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Protection against myocardial ischaemia/reperfusion injury by PPAR–α activation is related to production of nitric oxide and endothelin–1

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Abstract

Background

Ligands of peroxisome proliferator–activated receptor alpha (PPAR–α) have been shown to reduce ischaemia/reperfusion injury. The mechanisms behind this effect are not well known. We hypothesized that activation of PPAR–α exerts cardioprotection via a mechanism related to nitric oxide (NO) and endothelin–1 (ET–1).

Methods

Five groups of anaesthetized open–chest Sprague–Dawley rats were given the PPAR–α agonist WY 14643 1 mg/kg (WY; n = 7), dimethyl sulfoxide (DMSO, vehicle for WY; n = 6), the combination of WY and the NO synthase inhibitor N–nitro–L–arginine (L–NNA, 2 mg/kg) (n = 7), L–NNA only (n = 8) or 0.9% sodium chloride (NaCl, vehicle for DMSO and L–NNA; n = 8) i.v. before a 30 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), eNOS and iNOS protein and ET–1 mRNA expression were determined.

Results

There were no haemodynamic differences between the groups during the experiment. The IS was 78 ± 3% of the area at risk in the DMSO group and 77 ± 2% in the NaCl group (P = NS). WY reduced IS to 56 ± 3% (P < 0.001 vs. DMSO group). When WY was administered in combination with L–NNA the cardioprotective effect was abolished (IS 73 ± 3%, P < 0.01 vs. WY 14643). L–NNA did not affect IS per se (78 ± 2%, P = NS). The expression of eNOS but not iNOS protein in ischaemic myocardium from rats was increased in the group given WY (P < 0.05). ET–1 mRNA levels were lower in the ischaemic myocardium following WY administration.

Conclusion

The results suggest that the PPAR–α activation protects the rat myocardium against ischaemia/ reperfusion injury via a mechanism related to production of NO, and possibly ET–1.

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Authors and Affiliations

  1. Department of Cardiology, Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden

    A. A. Bulhak, P.-O. Sjöquist & J. Pernow

  2. BMC A13, WNC, Institute of Medicine, Lund University Hospital, 221 85, Lund, Sweden

    C.-B. Xu & L. Edvinsson

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  1. A. A. Bulhak
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  2. P.-O. Sjöquist
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  3. C.-B. Xu
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  4. L. Edvinsson
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  5. J. Pernow
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Correspondence to A. A. Bulhak.

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Bulhak, A.A., Sjöquist, PO., Xu, CB. et al. Protection against myocardial ischaemia/reperfusion injury by PPAR–α activation is related to production of nitric oxide and endothelin–1. Basic Res Cardiol 101, 244–252 (2006). https://doi.org/10.1007/s00395-005-0580-1

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  • DOI: https://doi.org/10.1007/s00395-005-0580-1

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