The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH were studied on the mechanical and metabolic changes elicited by the calcium-paradox phenomenon in isolated rat hearts submitted to 5 min Ca(2+)-depletion followed by reperfusion with reintegrated Ca(2+)medium. Hexarelin, (80 microg kg(-1)s.c.) administered to normal male young rats for 3 and 7-day, time-dependently antagonized the sudden increase in resting tension of the isolated perfused hearts upon Ca(2+)-repletion. The beneficial effect of hexarelin was particularly evident in the 7-day treatment. In this instance, ventricular contraction peaked at 30 +/- 2 mmHg (controls, 76 +/- 7 mmHg) and the recovery of left ventricular developed pressure (LVDP) was two times higher (P<0.001) than that recorded in controls (LVDP, 29 +/- 2 mmHg). Moreover, the release of creatine kinase into the heart effluent during Ca(2+)-repletion was reduced by 40% (P<0.001) as compared to controls. The protecting activity of hexarelin against the damage induced by calcium-paradox in the heart was apparently divorced from any stimulation of the GH/insulin-like growth factor (IGF) axis, since plasma and heart concentrations of IGF-1 were similar to those measured in control rats. In contrast to hexarelin, administration of GH (400 microg kg(-1) s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 microg ml(-1)) perfused for 60 min through the hearts in recirculating conditions did not modify heart contractility and failed to prevent ventricular hypercontractility developed on Ca(2+)-readmission. In conclusion, the mode of action of hexarelin in protecting the rat heart from calcium-paradox events is presently unknown; it would seem, however, that only prolonged exposure to hexarelin makes myocardial cells competent to maintain cytoplasmatic electrolyte balance and to control of Ca(2+)gain, two functions that are impaired during the 'calcium-paradox' phenomenon.
Copyright 2000 Academic Press.