Abstract
BackgroundConsecutive treatment of normal heart with a high dose of isoproterenol and adenosine (Iso/Ade treatment), confers strong protection against ischaemia/reperfusion injury. In preparation for translation of this cardioprotective strategy into clinical practice during heart surgery, we further optimised conditions for this intervention using a clinically-relevant dose of Iso and determined its cardioprotective efficacy in hearts isolated from a model of surgically-induced heart failure.MethodsIsolated Langendorff-perfused rat hearts were treated sequentially with 5 nM Iso and 30 μM Ade followed by different durations of washout prior to 30 min global ischaemia and 2 hrs reperfusion. Reperfusion injury was assessed by measuring haemodynamic function, lactate dehydrogenase (LDH) release and infarct size. Protein kinase C (PKC) activity and glycogen content were measured in hearts after the treatment. In a separate group of hearts, Cyclosporine A (CsA), a mitochondria permeability transition pore (MPTP) inhibitor, was added with Iso/Ade. Failing hearts extracted after 16 weeks of ligation of left coronary artery in 2 months old rats were also subjected to Iso/Ade treatment followed by ischaemia/reperfusion.ResultsRecovery of the rate pressure product (RPP) in Iso/Ade-treated hearts was significantly higher than in controls. Thus in Iso/Ade treated hearts with 5 nM Iso and no washout period, RPP recovery was 76.3 ± 6.9% of initial value vs. 28.5 ± 5.2% in controls. This was associated with a 3 fold reduction in LDH release irrespective to the duration of the washout period. Hearts with no washout of the drugs (Ade) had least infarct size, highest PKC activity and also showed reduced glycogen content. Cardioprotection with CsA was not additive to the effect of Iso/Ade treatment. Iso/Ade treatment conferred significant protection to failing hearts. Thus, RPP recovery in failing hearts subjected to the treatment was 69.0 ± 16.3% while in Control hearts 19.7 ± 4.0%. LDH release in these hearts was also 3 fold lower compared to Control.ConclusionsConsecutive Iso/Ade treatment of normal heart can be effective at clinically-relevant doses and this effect appears to be mediated by glycogen depletion and inhibition of MPTP. This intervention protects clinically relevant failing heart model making it a promising candidate for clinical use.
Highlights
Consecutive treatment of normal heart with a high dose of isoproterenol and adenosine (Iso/Ade treatment), confers strong protection against ischaemia/reperfusion injury
Optimization of the protocol of Iso/Ade treatment with a clinically relevant dose of Isoproterenol In the Iso/Ade group, rate pressure product (RPP) during heart perfusion with 5 nM Iso reached a maximum of 259.4 ± 12.4% of the pretreatment value, mostly due to an increase in Left ventricular developed pressure (LVDP)
RPP measured at the end of perfusion with 30 μM Ade fell to 42.3 ± 7.0% of the pre-treatment value, due to a significant reduction of both heart rate (HR) and LVDP
Summary
Consecutive treatment of normal heart with a high dose of isoproterenol and adenosine (Iso/Ade treatment), confers strong protection against ischaemia/reperfusion injury. When the consecutive activation of PKA and PKC was mimicked pharmacologically using the PKA activator isoproterenol (Iso) and the PKC activator adenosine (Ade), it resulted in a highly potent cardioprotective effect [4]. This was achieved using a concentration of Iso (200 nM) significantly higher than the concentration of isoproterenol in blood plasma used clinically (0.02-0.2 μg/kg/min; equivalent to about 1.3-13 nM) [6]. In our earlier work investigating this intervention, we had not explored what duration of the washout period prior to ischaemia produced the maximal cardioprotective effect by triggering signalling mechanisms
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