10 Cell-Permeable Cyclic AMP as a Novel Cardioprotective Agent

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.

Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen

“…Based on this strategy, we have found that the normal adult rat heart can be effectively protected against I/R injury by transient and consecutive treatment with clinically relevant doses of isoproterenol and adenosine (Iso/Aden) [ 6 ]. This intervention has also been shown to protect hearts when applied during hypothermic cardioplegic arrest [ 7 ] and in rat models of heart failure and aging [ 6 , 8 ]. Interestingly, this treatment results in a decrease in glycogen content in the myocardium [ 4 , 6 ].…”

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore

“…Therefore, the use of newly available cAMP analogues that can act selectively on either PKA or Epac, or both simultaneously, represents a valuable tool to identify the involvement and the relative contribution of these cAMP sensors in cardioprotection [19] Several such analogues are available and are in common use experimentally. In this and other recent work, we have used 8-Br-cAMP-AM (8-Br, an activator of both PKA and Epac), 6-Bnz-cAMP-AM (6-Bnz, a PKA agonist) and 8-CPT-2 -O-Me-cAMP-AM (CPT, an Epac agonist).…”

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and EPAC : A Role for the Mitochondrial Permeability Transition Pore

“…The cAMP/Epac pathway exists independently of and in parallel to the cAMP/PKA signaling pathway [13,14]. Therefore, the use of newly available cAMP analogues that can act selectively on either PKA or Epac, or both simultaneously, represents a valuable tool to identify the involvement and the relative contribution of these cAMP sensors in cardioprotection [15]. We have recently shown that simultaneous activation of PKA and Epac using cAMP permeable analogues provided a strong cardioprotection against I/R injury in adult hearts [16,17].…”