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10 Cell-Permeable Cyclic AMP as a Novel Cardioprotective Agent
  1. D J Dudley,
  2. M S Suleiman,
  3. M Bond,
  4. A F James,
  5. I Khaliulin
  1. Department of Biochemistry and the Bristol Heart Institute, Medical Sciences Building, University of Bristol, University Walk, Bristol BS8 1TD

Abstract

We have recently shown that consecutive heart perfusion with isoproterenol and adenosine strongly protects the heart against ischaemia/reperfusion injury. Isoproterenol activates β-adrenergic receptors increasing synthesis of cyclic AMP (cAMP) which in turn activates both protein kinase A (PKA) and a guanine nucleotide exchange factor- Epac- whilst adenosine activates protein kinase C. However, this treatment may not be effective if β-adrenergic sensitivity is impaired by some pathological conditions. We decided to check whether a cardioprotective effect can be achieved by direct activation of PKA and Epac using a cell-permeable cAMP analogue 8-Br-cAMP-AM. Isolated rat hearts were perfused with 1 μM 8-Br-cAMP-AM for 5 min followed by 5 min washout period prior to 30 min ischaemia and 2 h reperfusion. 8-Br-cAMP-AM itself did not change haemodynamic function but resulted in decreased function during the washout period prior to ischaemia and significantly reduced amplitude of ischaemic contracture. During reperfusion, the cell-permeable cAMP analogue decreased end diastolic pressure, lactate dehydrogenase release and infarct size and considerably improved haemodynamic functional recovery. These results demonstrate that the cell permeable cAMP analogue 8-Br-cAMP-AM, at a relatively low dose, can induce cardioprotective effect directly, without β-adrenergic stimulation. This could be the way to activate survival signal transduction pathways if β-adrenergic receptor sensitivity is impaired. Further study is needed in order to elucidate the signalling mechanisms of this protective effect and to optimise this intervention. Supported by the BHF.

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