Ghrelin Supresses Sympathetic Hyperexcitation in Acute Heart Failure in Male Rats: Assessing Centrally and Peripherally Mediated Pathways

Abstract

The hormone ghrelin prevents a dangerous increase in cardiac sympathetic nerve activity (SNA) after acute myocardial infarction (MI), although the underlying mechanisms remain unknown. This study aimed to determine whether ghrelin's sympathoinhibitory properties stem either from directly within the central nervous system, or via modulation of specific cardiac vagal inhibitory afferents. Cardiac SNA was recorded in urethane-anesthetized rats for 3 hours after the ligation of the left anterior descending coronary artery (ie, MI). Rats received ghrelin either sc (150 μg/kg) or intracerebroventricularly (5 μg/kg) immediately after the MI. In another two groups, the cervical vagi were denervated prior to the MI, followed by sc injection of either ghrelin or placebo. Acute MI induced a 188% increase in cardiac SNA, which was significantly attenuated in ghrelin-treated rats for both sc or intracerebroventricularly administration (36% and 76% increase, respectively). Consequently, mortality (47%) and the incidence of arrhythmic episodes (12 per 2 h) were improved with both routes of ghrelin administration (<13% and less than five per 2 h, respectively). Bilateral vagotomy significantly attenuated the cardiac SNA response to acute MI (99% increase). Ghrelin further attenuated the sympathetic response to MI in vagotomized rats so that the SNA response was comparable between vagotomized and vagal-intact MI rats treated with ghrelin. These results suggest that ghrelin may act primarily via a central pathway within the brain to suppress SNA after MI, although peripheral vagal afferent pathways may also contribute in part. The exact region(s) within the central nervous system whereby ghrelin inhibits SNA remains to be fully elucidated.

Ghrelin Preserves Ischemia-Induced Vasodilation of Male Rat Coronary Vessels Following β-Adrenergic Receptor Blockade

“…The apparent lack of an effect of the b-AR blockade on the coronary circulation of ghrelin-treated animals is likely linked to the sympathoinhibitory properties of ghrelin, as we have consistently confirmed that ghrelin effectively prevents adverse sympathetic activation following acute MI (5)(6)(7)40). It is plausible, therefore, that the effect of the b-AR blockade in ghrelin-treated MI animals was negligible, as the b-ARs were not activated in the first place.…”

“…However, all of the measured parameters of cardiac work (HR, LVESP, contractility, and ABP) for sham rats in this study were unaltered by ghrelin. Moreover, we have consistently reported that modulation of SNA by ghrelin is not evident in sham animals, rather only in those animals with an MI where SNA adversely increases (6,7,27).…”

“…Ever since its discovery in 1999 (17), ghrelin has emerged as an important therapeutic modulator of cardiac function in health and disease (18). Whereas the exact mechanisms that underpin the cardioprotective properties of ghrelin remain to be fully elucidated, various groups have shown that ghrelin prevents MI-induced sympathetic activation (6,7,19,20), inhibits myocardial apoptosis (21), promotes angiogenesis (22,23), reduces cardiac cachexia and dysfunction (24), preserves cardiac contractility (25), and attenuates cardiac remodeling (26). Although ghrelin is known to modulate coronary vasculature tone directly, at least in animal models, the few reports, to date, do not agree as to whether ghrelin dilates or constricts coronary vessels (10)(11)(12)(13).…”

“…As a growth hormone-releasing hormone, ghrelin has been shown to improve cardiac growth and function in patients with chronic heart failure (4). Moreover, the early administration of ghrelin, immediately following acute MI, acts centrally to prevent cardiac sympathetic activation (5,6), which ultimately reduces the incidence of arrhythmias and attenuates the severity of cardiac dysfunction and remodeling (7).…”

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

“…The functional preservation of Cx43 by eliciting CAP would play an irreplaceable role in antiarrhythmogenic properties during ICM. Interestingly, Shirai et al 40 reported that bilateral vagotomy attenuated the cardiac sympathetic nerve activity response to acute MI that, in turn, reduced the incidence of arrhythmic episodes. In contrast, our study suggested that unilateral vagotomy not only aggravated the abnormality of ICM rats and increased the inducibility quotient of ventricular arrhythmias but also attenuated the effects of eliciting CAP.…”