To better illustrate the involved
To better illustrate the involved neuronal postganglionic pathways, central apelin-13 injection was performed in rats received peripheral preadministration of NOS inhibitor L-NAME, sympatholytic agent guanethidine and/or muscarinic receptor agonist bethanechol. Compared with the rats received vehicle injection, treatment of guanethidine (63.4% ± 5.3, n = 6) or L-NAME (54.5% ± 4.3, n = 6) itself did not change solid GE noticeably, whereas bethanechol injection alone produced a slight, but significant increase (71.2% ± 2.5, n = 6). In vehicle-injected rats, solid GE was measured 60.42% ± 2.2 (n = 6), however it was decreased significantly in rats injected with apelin-13 (29.2% ± 2.3, n = 6, p < 0.05). L-NAME did not change the apelin-induced alterations in GE (31.4% ± 3.2, n = 6). In contrast, preadministration of guanethidine (41.1% ± 6.5; p < 0.05, n = 6) or bethanechol (50.3% ± 5.9; p < 0.05, n = 6) restored the apelin-induced delayed GE partially, whereas apelin no longer inhibited solid GE when both agents were combined (59.7% ± 6.2; p < 0.01, n = 6), (Fig. 5).
For evaluation the effects of central apelin-13 on sympathetic and parasympathetic outflow, HRV was assessed during pre- and post-injection periods of vehicle (PBS) or apelin-13 administration. Compared to vehicle, central administration of apelin-13 induced a significant (p < 0.05, n = 4) increase in HRV spectral activity in the LF range (0.05–0.75 Hz), while decreasing the HF (0.75–2.5 Hz) component. Apelin-13 decreased the ratio of LF:HF significantly (p < 0.05) which is considered as an indicator of sympathovagal balance (Fig.6).
Discussion Following ingestion of a solid meal, GE is regulated mainly by the tonic resistance of the pyloric sphincter and coordinated contractions from antrum towards pylorus which appear to be essential in propelling the gastric contents to the AK-7 sale during emptying phase (De Block et al., 2006; Haba and Sarna, 1993; Nakade et al., 2006). The vagal efferent fibers originating from moto-neurons in the DMV regulate gastric motor functions through their projections either to excitatory cholinergic or NANC postganglionic myenteric neurons, therefore, delayed GE may occur due to the diminished gastric motility as a result of inhibition of the vagal cholinergic and/or excitation of the vagal NANC pathway (Browning and Travagli, 2014; Travagli and Anselmi, 2016; Travagli et al., 2006). In contrast, as a general concept, the sympathetic branch of autonomic nervous system exhibits an inhibitory action on GI smooth muscle contractility which results in gastric relaxation and delayed GE (Nakade et al., 2005; Nakade et al., 2006). The neurons in NTS project several regions in brainstem including DMV and caudal ventrolateral medulla (CVLM)/RVLM which are the autonomic centers involved in regulation of parasympathetic and sympathetic neuronal activity, respectively. Within the medulla oblongatai the RVLM contains neurons that have a key role in determining peripheral sympathetic tone. The NTS neurons send their glutamatergic excitatory fibers to CVLM and once activated, the CVLM neurons inhibit the RVLM through mediation of GABA (Campos et al., 2008; Kumagai et al., 2012). Moreover, along with a subgroup neuronal cells in PVN, the fibers origination from RVLM directly project to sympathetic preganglionic neurons within the IML column of the spinal cord, which in turn innervating the noradrenergic cells in the celiac ganglion that inhibit the contractility of gastric smooth muscle via adrenergic receptors (Browning and Travagli, 2014; Nakade et al., 2005). Previous rodent studies have demonstrated that centrally-injected apelin inhibits motor functions both in upper (Birsen et al., 2016; Bulbul et al., 2016; Bulbul et al., 2018; Lv et al., 2011) and lower (Yang et al., 2010) GI tract in rodents. In rats received intra-DMV microinjection of apelin-13, the gastroinhibitory action was abolished by atropine and vagotomy suggesting that central apelin exerts these effects by diminishing the vagal-cholinergic pathway. On the other hand, the data of the recent rodent studies demonstrated that intra-RVLM and intra-PVN microinjection of apelin-13 increased renal sympathetic activity, brown adipose tissue temperature, heart rate and arterial pressure (Masaki et al., 2012; Seyedabadi et al., 2002; Yao et al., 2011; Zhang et al., 2009). These findings are consistent with the notion that the inhibitory effect of central apelin on gastric motor functions might be mediated by a dual mechanism which is involved with simultaneous modulation of parasympathetic and sympathetic outflow.