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Post‐conditioning restores pre‐ischaemic receptor coupling in rat isolated hearts
Author(s) -
Schreckenberg Rolf,
Maier Thorsten,
Schlüter KlausDieter
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2008.00053.x
Subject(s) - chelerythrine , wortmannin , chemistry , receptor antagonist , medicine , receptor , pharmacology , endocrinology , protein kinase c , antagonist , kinase , phosphatidylinositol , biochemistry
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.