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


METHODS
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.


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 (DeltaLVdevP: -6.1 +/- 1.7%). Wortmannin but not chelerythrine attenuated the re-sensitizing effect of IPoC on post-ischaemic receptor coupling (DeltaLVdevP: +6.2 +/- 10.5 and -15.0 +/- 7.7%). As observed with PTHrP receptors, IPoC restored beta-adrenoceptors (DeltaLVdevP: +9.3 +/- 11.8% vs. 62.3 +/- 15.8%).


CONCLUSIONS
IPoC restores PTHrP receptor coupling in a PI 3-kinase-dependent way. A similar mechanism may allow beta-adrenoceptor re-sensitization.
Justus-Liebig-University, Institute of Physiology, Aulweg, Giessen, Germany.
Rolf
R
Schreckenberg
Thorsten
T
Maier
Klaus-Dieter
KD
Schlüter
D000818:Animals; D004789:Enzyme Activation; D005260:Female; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
D007770:L-Lactate Dehydrogenase; D044162:Parathyroid Hormone-Related Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D044168:Receptor, Parathyroid Hormone, Type 1; D011943:Receptors, Adrenergic, beta