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Effect of hexarelin on transient outward potassium current in rat ventricular myocytes

Q. Sun and C. Chen, Endocrine Cell Biology, Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, VIC 3168, Australia.

Hexarelin is a synthetic peptide growth hormone secretagogue (GHS), which possesses a variety of cardiovascular protective effects mediated by the GHS receptor (GHSR), including improving cardiac dysfunction and remodeling (Xu et al., 2005). It has been reported that GHRP increased Ca2+ influx via voltage-gated Ca2+ channels in cultured neonatal rat cardiomyocytes (Xu et al., 2003). This increase in Ca2+-influx can be achieved by a direct increase in Ca2+ channel conductance and/or a decrease in K+ channel conductance with prolonged depolarization. Modification of ion channels and the intracellular signaling pathways by GHS are currently unknown and this study aims to fill this gap. Ventricular myocytes were enzymatically isolated from adult male Sprague-Dawley rats and kept in Tyrode solution. Nystatin-perforated whole-cell patch-clamp recording was performed on isolated cells within 6 hours after successful cell preparetion. Hexarelin (100 nmol, 10 nmol, 1 nmol, 0.1 nmol, and 0.01 nmol) inhibited transient outward potassium current (Ito) in a dose-dependent manner. The inhibition appeared at doses above 0.01 nmol. Ghrelin evoked similar inhibition on this K+ current. The inhibition was abolished in the presence of the GHS-R1a specific antagonist BIM28163. In term of triggered action potential duration (APD), ghrelin and hexarelin significantly prolonged APD in the presence of the calcium channel blocker CoCl2 (2 mmol) and the delayed rectifier K+ channel blocker tetraethylamonium (50 mmol/l) in bath solution. The hexarelin-induced Ito inhibition was abolished by the protein kinase C (PKC) inhibitor, Gö-6983, but not by the PKA inhibitor, H89. We therefore conclude that hexarelin and ghrelin activate PKC system through the stimulation of GHS-R1a, resulting in a decrease in the Ito amplitude, prolongation of action potential duration, and increase in Ca2+-influx.

Xu X-B, Cao J-M, Pang J-J. (2003) Endocrinology 44: 5050-7.

Xu XB, Pang JJ, Cao JM, Ni C, Xu RK, Peng XZ, Yu XX, Guo S, Chen MC & Chen C. (2005) American Journal of Physiol, 289 H1643-51.

Supported by project grant from NH&MRC.