Abstract
We have recently shown that brief episodes of hypothermic perfusion interspersed with periods of normothermic perfusion, referred to as temperature preconditioning (TP), are cardioprotective and can be mimicked by consecutive isoproterenol/adenosine treatment. Here we investigate the optimal temperature for TP and whether TP further enhances protection provided by hypothermic ischemia with or without polarized cardioplegic arrest. Three experimental groups of Langendorff-perfused rat hearts were used. In the first group, hearts were subjected to three episodes of hypothermic perfusion at 7, 17, 26 and 32°C during the TP protocol, followed by 30 min normothermic index ischemia and 60 min reperfusion (37°C). Protein kinase A (PKA) activity and cyclic AMP (cAMP) concentrations were measured prior to index ischemia. In the second group, TP (26°C) hearts were subjected to two hours hypothermic index ischemia at 26°C and two hours normothermic reperfusion. In the third group, TP (26°C) hearts or hearts treated with isoproterenol/adenosine (pharmacological simulation of TP) were subjected to four hours hypothermic index ischemia with procaine-induced polarized cardioplegia at 26°C followed by two hours normothermic reperfusion. Hemodynamic function recovery, lactate dehydrogenase release and infarct size were used to assess cardioprotection. TP at 26°C resulted in highest cardioprotection, increased cAMP concentration and PKA activity, while TP at 7°C exacerbated ischemia/reperfusion damage, and had no effect on cAMP concentration or PKA activity. TP at 26°C also protected hearts during hypothermic ischemia with or without polarized cardioplegia. Isoproterenol/adenosine treatment conferred additional protection similar to TP. In conclusion, the study shows that TP-induced cardioprotection is temperature dependent and is optimal at 26°C; TP confers additional protection to hypothermia and polarized cardioplegia; and that the pharmacological treatment based on the mechanism of TP (consecutive isoproterenol/adenosine treatment) is a potential cardioprotective strategy that can be used during heart surgery and transplantation.
Highlights
We have recently described a novel protocol for cardioprotection that involves subjecting the heart to brief, transient hypothermic (268C) episodes prior to index ischemia.[1]
protein kinase A (PKA) activity and [cyclic AMP (cAMP)] in hearts following the different temperature preconditioning (TP) protocols In this series of experiments, the cAMP concentration in TP26 hearts was significantly increased while in TP7 it was similar to controls (Figure 2a)
Measurements of PKA activity matched cAMP concentrations: a ratio of fluorescence intensity of phosphorylated to non-phosphorylated Pep Tagw A1 peptide was increased in TP26 but not in TP7 hearts (Figure 2b)
Summary
We have recently described a novel protocol for cardioprotection that involves subjecting the heart to brief, transient hypothermic (268C) episodes prior to index ischemia.[1]. The cardioprotective effects of TP, like IP, were associated with decreased oxidative stress at the end of index ischemia and during reperfusion which prevents opening of the mitochondria permeability transition pore (MPTP) leading to both improved contractile function and decreased necrotic damage.[1,3]
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