Hexarelin, but not growth hormone, protects heart from damage induced in vitro by calcium deprivation replenishment

The effects of hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts sub mitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-conta ining medium, the so-called calcium paradox phenomenon, were studied. Hexar elin (80 mug/kg bid, subcutaneously) administered for 7 d to male rats effe ctively antagonized the sudden increase in resting tension measured in vitr o on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatin e kinase activity (an index of cell damage) in the perfusate of these heart s was reduced up to 40% compared with controls. By contrast, administration of hexarelin for 3 d or GH (400 mug/kg bid, subcutaneously) for 7 d did no t affect the mechanical and metabolic alterations induced by the calcium pa radox. To assess its direct and acute cardiac effects, hexarelin (8 mug/ml) was perfused in vitro in recirculating conditions for 60 min through the h earts of normal rats. In this case, hexarelin did not stimulate heart contr actility and failed to prevent ventricular contracture upon Ca2+ readmissio n, whereas diltiazem, a Ca(2+)channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two function s largely impaired during the calcium paradox phenomenon. Moreover, because the effect of hexarelin is not acute but dependent on the length of in viv o treatment, we suggest that it requires modifications of myocardiocyte phy siology.