The synthetic
growth hormone (GH)
secretagogue hexarelin has important cardiac effects, that include a reduction of dysfunction in ischemic-reperfused hearts from GH-deficient rats after a chronic treatment and an increase of ejection fraction in acutely treated men. To investigate the mechanisms of its cardiac activity, we studied the effects of
hexarelin (1-10 microM) on contractility of rat papillary muscles. We observed, in
hexarelin treated papillary muscles, an improved recovery of contractility after
anoxia.
Hexarelin induced time- and frequency-dependent inotropic effects on papillary muscle. These effects were a transient increase in contractile force, abolished by
propranolol (0.2 microM), followed by a reduction at low (60-240/min), but not at high (400-600/min) beating frequencies. The typical negative force-frequency relationship present in rat papillary muscles was therefore modified, and a minor increase in diastolic tension occurred after a sudden increase in stimulus frequency. Blockade of NO synthesis with 1 mM
L-NAME, partially altered the response to
hexarelin.
MK-677 (1 microM), a non peptidyl GH
secretagogue, reduced contractility, but did not alter the force-frequency relationship. The remaining effects of
hexarelin were absent in papillary muscles pre-treated with
indomethacin (1 microM), or after removal of endocardial endothelium with 0.5%
triton X-100. The release of the
prostacyclin metabolite 6-keto-PGF1alpha was increased during reoxygenation after a period of
anoxia in
hexarelin treated papillary muscles.
Hexarelin had no significant effect on
calcium transients and on I(Ca) measured in isolated ventricular cells. These findings suggest that the effects of
hexarelin are mainly due to endothelium-released PGI2.