β1-Adrenergic receptor antagonism abrogates cardioprotective effects of intermittent hypoxia

Robert T. Mallet, Myoung Gwi Ryou, Arthur G. Williams, Linda Howard, H. Fred Downey

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Abstract

Adaptation to hypoxia lessens myocardial ischemic injury. This study tested whether hypoxia-induced β-adrenergic activity mobilizes mechanisms that protect myocardium during subsequent ischemia and reperfusion. Dogs were intermittent hypoxia conditioned (IHC) by a 20 days program of 5-8 daily, 5-10 min cycles of normobaric hypoxia (FIO2=9.5-10%), or sham conditioned with normoxic air, and metoprolol (β1-adrenoceptor antagonist) was administered throughout the IHC program. Twenty-four hours after the last IHC session, the left anterior descending coronary artery (LAD) was occluded for 60 min, and then reperfused for 5 h. Area at risk (AAR) and infarct size (IS) were measured. IHC lowered IS/AAR from 38 ± 6% in sham-conditioned dogs to 1.1 ± 0.3%, and eliminated ventricular tachycardia (VT) and fibrillation (VF) that occurred in 14 of 17 non-conditioned dogs. Metoprolol blunted IHC-evoked cardioprotection (IS/AAR=27 ± 3%), and VT and/or VF occurred in 5 of 6 dogs. Metoprolol did not exacerbate ischemic injury in sham-conditioned dogs (IS/AAR=38 ± 2%). Neither IHC nor metoprolol affected hematocrit or LAD collateral blood flow. A single IHC session failed to protect ischemic myocardium (IS/AAR = 36 ± 8%), and protection was incomplete after 10 days of IHC (IS/AAR = 13 ± 5%), suggesting that de novo protein synthesis was required for protection. Thus, episodic β1-adrenergic activation during IHC evokes progressive development of powerful resistance to myocardial ischemia.

Original languageEnglish
Pages (from-to)436-446
Number of pages11
JournalBasic Research in Cardiology
Volume101
Issue number5
DOIs
Publication statusPublished - 1 Sep 2006

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Keywords

  • Cardioprotection
  • Hypoxia
  • Infarction
  • Metoprolol
  • Ventricular fibrillation
  • Ventricular tachycardia

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