Protectant Activity of Hexarelin or Growth Hormone Against Postischemic Ventricular Dysfunction in Hearts from Aged Rats

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Abstract
The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 ± 5.7 to 33.5 ± 3.8 mm Hg; p < 0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 ± 5.2 to 116.8 ± 4.6 mm Hg; p < 0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 ± 4 to 298 ± 25 mU/min/g wet tissue; p < 0.001; n = 10). In vivo administration of hexarelin (80 μg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 ± 5.8 to 83.7 ± 5.9 mm Hg; p > 0.05; n = 9), and the increase in coronary resistance was minimal (from 67 ± 5.8 to 79.7 ± 6.9 mm Hg; p > 0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 ± 5.5 to 90 ± 7.2 mU/min/g wet tissue; p < 0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 μg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 ± 6.2 to 50 ± 3.5 mm Hg; p < 0.01; n = 6); 65% increase of coronary resistance (from 68 ± 4.3 to 112.2 ± 5.2 mm Hg; p < 0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 ± 3.8 to 232 ± 16 mU/min/g wet tissue; p < 0.01; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1α (PGF1α), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Collectively these data indicate that hexarelin displays a strong heart-protectant activity against myocardial stunning in senescent rats. The protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Neither compound appears able to interfere with the endothelium-dependent relaxant mechanism.