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Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor.

Abstract
Interventions such as glycogen depletion, which limit myocardial anaerobic glycolysis and the associated proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel glycogen phosphorylase inhibitor 5-Chloro-N-[(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (ingliforib; CP-368,296) could reduce infarct size in both in vitro and in vivo rabbit models of ischemia-reperfusion injury (30 min of regional ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of ingliforib started 30 min before regional ischemia and elicited a concentration-dependent reduction in infarct size; infarct size was reduced by 69% with 10 microM ingliforib. No significant drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of ingliforib (15 mg/kg loading dose; 23 mg.kg(-1).h(-1) infusion) selected to achieve a free plasma concentration equivalent to an estimated EC(50) in the isolated hearts (1.2 microM, 0.55 microg/ml) significantly reduced infarct size by 52%, and reduced plasma glucose and lactate concentrations. Furthermore, myocardial glycogen phosphorylase a and total glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and glycogen stores were preserved in ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the ingliforib group, although heart rate was modestly decreased postischemia. In conclusion, glycogen phosphorylase inhibition with ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of cardiovascular disease.
AuthorsW Ross Tracey, Judith L Treadway, William P Magee, Jill C Sutt, R Kirk McPherson, Carolyn B Levy, Donald E Wilder, Li J Yu, Yue Chen, Ravi M Shanker, Alison K Mutchler, Andrew H Smith, David M Flynn, Delvin R Knight
JournalAmerican journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 286 Issue 3 Pg. H1177-84 (Mar 2004) ISSN: 0363-6135 [Print] United States
PMID14615278 (Publication Type: Journal Article)
Chemical References
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Indoles
  • Pyrrolidines
  • Glycogen
  • Glycogen Phosphorylase
  • ingliforib
Topics
  • Animals
  • Cardiotonic Agents (chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (chemistry, pharmacology)
  • Glycogen (metabolism)
  • Glycogen Phosphorylase (antagonists & inhibitors)
  • In Vitro Techniques
  • Indoles (chemistry, pharmacology)
  • Male
  • Myocardial Infarction (drug therapy, metabolism)
  • Myocardial Reperfusion Injury (drug therapy, metabolism)
  • Pyrrolidines (chemistry, pharmacology)
  • Rabbits

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