Weekers F, Van Herck E, Isgaard J, Van den Berghe G
Department of Intensive Care Medicine and Center for Experimental Surgery & Anaesthesiology, Catholic University of Leuven, Belgium.
Endocrinology. 2000 Nov;141(11):3993-9. doi: 10.1210/endo.141.11.7768.
Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg x day (n = 9) or 160 microg/kg x day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pretreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I vs. 8 +/- 15% with GHRP-2 (P < 0.001) and increased body weight with 6.8 +/- 2.5% vs. 3.4 +/- 3.3% with GHRP-2 (P = 0.01). A bolus injection of rhGH did not alter myocardial function compared with saline allowing data from these experiments to be pooled into one ischemic control group for further analysis of the effect of pretreatment. No difference in postischemic recovery of left ventricular systolic function among the unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) persisted in the unpretreated and rhGH pretreated hearts compared with the nonischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P < or = 0.02), a level which was indistinguishable from that in the non-ischemic hearts, suggesting full postischemic recovery of diastolic function. There were no signs of increased apoptosis in the experimental groups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected selectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardioprotective agents.
短暂冠状动脉闭塞后再灌注会导致可逆性心肌功能障碍（心肌顿抑），这可能会引发其他器官系统的不可逆损伤。我们在血液灌注的离体兔心模型中研究了重组人生长激素（rhGH）和生长激素促分泌素GHRP - 2预处理对心肌顿抑的影响。在第一组实验中，将未预处理动物主动脉根部推注rhGH（3.5mg/kg）（n = 5）的效果与注射生理盐水（n = 6）的效果进行比较。在第二组实验中，动物分别用皮下注射rhGH 3.5mg/kg×天（n = 9）或160μg/kg×天GHRP - 2（n = 8）分两次给药进行14天的预处理。在预处理前和14天结束时测定体重以及rhGH、兔生长激素（rGH）和胰岛素样生长因子 - I（IGF - I）的血浆浓度。心脏切除后进行15分钟缺血，随后80分钟再灌注，之后将缺血后恢复情况与安装在同一系统中的非缺血心脏进行比较。在研究结束时，所有心脏均速冻以检测凋亡标志物。所有动物的循环兔生长激素（rGH）水平保持不变。用rhGH预处理14天使血清IGF - I升高142±116%，而用GHRP - 2处理升高8±15%（P < 0.001），rhGH使体重增加6.8±2.5%，GHRP - 2使体重增加3.4±3.3%（P = 0.01）。与注射生理盐水相比，推注rhGH未改变心肌功能，因此这些实验数据可合并入一个缺血对照组，以进一步分析预处理的效果。未预处理、rhGH预处理和GHRP - 2预处理的心脏在缺血后左心室收缩功能恢复方面无明显差异。再灌注结束时，未预处理和rhGH预处理的心脏舒张末期压力（EDP）比非缺血心脏持续高3倍。在GHRP - 2预处理的心脏中，EDP降至未预处理和rhGH预处理心脏所观察到压力的一半（所有P≤0.02），这一水平与非缺血心脏无法区分，表明舒张功能在缺血后完全恢复。实验组未出现凋亡增加的迹象。总之，在该模型中，用GHRP - 2预处理14天可选择性地保护心肌顿抑的舒张功能障碍，而rhGH则无此作用。这一观察结果可能为将生长激素促分泌素作为心脏保护剂开辟前景。
