).

Dipyridamole (DIP) blocks the cellular reuptake of adenosine, thus increasing interstitial adenosine concentrations (17, 37). When administered intravenously at high doses (i.e., 0.56 mg/kg over 4 min), DIP may exacerbate myocardial ischemia by diverting blood flow from the diseased vessels with fixed narrowings to healthier branches undergoing vasodilatation (1). However, at low doses (300–400 mg/day) oral DIP has minimal hemodynamic and significant antiplatelet effects and has been used in the clinical setting to prevent cardiovascular and cerebrovascular events (37).

DIP alone has no effect on myocardial IS, but it does augment the effects of ischemic preconditioning (22, 31, 42, 45) since adenosine is one of the triggers of preconditioning (16).

We asked whether DIP and atorvastatin (ATV) have synergistic effects on augmenting myocardial protection by increasing the myocardial adenosine levels.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal care. All animals received humane care in compliance with The Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health (Publication No. 85-23, Revised 1996). The protocol was approved by the University of Texas Medical Branch Institutional Animal Care and Use Committee. Experiments were conducted on male Sprague-Dawley rats.

Materials. We used crushed tablets of ATV (Lipitor, Pfizer). DIP (an adenosine reuptake inhibitor) was purchased from Sigma (St. Louis, MO) and aminophylline (Ami, a nonselective adenosine receptor inhibitor) from American Regent (Shirley, NY). Monoclonal anti-eNOS antibodies were purchased from BD Bioscience (San Jose, CA) and a monoclonal anti-beta-actin antibody from Sigma (St. Louis, MO). Anti-Akt antibodies, anti-Ser473 phosphorylated (p)-Akt antibodies, and anti-Ser1177 p-eNOS antibodies were purchased from Cell Signaling (Beverly, MA).

Treatment. In protocol 1, rats received a 3-day pretreatment with water alone, ATV (2 mg·kg–1·day–1), DIP (6 mg·kg–1·day–1), or ATV + DIP. ATV was administered by oral gavage once daily. DIP was added to the drinking water at a concentration of 0.6 mg/ml. On the fourth day, rats underwent coronary artery ligation for 30 min followed by 4 h of reperfusion (IS protocol), or hearts were harvested under deep anesthesia for immunoblotting and a determination of tissue adenosine levels.

In protocol 2, rats received a 3-day pretreatment with Ami (10 mg·kg–1·day–1) or Ami + ATV (2 mg·kg–1·day–1) + DIP (6 mg·kg–1·day–1). Ami was added to the drinking water at a concentration of 1 mg/ml. On the fourth day, rats underwent coronary artery ligation for 30 min followed by 4 h of reperfusion (IS protocol), or hearts were harvested under deep anesthesia for immunoblotting.

IS surgical protocol. The rat model of myocardial ischemia-reperfusion injury has been described in detail (3, 6, 10, 53). On the fourth day, rats were anesthetized with an intraperitoneal injection of ketamine (60 mg/kg) and xylazine (6 mg/kg), intubated, and ventilated (fractional inspired O2 = 30%). The rectal temperature was monitored, and body temperature was maintained between 36.7° and 37.3°C throughout the experiment. The left carotid artery was cannulated. The chest was opened, and the left coronary artery was encircled with a suture and ligated for 30 min. Isoflurane (1–2.5% titrated to effect) was added after the beginning of ischemia to maintain anesthesia. After 30 min of ischemia, the snare was released, and myocardial reperfusion was verified by a change in the color of the myocardium. In the IS protocol, subcutaneous 0.1 mg/kg buprenorphine was administered, the chest was closed, and the rats were recovered from anesthesia. Four hours after reperfusion, the rats were reanesthetized, the coronary artery was reoccluded, 1.5 ml of Evans blue dye 3% was injected into the right ventricle, and the rats were euthanized under deep anesthesia. Heart rate and mean blood pressure were noted immediately before coronary artery occlusion, at 25 min of ischemia, and at 20 min of reperfusion.

The prespecified exclusion criteria were a lack of signs of ischemia during coronary artery ligation, lack of signs of reperfusion after release of the snare, prolonged ventricular arrhythmia with hypotension, and area at risk (AR) ≤ 10% of the left ventricular (LV) weight.

Determination of AR and IS. Hearts were excised, and the LV was sliced transversely into six sections. Slices were incubated for 10 min at 37°C in 1% buffered (pH = 7.4) 2,3,5-triphenyltetrazolium chloride, fixed in a 10% formaldehyde, and photographed to identify the AR (uncolored by the blue dye), the IS (unstained by 2,3,5-triphenyltetrazolium chloride), and the nonischemic zones (colored by blue dye). The areas of AR and IS in each slice were determined by planimetry, converted into percentages of the whole for each slice, and multiplied by the weight of the slice, and the results were summed to obtain the weight of the myocardial AR and IS (3, 6, 10, 53).

Myocardial adenosine levels. Adenosine was analyzed by high-performance liquid chromatography (HPLC) according to the procedure of Wojcik and Neff (49). Myocardial samples were homogenized with ~10 volumes of 0.25 M ZnSO4. The protein concentration was determined by Lowry assay. Ten volumes of 0.25 M BaOH2 were added, and samples were centrifuged at 30,000 g for 10 min. Supernatants were then transferred to a conical tube, and 5 µl chloroacetaldehyde were added to 20 µl of supernatant. Tubes were capped, mixed, and submerged in boiling water for 10 min. The samples were analyzed by HPLC using a Waters C18 reversed-phase 150 mm x 4.6 mm column. The mobile phase was a 50 mM acetate buffer (pH 4.5) and 6.5% aqueous acetonitrile (vol/vol) with 2 mM sodium octyl sulfonate dissolved in it. The flow rate was 1.1 ml/min. The excitation monochromator was set to a wavelength of 270 nm, and the cutoff wavelength of the emission filter was 389 nm.

Immunoblotting. Myocardial samples from the LV wall were homogenized in RIPA lysis buffer (Santa Cruz Biotechnology) and centrifuged at 14,000 rpm for 15 min at 4°C. The supernatant was collected, and the total protein concentration was determined using the Lowry protein assay. Protein samples with loading buffer were run in 4–20% Tris·HCl Ready Gel at a 100 V for 2 h until the desired molecular weight bands were separated. After electrophoresis, the gel was equilibrated in transfer buffer (25 mM Tris, 193 mM glycine, 0.1% SDS, and 10% methanol), and the proteins were transferred to a nitrocellulose membrane. Protein signals were quantified by an image-scanning densitometer, and the strength of each protein signal was normalized to the corresponding beta-actin stain signal. Data are expressed as a ratio between the protein and the corresponding beta-actin signal density.

Statistical analyses. Data are expressed as means ± SE. Comparisons among the groups were performed by one-way ANOVA with Dunnett's correction for multiple comparisons (SPSS, version 14.0). The differences in heart rate and mean blood pressure were compared using two-way repeated-measures ANOVA with Holm-Sidak multiple comparison procedures. Values of P < 0.05 were considered statistically significant.

The authors had full access to the data and take responsibility for its integrity. All authors have read and approved this study.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Infarct size. In protocol 1, a total of 33 rats were included. Two rats died during coronary artery occlusion (one in the control group and one in the ATV + DIP group). Body weight, LV weight, and AR were comparable among groups (Table 1). IS, expressed either as a percentage of the LV (Table 1) or as a percentage of the AR (IS) (Fig. 1), was significantly smaller in the ATV + DIP group (12.2 ± 0.5% of the AR) compared with the other three groups. IS in the control group was 34.0 ± 2.8% of the AR. ATV at 2 mg·kg–1·day–1 alone (33.1 ± 2.1% of the AR) and DIP alone at 6 mg·kg–1·day–1 (30.5 ± 1.5% of the AR) did not affect IS. There was no treatment effect on heart rate (P = 0.224) or mean blood pressure (P = 0.062), although there was a significant time effect, i.e., significant differences between preocclusion, occlusion, and reperfusion (P < 0.001 for both heart rate and blood pressure).


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  		Table 1. Protocol 1: body weight, left ventricular weight, area at risk, and infarct size of rats

 

Figure 1
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  		Fig. 1. Protocol 1: infarct size [IS; as a % of the area at risk (AR)] in rats. Overall, there were significant differences among groups (P < 0.001). Atorvastatin (ATV) alone and dipyridamole (DIP) alone did not affect IS. In contrast, IS in the combination group was significantly smaller (P < 0.001) than IS in the other 3 groups.

 
In protocol 2, a total of 12 rats was included. One rat treated with ATV + DIP + Ami died during the reperfusion period. Body weight (251 ± 1 vs. 251 ± 1 g; P = 0.817), LV weight (1,172 ± 16 vs. 1,246 ± 80 mg; P = 0.345), and AR (35.1 ± 0.4% vs. 35.8 ± 1.6% of the LV; P = 0.662) were comparable between the Ami and the ATV + DIP + Ami groups. IS was comparable between the groups (16.9 ± 0.4% vs. 16.4 ± 1.1% of the LV; P = 0.623). Figure 2 shows IS (as a percentage of AR) in the two groups. There were no significant differences between the two groups in heart rate (P = 0.108) or mean blood pressure (P = 0.5), although there was a significant time effect, i.e., significant differences between preocclusion, occlusion, and reperfusion (P < 0.001 for both heart rate and blood pressure).


Figure 2
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  		Fig. 2. Protocol 2: IS (as a % of the AR) in rats. ATV + DIP did not limit IS in rats treated with aminophylline (Ami) (P = 0.422).

 
Myocardial adenosine levels. Myocardial adenosine levels in the control group were 30.6 ± 3.6 pg/µl. ATV alone caused a small increase in myocardial adenosine levels (51.0 ± 4.9 pg/µl; P = 0.028) (Fig. 3). DIP alone also caused a small increase in myocardial adenosine levels (51.5 ± 6.8 pg/µl; P = 0.025). In contrast, myocardial adenosine levels were much higher in the ATV + DIP group than in the control group (66.4 ± 3.1 pg/µl; P = 0.00 1).


Figure 3
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  		Fig. 3. Myocardial adenosine levels. Overall, there were significant differences among groups (P = 0.002). ATV alone (P = 0.028) and DIP alone (P = 0.025) caused a small increase in myocardial adenosine levels compared with levels in the control (Cont) group. Myocardial adenosine levels were significantly higher in the ATV + DIP group than in the control group (P = 0.001).

 
Immunoblotting. ATV and DIP, alone or in combination, did not affect myocardial total Akt (Fig. 4, A and B) or total eNOS (Fig. 4, C and D) levels. ATV alone (99.39 ± 4.71%) and DIP alone (103.34 ± 3.76%) did not significantly affect p-Akt (Fig. 4, E and F) and p-eNOS (99.30 ± 6.18% and 110.48 ± 2.42%, respectively) (Fig. 4, G and H) levels. However, the combination of ATV + DIP caused a significant increase in myocardial p-Akt (255.84 ± 11.11%) and p-eNOS levels (473.66 ± 23.65%).


Figure 4
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  		Fig. 4. Representative immunoblots and densitometric analyses of myocardial levels of total Akt (A and B), total endothelial nitric oxide synthase (eNOS; C and D), phosphorylated (p)-Akt (E and F), and p-eNOS (G and H) are shown (protocol 1). ATV and DIP, alone or in combination, did not affect total Akt and eNOS expression. Although ATV alone and DIP alone did not affect p-Akt and p-eNOS levels, their combination resulted in a significant increase in p-Akt and p-eNOS levels. *P < 0.05 vs. control; {dagger}P < 0.05 vs. DIP; {ddagger}P < 0.05 vs. ATV.

 
Ami completely blocked the ATV + DIP induction of Akt and eNOS phosphorylation (Fig. 5).


Figure 5
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  		Fig. 5. Representative immunoblots and densitometric analyses of myocardial levels of total p-Akt (A and B) and p-eNOS (C and D) are shown (protocol 2). Ami completely blocked the induction of Akt and eNOS phosphorylation by ATV + DIP. *P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We have shown that DIP and ATV have synergistic effects on myocardial protection against ischemia-reperfusion injury mediated by augmentation of myocardial adenosine levels, leading to enhanced Akt and eNOS phosphorylation. The protective effect of ATV + DIP was completely abrogated with Ami. Moreover, Ami completely blocked the induction of Akt and eNOS phosphorylation by ATV + DIP. These data support the essential role of adenosine in mediating the protective effect of ATV + DIP.

Although several investigators have shown that statin pretreatment limits IS (3, 6, 10, 23, 24, 34–36, 43, 44, 48, 50–53), high oral doses are needed to achieve maximal cardioprotection. For example, a 3-day pretreatment with oral ATV at 10 and 75 mg·kg–1·day–1 reduces IS, whereas at 2 mg·kg–1·day–1 ATV alone does not affect IS (6). Also, a 3-day pretreatment with ATV at 1 mg·kg–1·day–1 does not affect myocardial levels of p-eNOS or calcium-dependent nitric oxide synthase activity and does not limit IS (34). Thus, to achieve maximal protection, high doses of statins are needed. Another confound is that although blood levels of ATV 16 h after a third dose of ATV (10 mg·kg–1·day–1) in the rat are comparable with those in humans treated with ATV at 80 mg/day (8), not all patients can tolerate maximal doses of statins. Thus it is useful to assess the efficacy of drug combinations that enhance the protective effect and decrease of IS. It is known that sildenafil augments the IS-limiting effect of statins (34), whereas selective cyclooxygenase-2 inhibitors (3, 10) and aspirin (7) attenuate it. Since Akt (5, 11, 12, 18, 19, 27, 30, 35, 38, 50, 53) and eNOS (2, 5, 13, 23, 52) activation plays an important role in statin protection from ischemia-reperfusion injury and since statins activate ecto-5-nucleotidase and increase tissue levels of adenosine (9, 35, 46), which in turn activates Akt (26) and eNOS (15, 29, 39, 40, 47), we asked whether ATV, which generates adenosine via ecto-5-nucleotidase activation (9, 35, 46), and DIP, which prevents the reuptake and degradation of adenosine (17, 37), could have synergistic effects on eNOS activation and IS limitation.

It is known that although acute administration of DIP does not affect IS, it potentiates the protective effect of ischemic preconditioning (22, 31, 42, 45) and adenosine (4). Others have shown this in guinea pigs (14) and humans (20, 21, 32, 33, 41) DIP alone may be protective. For example, Figueredo et al. (14) showed that oral DIP at 4 mg·kg–1·day–1 for 6 wk was cardioprotective in guinea pigs (14). Riksen reported that at 200 mg/day for 1 wk DIP ameliorated ischemia-reperfusion injury in forearm skeletal muscle of normal volunteers (33). Kitakaze et al. (25) showed that oral DIP (300 mg/day) for 6 mo ameliorated the severity of heart failure in patients. Several studies have shown that intracoronary administration of DIP at 0.5 mg/kg before percutaneous transluminal angioplasty reduced the severity of chest pain and the magnitude of ST deviation and ameliorated the decrease in LV systolic and diastolic dysfunction during balloon inflation (20, 21, 41).

Many patients who are at risk or have established cardiovascular disease are on antiplatelet therapy, mainly aspirin (alone or in combination with clopidogrel or DIP). The majority of these patients are also receiving concomitant statin treatment. The combination of DIP, an agent with antiplatelet properties (37), with statins is especially appealing given that aspirin attenuates the IS-limiting effects of ATV in a dose-dependent way in the rat (7). Thus, adding DIP may augment the pleiotropic effects of statins that are mediated by eNOS activation, including vasodilatation and protection against ischemia-reperfusion injury, and thus enable us to lower the aspirin dose. Further studies are needed to confirm that the synergistic effects of DIP and statins are persisting over time and that this combination enhances the anti-inflammatory and antiatherosclerotic effects of statins. Moreover, the optimal DIP dose should be determined. The current recommended oral dose of DIP for risk reduction of thrombotic events is 300–400 mg/day (37). It might be that with higher doses and/or longer duration of therapy, DIP alone could have a protective effect and that the effects of the combination treatment could be greater.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Y. Birnbaum, Div. of Cardiology, Univ. of Texas Medical Branch, 5.106 John Sealy Annex, 301 Univ. Blvd., Galveston, TX 77555-0553 (e-mail: yobirnba{at}utmb.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 RESULTS
 DISCUSSION
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  1. Ali Raza J, Reeves WC, Movahed A. Pharmacological stress agents for evaluation of ischemic heart disease. Int J Cardiol 81: 157–167, 2001.[CrossRef][ISI][Medline]
  2. Amin-Hanjani S, Stagliano NE, Yamada M, Huang PL, Liao JK, Moskowitz MA. Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 32: 980–986, 2001.[Abstract/Free Full Text]
  3. Atar S, Ye Y, Lin Y, Freeberg SY, Nishi SP, Rosanio S, Huang MH, Uretsky BF, Perez-Polo JR, Birnbaum Y. Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2. Am J Physiol Heart Circ Physiol 290: H1960–H1968, 2006.[Abstract/Free Full Text]
  4. Auchampach JA, Gross GJ. Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. Am J Physiol Heart Circ Physiol 264: H1327–H1336, 1993.[Abstract/Free Full Text]
  5. Bell RM, Yellon DM. Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol 41: 508–515, 2003.[Abstract/Free Full Text]
  6. Birnbaum Y, Ashitkov T, Uretsky BF, Ballinger S, Motamedi M. Reduction of infarct size by short-term pretreatment with atorvastatin. Cardiovasc Drugs Ther 17: 25–30, 2003.[CrossRef][ISI][Medline]
  7. Birnbaum Y, Lin Y, Ye Y, Martinez JD, Huang MH, Lui CY, Perez-Polo JR, Uretsky BF. Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin. Am J Physiol Heart Circ Physiol 292: H2891–H2897, 2007.[Abstract/Free Full Text]
  8. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, Huang MH, Uretsky BF, Perez-Polo JR. Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat. Circulation 114: 929–935, 2006.[Abstract/Free Full Text]
  9. Birnbaum Y, Ye Y, Lin Y, Uretsky BF, Kitakaze M, Perez-Polo JR. Mechanisms of myocardial protection by atorvastatin: 5'-nucleotidase is upstream to eNOS activation (Abstract). Circ Res 99: E26, 2006.
  10. Birnbaum Y, Ye Y, Rosanio S, Tavackoli S, Hu ZY, Schwarz ER, Uretsky BF. Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury. Cardiovasc Res 65: 345–355, 2005.[Abstract/Free Full Text]
  11. Brouet A, Sonveaux P, Dessy C, Moniotte S, Balligand JL, Feron O. Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins. Circ Res 89: 866–873, 2001.[Abstract/Free Full Text]
  12. Efthymiou CA, Mocanu MM, Yellon DM. Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling. J Cardiovasc Pharmacol 45: 247–252, 2005.[CrossRef][ISI][Medline]
  13. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 95: 8880–8885, 1998.[Abstract/Free Full Text]
  14. Figueredo VM, Diamond I, Zhou HZ, Camacho SA. Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 277: H2091–H2097, 1999.[Abstract/Free Full Text]
  15. Gao F, Christopher TA, Lopez BL, Friedman E, Cai G, Ma XL. Mechanism of decreased adenosine protection in reperfusion injury of aging rats. Am J Physiol Heart Circ Physiol 279: H329–H338, 2000.[Abstract/Free Full Text]
  16. Gross ER, Gross GJ. Ligand triggers of classical preconditioning and postconditioning. Cardiovasc Res 70: 212–221, 2006.[Abstract/Free Full Text]
  17. Harker LA, Kadatz RA. Mechanism of action of dipyridamole. Thromb Res Suppl 4: 39–46, 1983.[Medline]
  18. Harris MB, Blackstone MA, Sood SG, Li C, Goolsby JM, Venema VJ, Kemp BE, Venema RC. Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol 287: H560–H566, 2004.[Abstract/Free Full Text]
  19. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 61: 448–460, 2004.[Abstract/Free Full Text]
  20. Heidland UE, Heintzen MP, Michel CJ, Strauer BE. Intracoronary administration of dipyridamole prior to percutaneous transluminal coronary angioplasty provides a protective effect exceeding that of ischemic preconditioning. Coron Artery Dis 11: 607–613, 2000.[CrossRef][ISI][Medline]
  21. Heidland UE, Heintzen MP, Schwartzkopff B, Strauer BE. Preconditioning during percutaneous transluminal coronary angioplasty by endogenous and exogenous adenosine. Am Heart J 140: 813–820, 2000.[CrossRef][ISI][Medline]
  22. Itoya M, Miura T, Sakamoto J, Urabe K, Iimura O. Nucleoside transport inhibitors enhance the infarct size-limiting effect of ischemic preconditioning. J Cardiovasc Pharmacol 24: 846–852, 1994.[ISI][Medline]
  23. Jones S, Gibson M, Rimmer D, Gibson T, Sharp B, Lefer D. Direct vascular and cardioprotective effects of rosuvastatin, a new HMG-CoA reductase inhibitor. J Am Coll Cardiol 40: 1172–1178, 2002.[Abstract/Free Full Text]
  24. Jones SP, Trocha SD, Lefer DJ. Pretreatment with simvastatin attenuates myocardial dysfunction after ischemia and chronic reperfusion. Arterioscler Thromb Vasc Biol 21: 2059–2064, 2001.[Abstract/Free Full Text]
  25. Kitakaze M, Minamino T, Node K, Koretsune Y, Komamura K, Funaya H, Kuzuya T, Hori M. Elevation of plasma adenosine levels may attenuate the severity of chronic heart failure. Cardiovasc Drugs Ther 12: 307–309, 1998.[CrossRef][ISI][Medline]
  26. Krieg T, Qin Q, McIntosh EC, Cohen MV, Downey JM. ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. Am J Physiol Heart Circ Physiol 283: H2322–H2330, 2002.[Abstract/Free Full Text]
  27. Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, Lefer DJ, Sessa WC, Walsh K. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6: 1004–1010, 2000.[CrossRef][ISI][Medline]
  28. Lee TM, Su SF, Chou TF, Tsai CH. Effect of pravastatin on myocardial protection during coronary angioplasty and the role of adenosine. Am J Cardiol 88: 1108–1113, 2001.[CrossRef][ISI][Medline]
  29. Li J, Fenton RA, Wheeler HB, Powell CC, Peyton BD, Cutler BS, Dobson JG Jr. Adenosine A2a receptors increase arterial endothelial cell nitric oxide. J Surg Res 80: 357–364, 1998.[CrossRef][ISI][Medline]
  30. Mensah K, Mocanu MM, Yellon DM. Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten? J Am Coll Cardiol 45: 1287–1291, 2005.[Abstract/Free Full Text]
  31. Miura T, Ogawa T, Iwamoto T, Shimamoto K, Iimura O. Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning. Circulation 86: 979–985, 1992.[Abstract/Free Full Text]
  32. Pasini FL, Guideri F, Ferber D, Galgano G, Bianchi A, Isidori S, De Giorgi L, Petri S, Capecchi PL, Di Perri T. Pharmacological preconditioning of ischemic heart disease by low-dose dipyridamole. Int J Cardiol 56: 17–27, 1996.[ISI][Medline]
  33. Riksen NP, Oyen WJ, Ramakers BP, Van den Broek PH, Engbersen R, Boerman OC, Smits P, Rongen GA. Oral therapy with dipyridamole limits ischemia-reperfusion injury in humans. Clin Pharmacol Ther 78: 52–59, 2005.[CrossRef][ISI][Medline]
  34. Rosanio S, Ye Y, Atar S, Rahman AM, Freeberg SY, Huang MH, Uretsky BF, Birnbaum Y. Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin. Cardiovasc Drugs Ther 20: 27–36, 2006.[CrossRef][ISI][Medline]
  35. Sanada S, Asanuma H, Minamino T, Node K, Takashima S, Okuda H, Shinozaki Y, Ogai A, Fujita M, Hirata A, Kim J, Asano Y, Mori H, Tomoike H, Kitamura S, Hori M, Kitakaze M. Optimal windows of statin use for immediate infarct limitation: 5'-nucleotidase as another downstream molecule of phosphatidylinositol 3-kinase. Circulation 110: 2143–2149, 2004.[Abstract/Free Full Text]
  36. Scalia R, Gooszen ME, Jones SP, Hoffmeyer M, Rimmer DM, 3rd Trocha SD, Huang PL, Smith MB, Lefer AM, Lefer DJ. Simvastatin exerts both anti-inflammatory and cardioprotective effects in apolipoprotein E-deficient mice. Circulation 103: 2598–2603, 2001.[Abstract/Free Full Text]
  37. Schaper W. Dipyridamole, an underestimated vascular protective drug. Cardiovasc Drugs Ther 19: 357–363, 2005.[CrossRef][ISI][Medline]
  38. Skaletz-Rorowski A, Lutchman M, Kureishi Y, Lefer DJ, Faust JR, Walsh K. HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells. Cardiovasc Res 57: 253–264, 2003.[Abstract/Free Full Text]
  39. Smits P, Williams SB, Lipson DE, Banitt P, Rongen GA, Creager MA. Endothelial release of nitric oxide contributes to the vasodilator effect of adenosine in humans. Circulation 92: 2135–2141, 1995.[Abstract/Free Full Text]
  40. Sobrevia L, Yudilevich DL, Mann GE. Activation of A2-purinoceptors by adenosine stimulates L-arginine transport (system y+) and nitric oxide synthesis in human fetal endothelial cells. J Physiol 499: 135–140, 1997.[Abstract/Free Full Text]
  41. Strauer BE, Heidland UE, Heintzen MP, Schwartzkopff B. Pharmacologic myocardial protection during percutaneous transluminal coronary angioplasty by intracoronary application of dipyridamole: impact on hemodynamic function and left ventricular performance. J Am Coll Cardiol 28: 1119–1126, 1996.[Abstract]
  42. Suzuki K, Miura T, Miki T, Tsuchida A, Shimamoto K. Infarct-size limitation by preconditioning is enhanced by dipyridamole administered before but not after preconditioning: evidence for the role of interstitial adenosine level during preconditioning as a primary determinant of cardioprotection. J Cardiovasc Pharmacol 31: 1–9, 1998.[CrossRef][ISI][Medline]
  43. Tavackoli S, Ashitkov T, Hu ZY, Motamedi M, Uretsky BF, Birnbaum Y. Simvastatin-induced myocardial protection against ischemia-reperfusion injury is mediated by activation of ATP-sensitive K+ channels. Coron Artery Dis 15: 53–58, 2004.[CrossRef][ISI][Medline]
  44. Tiefenbacher CP, Kapitza J, Dietz V, Lee CH, Niroomand F. Reduction of myocardial infarct size by fluvastatin. Am J Physiol Heart Circ Physiol 285: H59–H64, 2003.[Abstract/Free Full Text]
  45. Todosiichuk VV, Kuznetsov VA. Effect of dipyridamole on the phenomenon of ischemic preconditioning in patients with ischemic heart disease during paired bicycle ergometer tests. [In Russian.] Kardiologiia 45: 23–25, 2005.[Medline]
  46. Ueda Y, Kitakaze M, Komamura K, Minamino T, Asanuma H, Sato H, Kuzuya T, Takeda H, Hori M. Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol 34: 2120–2125, 1999.[Abstract/Free Full Text]
  47. Vials A, Burnstock G. A2-purinoceptor-mediated relaxation in the guinea-pig coronary vasculature: a role for nitric oxide. Br J Pharmacol 109: 424–429, 1993.[ISI][Medline]
  48. Wayman NS, Ellis BL, Thiemermann C. Simvastatin reduces infarct size in a model of acute myocardial ischemia and reperfusion in the rat. Med Sci Monit 9: BR155–BR159, 2003.[Medline]
  49. Wojcik WJ, Neff NH. Adenosine measurement by a rapid HPLC-fluorometric method: induced changes of adenosine content in regions of rat brain. J Neurochem 39: 280–282, 1982.[CrossRef][ISI][Medline]
  50. Wolfrum S, Dendorfer A, Schutt M, Weidtmann B, Heep A, Tempel K, Klein HH, Dominiak P, Richardt G. Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway. J Cardiovasc Pharmacol 44: 348–355, 2004.[CrossRef][ISI][Medline]
  51. Wolfrum S, Grimm M, Heidbreder M, Dendorfer A, Katus HA, Liao JK, Richardt G. Acute reduction of myocardial infarct size by a hydroxymethyl glutaryl coenzyme A reductase inhibitor is mediated by endothelial nitric oxide synthase. J Cardiovasc Pharmacol 41: 474–480, 2003.[CrossRef][ISI][Medline]
  52. Yamakuchi M, Greer JJ, Cameron SJ, Matsushita K, Morrell CN, Talbot-Fox K, Baldwin WM 3rd, Lefer DJ, Lowenstein CJ. HMG-CoA reductase inhibitors inhibit endothelial exocytosis and decrease myocardial infarct size. Circ Res 96: 1185–1192, 2005.[Abstract/Free Full Text]
  53. Ye Y, Lin Y, Atar S, Huang MH, Perez-Polo JR, Uretsky BF, Birnbaum Y. Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. Am J Physiol Heart Circ Physiol 291: H1158–H1169, 2006.[Abstract/Free Full Text]
  54. Ye Y, Ramanna M, Lin Y, Martinez JD, Uretsky BF, Perez-Polo JR, Birnbaum Y. The role of adenosine in activation of endothelial nitric oxide synthase (eNOS) by atorvastatin: adenosine, generated by ecto-5'-nucleotidase, is needed for Akt phosphorylation by phosphorylated 3-phosphoinositide-dependent kinase 1 (PDK1) (Abstract). J Am Col Cardiol Suppl A 49: 184A, 2007.



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