Role of endothelial cells in modulation of contractility induced by hexarelin in rat ventricle.
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.
Bedendi
I
I
Dipartimento di Biologia Animale e dell'Uomo, Torino, Italy.
Gallo
M P
MP
Malan
D
D
Levi
R C
RC
Alloatti
G
G
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D016276:Ventricular Function
D009842:Oligopeptides; C086184:hexarelin; D009569:Nitric Oxide