G. Rossoni et al., Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium, PHARMAC RES, 42(2), 2000, pp. 129-136
The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogu
e, and of human GH were studied on the mechanical and metabolic changes eli
cited by the calcium-paradox phenomenon in isolated rat hearts submitted to
5 min Ca2+-depletion followed by reperfusion with reintegrated Ca2+ medium
. Hexarelin, (80 mu g kg(-1) s.c.) administered to normal male young rats f
or 3 and 7-day, time-dependently antagonized the sudden increase in resting
tension of the isolated perfused hearts upon Ca2+-repletion. The beneficia
l effect of hexarelin was particularly evident in the 7-day treatment. In t
his 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 efflue
nt during Ca2+-repletion was reduced by 40% (P < 0.001) as compared to cont
rols. The protecting activity of hexarelin against the damage induced by ca
lcium-paradox in the heart was apparently divorced from any stimulation of
the GH/insulin-like growth factor (IGF) axis, since plasma and heart concen
trations of IGF-1 were similar to those measured in control rats. In contra
st to hexarelin, administration of GH (400 mu g 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 mu g ml(-1)) perfused for 60 min through the hearts in recircu
lating conditions did not modify heart contractility and failed to prevent
ventricular hypercontractility developed on Ca2+ 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, t
hat only prolonged exposure to hexarelin makes myocardial cells competent t
o maintain cytoplasmatic electrolyte balance and to control of Ca2+ gain, t
wo functions that are impaired during the 'calcium-paradox' phenomenon. (C)
2000 Academic Press.