Effect of ghrelin and synthetic growth hormone secretagogues in normal and ischemic rat heart

Abstract

Receptors for growth hormone secretagogues have been identified in cardiac tissue, but their functional role is unknown. We have investigated the effect of different growth hormone secretagogues on contractile performance and on the susceptibility to ischemic injury, in isolated working rat hearts. In particular, we tested the endogenous secretagogue ghrelin and the synthetic secretagogues hexarelin and MK-0677. Under aerobic conditions, none of these substances produced any significant hemodynamic effects. In hearts subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion, the synthetic peptidyl secretagogue hexarelin (1 microM) significantly reduced infarct size, as estimated on the basis of triphenyltetrazolium chloride staining, while the non-peptidyl secretagogue MK-0677 was ineffective. The endogenous peptidyl secretagogue ghrelin (20 nM) was also protective, while desacylated ghrelin, which is devoid of biological effects, did not modify ischemic injury. The protection provided by hexarelin was partly abolished by the protein kinase C inhibitor chelerythrine. We conclude that ghrelin and hexarelin have a specific cardioprotective effect, which is independent of growth hormone secretion, and might be related to protein kinase C activation.

Ghrelin, des-acyl ghrelin and obestatin: Three pieces of the same puzzle

“…These may result not only from an increase in GH, appetite and vasodilation, and decrease in cytokine production, but also from direct effects of ghrelin on cardiomyocytes. In vitro, ghrelin decreases inotropism [10,133] and lusitropism [133], inhibits apoptosis of cardiomyocytes [4], improves myocardial function during ischemia/reperfusion and isoproterenol-induced injury [27,92] and reduces infarct size [49]. In healthy volunteers [106] and patients with chronic heart failure [107], ghrelin decreases systemic vascular resistance, which results in increased cardiac output as shown by increased cardiac index and stroke-volume index.…”

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

“…The cardioprotective effects of hexarelin and ghrelin have been well investigated. Many studies have shown their beneficial effects on the cardiovascular system such as protection against cardiac ischemia, cardiac fibrosis, improving cardiac function, and decreasing peripheral resistance after myocardial infarction (MI) in animals [164][165][166] and humans [167]. Our group showed that treatment of spontaneously hypertensive rats (SHRs) with hexarelin for 5…”

Ghrelin in cardiovascular disease and atherogenesis

“…The possible protective effect of ghrelin and the synthetic secretagogues hexarelin and MK-0677 were tested on isolated perfused rat hearts subjected to I/R (Frascarelli et al, 2003). While hexarelin and AG significantly reduced infarct size, MK-0677 and UAG were ineffective.…”

“…Ghrelin has been shown to have protective effects by inhibiting cardiomyocyte and endothelial cell apoptosis (Baldanzi et al, 2002), and to improve left ventricular (LV) function during ischemia-reperfusion (I/R) injury (Frascarelli et al, 2003). In rats with heart failure (HF), ghrelin improves LV dysfunction and attenuates the development of cardiac cachexia (Nagaya 2001b).…”