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Cardioprotective-Mimetics Reduce Myocardial Infarct Size in Animals Resistant to Ischemic Preconditioning

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Summary

Background: Ischemic preconditioning (IPC) elicits two distinct windows of cardioprotection, an early phase that lasts for 1–2 h and a delayed phase that lasts for 24–72 h. However, there is conflicting data as to how long the heart is resistant to IPC-induced cardioprotection after the initial protection wanes, leading to the demonstration of IPC-resistance. This resistance to IPC appears to be dependent on the timing of the next IPC stimulus, the species of animals used and the model studied. Furthermore, the mechanisms responsible IPC-resistance are unknown. It is also important to demonstrate therapeutic interventions that will produce cardioprotection during this period of IPC-resistance.

Methods and Results: To examine potential mechanisms responsible for acute IPC-induced resistance, the NHE-1 inhibitor EMD 85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoylguanidine), which exerts its effects via mechanisms distinct from IPC, and the K ATP channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open K ATP channels, were examined in a canine model of IPC-resistance. One 10 min. IPC stimulus followed by 10 min. of reperfusion produced a significant reduction in IS/AAR compared to Control (7.1 ± 2.6% versus 26.0 ± 6.2%; P < 0.05). However, IPC did not significantly protect the myocardium if a 2 h reperfusion period occurred between the initial IPC stimulus and the subsequent prolonged (60 min) ischemic challenge (IS/AAR: 22.5 ± 4.8%: P > 0.05). Furthermore, hearts treated with IPC followed by 2 h of reperfusion were resistant to an additional IPC stimulus administered just prior to the subsequent 60 min. occlusion period (IS/AAR: 22.9 ± 3.2%: P > 0.05). In contrast, administration of the NHE-1 inhibitor EMD 85131 (IS/AAR: 7.4 ± 2.5%: P < 0.05) or the K ATP channel opener bimakalim (IS/AAR: 11.8 ± 2.4%: P < 0.05) both afforded significant cardioprotection when administered at 2 h of reperfusion in previously preconditioned canine hearts resistant to IPC.

Conclusions: IPC resistance occurs in this canine model of ischemia-reperfusion injury. However, in spite of IPC resistance, hearts can still be pharmacologically protected by direct application of the K ATP channel opener bimakalim or the NHE inhibitor EMD 85131.

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Abbreviations

NHE:

sodium/hydrogen exchanger

LAD:

left anterior descending artery

IS:

infarct size

AAR:

area-at-risk

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Authors and Affiliations

  1. Interventional Cardiology Fellow, Division of Cardiovascular Medicine, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN

    Richard J. Gumina

  2. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA (RJG, JS, TM, GJG)

    Jo El Schultz, Jeanine Moore, Norbert Beier, Pierre Schelling & Garrett J. Gross Ph.D.

  3. Department of Cardiovascular Pharmacology, Biomed FO/HK, Merck KGaA, Frankfurter Strabe 250, Darmstadt, D-64271, Germany (N.B., P.S.)

    Jo El Schultz, Jeanine Moore, Norbert Beier, Pierre Schelling & Garrett J. Gross Ph.D.

  4. Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Garrett J. Gross Ph.D.

Authors
  1. Richard J. Gumina
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  2. Jo El Schultz
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  3. Jeanine Moore
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  4. Norbert Beier
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  5. Pierre Schelling
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  6. Garrett J. Gross Ph.D.
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Gumina, R.J., Schultz, J., Moore, J. et al. Cardioprotective-Mimetics Reduce Myocardial Infarct Size in Animals Resistant to Ischemic Preconditioning. Cardiovasc Drugs Ther 19, 315–322 (2005). https://doi.org/10.1007/s10557-005-3693-8

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