后适应可恢复大鼠离体心脏缺血前的受体偶联。
Post-conditioning restores pre-ischaemic receptor coupling in rat isolated hearts.
作者信息
Schreckenberg Rolf, Maier Thorsten, Schlüter Klaus-Dieter
机构信息
Justus-Liebig-University, Institute of Physiology, Aulweg, Giessen, Germany.
出版信息
Br J Pharmacol. 2009 Mar;156(6):901-8. doi: 10.1111/j.1476-5381.2008.00053.x.
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 (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 AND IMPLICATIONS
IPoC restores PTHrP receptor coupling in a PI 3-kinase-dependent way. A similar mechanism may allow beta-adrenoceptor re-sensitization.
背景与目的
缺血预处理（IPC）和缺血后处理（IPoC）激活的信号转导通路也参与受体的失敏和再敏化过程，如磷脂酰肌醇（PI）3激酶。因此，IPC和IPoC可能影响梗死后的受体偶联。
实验方法
将大鼠离体心脏（Langendorff模式，恒流灌注）进行45分钟的停流处理，随后进行120分钟的再灌注，其中包括IPC或IPoC处理。对照组心脏不进行45分钟的停流处理。测定左心室舒张末压（LVdevP）。再灌注30分钟后，将心脏暴露于甲状旁腺激素相关肽（PTHrP）或异丙肾上腺素10分钟，以监测受体反应性。通过酶释放量来量化再灌注损伤。
主要结果
与单纯缺血再灌注相比，IPC和IPoC分别使酶释放量显著降低75%和62%。渥曼青霉素或白屈菜红碱分别抑制PI 3激酶或蛋白激酶C后，减弱了保护作用。再灌注30分钟后应用PTHrP对经历缺血的心脏的LVdevP无影响（+1±11%），但IPoC恢复了对PTHrP的正常非缺血反应，其特征为负性肌力作用（-8.3±3.9%和-12.9±6.1%）。IPC恢复了较小的负性肌力作用（-4.4±4.7%）。在45分钟停流期间应用PTHrP受体拮抗剂可减弱受体失敏（ΔLVdevP：-6.1±1.7%）。渥曼青霉素而非白屈菜红碱减弱了IPoC对缺血后受体偶联的再敏化作用（ΔLVdevP：+6.2±10.5和-15.0±7.7%）。与PTHrP受体情况相同，IPoC恢复了β肾上腺素能受体功能（ΔLVdevP：+9.3±11.8%对62.3±15.8%）。
结论与意义
IPoC以PI 3激酶依赖的方式恢复PTHrP受体偶联。类似机制可能使β肾上腺素能受体再敏化。
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