Post-conditioning restores pre-ischaemic receptor coupling in rat isolated hearts

Abstract

Background and purpose: Ischaemic preconditioning (IPC) and ischaemic post-conditioning (IPoC) activate signal transduction pathways that are also involved in receptor de- and re-sensitization such as phosphatidylinositol (PI) 3-kinase. Therefore, IPC and IPoC may affect post-infarct receptor coupling. Experimental approach: Rat isolated hearts (Langendorff mode, constant flow) were exposed to 45 min flow arrest followed by 120 min reperfusion, including IPC or IPoC. Control hearts were perfused without a 45 min flow arrest. Left ventricular developed pressure (LVdevP) was determined. Thirty min after reperfusion, hearts were exposed to parathyroid hormone-related peptide (PTHrP) or isoprenaline for 10 min to monitor receptor responsiveness. Reperfusion injury was quantified by enzyme release. Key results: IPC and IPoC significantly reduced enzyme release compared with ischaemia and reperfusion alone by 75% and 62% respectively. Wortmannin or chelerythrine inhibiting either PI 3-kinase or protein kinase C, respectively, attenuated protection. Application of PTHrP 30 min after reperfusion did not change LVdevP in hearts exposed to ischaemia (+1 ± 11%), but IPoC restored the normal and non-ischaemic response to PTHrP characterized by a negative inotropism (-8.3 ± 3.9% and -12.9 ± 6.1%). IPC restored a small negative inotropic effect (-4.4 ± 4.7%). Application of a PTHrP receptor antagonist during the 45 min flow arrest attenuated receptor desensitization (ΔLVdevP: -6.1 ± 1.7%). Wortmannin but not chelerythrine attenuated the re-sensitizing effect of IPoC on post-ischaemic receptor coupling (ΔLVdevP: +6.2 ± 10.5 and -15.0 ± 7.7%). As observed with PTHrP receptors, IPoC restored β-adrenoceptors (ΔLVdevP: +9.3 ± 11.8% vs. 62.3 ± 15.8%). Conclusions and implications: IPoC restores PTHrP receptor coupling in a PI 3-kinase-dependent way. A similar mechanism may allow β-adrenoceptor re-sensitization. © 2009 The British Pharmacological Society.