Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function

Abstract

Key points• Apelin receptor mRNA is expressed in the subfornical organ.• Apelin influences the excitability of the majority of subfornical organ neurons, with similar proportion showing depolarizing and hyperpolarizing effects.• Hyperpolarizations appear to result from the activation of a sustained voltage-activated potassium conductance, while depolarizations may result from modulation of a non-selective cationic conductance.• In vivo microinjection of apelin into the subfornical organ results in decreases in blood pressure.Abstract Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood-brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nM apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 ± 0.8 mV) or hyperpolarizing (28.6%, mean −10.4 ± 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve −1492.3 ± 357.1 mmHg.s, n = 5) and heart rate (HR) (−32.4 ± 10.39 beats, n = 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons.

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

“…Similarly, studies of peripheral apelin administration in conscious rats have reported both increases and decreases in MABP (Cheng et al 2003;Kagiyama et al 2005). These are ambiguous results in comparison to the MABP decreases consistently observed in anesthetized rats (Cheng et al 2003;Dai et al 2013;Lee et al 2000;Lee et al 2005;Reaux et al 2001;Tatemoto et al 2001). Interestingly, and perhaps of relevance to the different responses reported in rats, a study in sheep given a large systemic dose of apelin-13 led to a biphasic response in blood pressure (BP), with an initial transient decrease in BP immediately giving way to an increase in BP.…”

“…Microinjection of apelin into the RVLM caused chronic increases in mean arterial blood pressure (MABP) and cardiac hypertrophy. In contrast to these CNS effects, peripherally administered apelin has typically been shown to decrease MABP (Cheng et al 2003;Dai et al 2013;Lee et al 2000;Lee et al 2005;Reaux et al 2001;Tatemoto et al 2001). Interestingly, this effect is fully blocked by the C-terminally modified apelin-13 analogue F13A, which acts as an antagonist at the AR, preventing the typical apelin-induced MABP reduction (Lee et al 2005).…”

Protective axis of the renin–angiotensin system in the brain

“…ACE2 hydrolyses apelin or AngII with similar catalytic efficiency [77]. Intracerebroventricular administration of apelin does not modify BP [78], but its administration into the SFO decreases BP and heart rate as a consequence of its modulating effects on neuron excitability in this area [79]. A neuroprotective role has been attributed to apelin, as it has been shown that it attenuates neuron apoptosis after ischaemia/reperfusion injury [80].…”

The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis

“…More recently, however, it has been shown that microinjection of apelin-13 into the subfornical organ, which detects circulating signalling molecules, decreases BP and HR (Dai et al 2013). Additionally, the apelinergic system has an important role in cardiac function.…”