Effects of GH Secretagogues on Contractility and Ca²⁺Homeostasis of Isolated Adult Rat Ventricular Myocytes

Abstract

Ghrelin and its synthetic analogue hexarelin are specific ligands of GH secretagogue receptor (GHS-R) and induce a variety of cardiovascular protective and cardiac positive inotropic effects. The signaling system underlying immediate effects of both GHSs in cardiomyocytes remains undefined. In the present study, we investigated the immediate effects of GHSs on isolated ventricular myocyte shortening, intracellular Ca(2+) ([Ca(2+)](i)) transients, and the L-type Ca(2+) current (I(Ca,L)). Putative intracellular signalling cascades were studied with specific receptor and signalling blockers. In fresh isolated adult Wistar rat ventricular myocytes, GHSs produced a positive inotropic effect in a concentration-dependent manner and increased the amplitude of [Ca(2+)](i) transients and the I(Ca,L). The positive inotropic response was abolished by the GHS-R1a antagonist [D-Lys(3)]-GH-releasing peptide-6 (10 microm). GHS-induced increase in the I(Ca,L) was abolished by [D-Lys(3)]-GH-releasing peptide-6 and protein kinase C inhibitor, chelerythrine chloride (5 microm), but not by protein kinase A inhibitor, KT 5720 (10 microm). We conclude that hexarelin and ghrelin increase the I(Ca,L), through GHS-R1a receptor and protein kinase C signalling cascade, which contribute to its direct positive inotropic effect on cardiomyocytes.

Characterization of a far-red analog of ghrelin for imaging GHS-R in P19-derived cardiomyocytes

“…Cardiomyocyte contraction in normal isolated cardiomyocytes and inhibition of sympathetic activity appear to be mediated through ghrelin activation of GHS-R1a [14,26]. Both actions could contribute either directly or indirectly to the promotion of cardiomyocyte survival.…”

“…In addition to effects on whole-body metabolism, there is a growing body of evidence to support the hypothesis that ghrelin exerts effects on the cardiovascular system, and in particular, directly on cardiomyocytes. In fact, ghrelin is synthesized in and secreted from human cardiomyocytes [6], binds in a specific and saturable manner to human left ventricular tissue [8], and stimulates contractility in isolated rat ventricular myocytes through increasing Ca2+ current via GHS-R [26]. Additionally, ghrelin administration inhibits cardiomyocyte apoptosis [1] and promotes differentiation of human embryonic stem cells to mature cardiomyocytes through the extracellular signal-regulated kinase (ERK 1/2) signaling pathway [4], but it is not clear if these effects are mediated through GHS-R.…”

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

“…AG has been shown to increase Ca 2+ release in cardiomyocytes (Sun et al. 2010) and CaMKII activation in glial cells (Chen et al. 2011).…”

The Growth Hormone Secretagogue Hexarelin Protects Rat Cardiomyocytes From <i>in vivo</i> Ischemia/Reperfusion Injury Through Interleukin-1 Signaling Pathway

“…8) Hexarelin, a synthetic analog of ghrelin, shows effects similar to those of ghrelin and is more chemically stable, making it a potential alternative to ghrelin. Its beneficial action on the cardiovascular system has been reported by a lot of research, including inhibition of cardiomyocyte apoptosis, [9][10][11] anti-atherosclerosis, 12,13) improving cardiac output, [14][15][16][17] and suppressing cardiac fibrosis. 18) These effects are considered to be mediated not only by GHSR1a but also by activation of cardiac CD36 receptors.…”