Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning

Richard J. Gumina, Jo El Schultz, Jeanine Moore, Norbert Beier, Pierre Schelling, Garrett J. Gross

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 KATP channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open KATP 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 KATP 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 KATP channel opener bimakalim or the NHE inhibitor EMD 85131.

Original languageEnglish (US)
Pages (from-to)315-322
Number of pages8
JournalCardiovascular Drugs and Therapy
Volume19
Issue number5
DOIs
StatePublished - Oct 1 2005

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Ischemic Preconditioning
Myocardial Infarction
KATP Channels
Reperfusion
Canidae

Keywords

  • Ischemic preconditioning resistance
  • KATP channel
  • Myocardial infarction
  • Sodium-hydrogen exchanger

ASJC Scopus subject areas

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

Cite this

Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning. / Gumina, Richard J.; El Schultz, Jo; Moore, Jeanine; Beier, Norbert; Schelling, Pierre; Gross, Garrett J.

In: Cardiovascular Drugs and Therapy, Vol. 19, No. 5, 01.10.2005, p. 315-322.

Research output: Contribution to journalArticle

Gumina, Richard J. ; El Schultz, Jo ; Moore, Jeanine ; Beier, Norbert ; Schelling, Pierre ; Gross, Garrett J. / Cardioprotective-mimetics reduce myocardial infarct size in animals resistant to ischemic preconditioning. In: Cardiovascular Drugs and Therapy. 2005 ; Vol. 19, No. 5. pp. 315-322.
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AU - Gumina, Richard J.

AU - El Schultz, Jo

AU - Moore, Jeanine

AU - Beier, Norbert

AU - Schelling, Pierre

AU - Gross, Garrett J.

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N2 - 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 KATP channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open KATP 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 KATP 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 KATP channel opener bimakalim or the NHE inhibitor EMD 85131.

AB - 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 KATP channel opener bimakalim, which bypasses the signaling mechanisms of IPC to directly open KATP 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 KATP 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 KATP channel opener bimakalim or the NHE inhibitor EMD 85131.

KW - Ischemic preconditioning resistance

KW - KATP channel

KW - Myocardial infarction

KW - Sodium-hydrogen exchanger

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