Ghrelin Prevents Incidence of Malignant Arrhythmia after Acute Myocardial Infarction through Vagal Afferent Nerves

Abstract

Ghrelin is a GH-releasing peptide mainly excreted from the stomach. Ghrelin administration has been shown to inhibit cardiac sympathetic nerve activity (CSNA), reduce malignant arrhythmia, and improve prognosis after acute myocardial infarction (MI). We therefore investigated the effects and potential mechanisms of the action of endogenous ghrelin on survival rate and CSNA after MI by using ghrelin-knockout (KO) mice. MI was induced by left coronary artery ligation in 46 KO mice and 41 wild-type mice. On the first day, malignant arrhythmia-induced mortality was observed within 30 min of the ligation and had an incidence of 2.4% in wild-type and 17.4% in KO mice (P < 0.05). We next evaluated CSNA by spectral analysis of heart rate variability. CSNA, represented by the low frequency/high frequency ratio, was higher in KO mice at baseline (2.18 ± 0.43 vs. 0.98 ± 0.09; P < 0.05), and especially after MI (25.5 ± 11.8 vs. 1.4 ± 0.3; P < 0.05), than in wild-type mice. Ghrelin (150 μg/kg, s.c.) 15 min before ligation suppressed the activation of CSNA and reduced mortality in KO mice. Further, this effect of ghrelin was inhibited by methylatropine bromide (1 mg/kg, i.p.) or by perineural treatment of both cervical vagal trunks with capsaicin (a specific afferent neurotoxin). Our data demonstrated that both exogenous and endogenous ghrelin suppressed CSNA, prevented the incidence of malignant arrhythmia, and improved the prognosis after acute MI. These effects are likely to be via the vagal afferent nerves.

Endogenous Ghrelin Attenuates Pressure Overload–Induced Cardiac Hypertrophy via a Cholinergic Anti-Inflammatory Pathway

“…22 In cases of methylatropine bromide (1 mg/kg) administration, it was injected intraperitoneally 5 minutes after the ghrelin injection. 23 …”

Ghrelin As a Treatment for Cardiovascular Diseases

“…Costaining with acetylcholine esterase and choline acetyltransferase suggested that GHSR1a is localized on or in close proximity to the vagal nerve terminals in the heart. 60,61 Therefore, substantial evidence indicates that ghrelin has a cardiovascular function.…”

“…60,61,70 Ghrelin receptors are synthesized in vagal afferent neurons and are transported to the afferent terminals in the stomach. Ghrelin produced in the stomach stimulates the gastric vagal afferent nerve that leads to the nucleus tractus solitarius, influencing its neuronal activity and increasing feeding behavior.…”

“…71 We showed that GHSR1a is present in the myocardia of rats and mice, where it is localized at or in proximity to vagal nerve terminals in the heart. 60,61 Blocking the vagal afferent nerves by pretreating them with capsaicin, a toxin specific for sensory afferent neurons, markedly attenuates the beneficial effects of ghrelin treatment after MI, such as the inhibition of cardiac SNA and arrhythmias and the improvement of prognoses. 61 Similarly, the sympathoinhibitory effect of intravenous ghrelin administration in postgastrectomy vagotomized patients is abolished, suggesting that vagal sensory afferents mediate the effects of peripheral ghrelin.…”

Decreased Serum Ghrelin Levels in Patients with Acute Myocardial Infarction

“…GHS-R mRNA is found not only in the hypothalamus and pituitary gland but also in the heart and blood vessels (Gnanapavan et al 2002). Significant evidence for a cardiovascular function of ghrelin and its role in the regulation of autonomic activity has been reported (Soeki et al 2008;Mao et al 2012). Although recent experimental studies have demonstrated that administration of ghrelin could protect against ischemia and reperfusion injury, attenuate post-infarction ventricular dysfunction and remodeling, and improve the prognosis of myocardial infarction and heart failure (Nagaya et al 2001;Chang et al 2004;Schwenke et al 2008;Soeki et al 2008;Mao et al 2012), the role of ghrelin in the clinical setting remains unknown.…”