Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model

Brief coronary occlusion followed by reperfusion leads to reversible myocar dial dysfunction (stunning) which can induce irreversible damage of other o rgan 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 wit h those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg day (n = 9) or 160 mug/kg. day GHRP-2 (n = 8) i n 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 pretrea tment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonisc hemic hearts mounted into the same system. At study end, all hearts were sn ap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pr etreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I us. 8 +/- 15% with GHRP-2 (P < 0.001) and in-creased 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 s aline allowing data from these experiments to be pooled into one ischemic c ontrol group for further analysis of the effect of pretreatment. No differe nce in postischemic recovery of left ventricular systolic function among th e unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) per sisted in the unpretreated and rhGH pretreated hearts compared with the non ischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P <less than or equal to> 0.02), a level which was indistinguishable from that in t he nonischemic hearts, suggesting full postischemic recovery of diastolic f unction. There were no signs of increased apoptosis in the experimental gro ups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected se lectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardi oprotective agents.