Effects of central and peripheral injections of apelin on fluid intake and cardiovascular parameters in rats
Introduction
Apelin is the endogenous ligand for a G-protein coupled receptor, APJ, originally an orphan receptor [1], [2]. The principal endogenous ligand for the APJ receptor is thought to be apelin-36, one of several cleavage products of preproapelin, a 77 amino acid precursor [2], [3]. Apelin-36, apelin-13 and pyroglutamylated apelin-13 ([< Glu65]apelin-13; [pGlu]-apelin-13) have been detected in several tissues including the central nervous system where it may serve as a neurotransmitter or modulator. In the rat brain, APJ mRNA has been found in hippocampus, striatum, cerebellum, paraventricular (PVN) and supraoptic (SON) nuclei [1], [4], [5]. Neurons synthesizing apelin have been found in the median preoptic nucleus (MnPO), PVN and SON [5]. Apelin immunoreactivity has also been detected in the circumventricular organs — subfornical organ (SFO), organum vasculosum laminae terminalis (OVLT), and area postrema [6].
The presence of apelin in regions of the brain involved in the actions of angiotensin II (Ang II) in the regulation of fluid balance and blood pressure, including SFO, OVLT, MnPO, SON and PVN, has led to the suggestion that apelin plays a role in these regulatory functions. ACE2, an enzyme that is part of the renin–angiotensin system (RAS) also affects the degradation of apelin, suggesting some cross talk between apelin and the RAS. Additional support for apelin's role in blood pressure regulation comes from studies in which systemic administration of either apelin-12, apelin-13 or [pGlu]-apelin-13 was found to decrease mean arterial pressure (MAP) in anesthetized rats [7], [8], [9], [10]. In contrast, the same systemic administration in awake rats has produced less consistent findings with either increases [11] or decreases [9], [12] in MAP. The literature on fluid intake is likewise inconsistent. A dipsogenic effect of apelin has been reported in water-replete rats following systemic [7] or central [13] administration of apelin. In contrast, an inhibitory effect on drinking has been found in dehydrated rats [5]. The reasons for these inconsistencies are not clear, but may reflect procedural differences between the laboratories.
The aim of this paper is to examine in one laboratory the effects of peripheral and central administration of apelin on fluid intake in dehydrated and non-dehydrated rats, as well as the effects of these treatments on blood pressure in anesthetized and non-anesthetized rats. In some of the studies, Ang II is used as a positive control treatment.
Section snippets
Animals and housing environment
Adult male Sprague-Dawley rats (Harlan Laboratories, Indianapolis, IN) weighing 400–450 g at the time of study were housed individually in polycarbonate cages with stainless steel wire mesh lids in a temperature (21–24 °C) and humidity (45–55%) controlled vivarium. The cages contained approximately 5 cm of Sani-chip® bedding (from Teklad-Harlan, Madison, WI). Animals had ad libitum access to tap water and standard rat chow (Purina 5001 Chow Pellets) except as noted. The vivarium was maintained
Drinking studies
The results of the drinking studies are summarized in Fig. 1, Fig. 2. These indicate that while the animals drank to i.c.v. Ang II (10 pmol), [pGlu]-apelin-13 (30 nmol) was not able to either stimulate water intake in undeprived rats or to suppress water intake in water-deprived rats. Central injection of apelin produced no change in sodium appetite in sodium depleted rats. Intravenous infusion of [pGlu]-apelin induced a drinking response in only 1 out of 13 rats tested (intake = 1.8 ml). Under
Discussion
The finding that the APJ receptor has some sequence homology to the AT1a receptor [1] led to the suggestion that apelin may be involved in fluid consumption and blood pressure regulation. Results by other investigators [5], [7], [8], [9], [10], [11], [12], [13] have not found consistent effects of apelin on either fluid or blood pressure regulation. In the current study we attempted to reproduce the critical features from previous studies to evaluate both central and peripheral effects of
Acknowledgements
Special thanks to Kim Robertson and Justin Grobe for their keen insights and technical assistance.
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2016, Bioorganic and Medicinal ChemistryCitation Excerpt :Taken together, APJ has emerged as an intriguing target for cardiovascular diseases. APJ has also emerged as an attractive target because of its possible involvement in fluid homeostasis,20,21 liver fibrosis,22 obesity,23–28 diabetes,29–31 neuroprotection,32–34 immune response,35,36 nociception37 and others. Pathophysiological roles played by APJ are currently being elucidated using various apelin peptides.21,29,38,39
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