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Pretreatment with Growth Hormone-Releasing Peptide-2 Directly Protects against the Diastolic Dysfunction of Myocardial Stunning in an Isolated, Blood-Perfused Rabbit Heart Model¹

Department of Intensive Care Medicine and Center for Experimental Surgery & Anaesthesiology (F.W., G.V.d.B.) and Laboratory for Experimental Medicine and Endocrinology (E.V.H.), Catholic University of Leuven, Leuven, Belgium; Research Center for Endocrinology and Metabolism, Sahlgrenska University Hospital (J.I.), Göteborg, Sweden

Address all correspondence and requests for reprints to: Frank Weekers, M.D., Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Frank.Weekers{at}uz.kuleuven.ac.be

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·day (n = 9) or 160 µg/kg·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 0.02), a level which was indistinguishable from that in the nonischemic 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.

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