Failure to confer cardioprotection and to increase the expression of heat-shock protein 70 by preconditioning with a kappa-opioid receptor agonist during ischaemia and reperfusion in streptozotocin-induced diabetic rats

Diabetologia. 2004 Feb;47(2):214-20. doi: 10.1007/s00125-003-1288-0. Epub 2004 Jan 9.

Abstract

Aims/hypothesis: The aim of this study was to determine the effects of preconditioning on injury and expression of heat shock proteins 70 in diabetic rat hearts.

Methods: Diabetes was induced by an intraperitoneal injection of 65 mg kg(-1) streptozotocin. Daily subcutaneous injection of 4 IU insulin started 2 weeks after streptozotocin treatment for 4 weeks. Rats were preconditioned by intravenous injection of 10 mg kg(-1) U50,488H, a selective kappa-opioid receptor agonist (U50,488H preconditioning). The effects of U50,488H preconditioning had previously been shown to be blocked by a selective kappa-opioid receptor antagonist, nor-binaltorphimine. Twenty-four hours later, rats were subjected to 30 min of regional ischaemia by occlusion of the left coronary artery followed by 4 h of reperfusion. Infarct size was determined at the end of reperfusion. Stress-inducible and constitutive heat shock proteins 70 were analysed at the end of ischaemia and reperfusion by Western blotting.

Results: Myocardial infarcts induced by ischaemia and reperfusion were greater in diabetic rats. U50,488H preconditioning significantly reduced the infarct size and increased the expression of stress-inducible heat-shock protein 70 in normal rats. The effects of U50,488H preconditioning were abolished in streptozotocin-induced diabetic rats, but restored by insulin replacement.

Conclusion/interpretation: In addition to a greater susceptibility to ischaemic insults, the delayed cardioprotection of U50,488H preconditioning was lost, which could at least partly be due to impaired synthesis of stress-inducible heat-shock protein 70 in diabetic rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Animals
  • Blood Glucose / analysis
  • Blood Glucose / drug effects
  • Blotting, Western
  • Body Weight / drug effects
  • Cardiotonic Agents / pharmacology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Gene Expression / drug effects
  • HSC70 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heart / drug effects
  • Heart / physiopathology
  • Insulin / pharmacology
  • Male
  • Myocardial Ischemia / metabolism*
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Organ Size / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / antagonists & inhibitors*

Substances

  • Blood Glucose
  • Cardiotonic Agents
  • HSC70 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Hspa8 protein, rat
  • Insulin
  • Receptors, Opioid, kappa
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer