Elsevier

Regulatory Peptides

Volume 105, Issue 1, 15 April 2002, Pages 29-34
Regulatory Peptides

Cardiovascular actions of central neuromedin U in conscious rats

https://doi.org/10.1016/S0167-0115(01)00381-0Get rights and content

Abstract

Neuromedin U (NMU) is a brain–gut peptide, which peripherally stimulates smooth muscle, increases of blood pressure, alters ion transport in the gut, controls local blood flow, and regulates adrenocortical function. Although intracerebroventricular (i.c.v.) administration of NMU is known to decrease food intake and body weight, little is known about its effect on other physiological functions. We examined the effects of i.c.v. administration of NMU on mean arterial pressure (MAP), heart rate (HR), and plasma norepinephrine in conscious rats. Neuromedin U (0.05 and 0.5 nmol) provoked an increase in MAP (93.8±0.5 to 123.5±1.7 and 94.7±0.8 to 132.7±3.0 mm Hg, respectively) and HR (334.9±6.0 to 494.1±6.9 and 346.3±3.3 to 475.1±8.9 beats/min, respectively). In contrast, plasma norepinephrine increased only with a high dose of neuromedin U. Intravenously administered NMU (0.5 nmol) elicited a small and short lasting increase in MAP, compared to that by i.c.v. NMU. These results indicate that central neuromedin U regulates sympathetic nervous system activity and affects cardiovascular function.

Introduction

Neuromedin U (NMU), which was first isolated from porcine spinal cord and later from other species and organs, is a neuropeptide with potent activity on smooth muscle. It is widely distributed in the gut and central nervous system [1], [2], [3], [4], [5], [6], [7], [8]. The peripheral activities of MNU include stimulation of smooth muscle, increase of blood pressure, alteration of ion transport in the gut, control of local blood flow, and regulation of adrenocortical function. Intracerebroventricular (i.c.v.) administration of NMU to free-feeding rats has been reported to decrease food intake and body weight [9]. However, little is known about its other physiological roles. NMU is expressed in the ventromedial hypothalamus in rats, and its level is significantly reduced following fasting [10]. This supports its proposed role in the regulation of feeding and energy balance. Peptides that affect food intake have been shown to influence cardiovascular response and sympathetic nervous system activity [11], [12].

The recent identification of two NMU receptors in rat brain has provided a springboard for further investigation into its role in the central nervous system. An orphan G-protein-coupled receptor, FM-3 [13], and a newly discovered one, FM-4, are cognate receptors for NMU. FM-3, designated NMU1R, is abundantly expressed in peripheral tissues, whereas FM-4, designated NMU2R, is expressed in specific regions of the brain [10], [14], [15]. In the rat brain [10], NMU2R is expressed in the paraventricular nucleus (PVN) of the hypothalamus. PVN neurons project directly to the sympathetic preganglionic neurons in the spinal cord and control sympathetic outflow [16]. These findings raise the possibility that NMU affects cardiovascular function through its action on the central nervous system. Because anesthesia is well known to affect the cardiovascular and autonomic nervous systems profoundly [17], the present study was carried out in conscious, freely moving rats to investigate the effect of i.c.v.-administered NMU on mean arterial pressure (MAP), heart rate (HR), and sympathetic nervous outflow.

Section snippets

Animal preparation and data collection

The experiments were approved by the Committee on Animal Care of Miyazaki Medical College. Male Wistar rats weighing 350–450 g each were implanted with a lateral cerebroventricular cannula under anesthesia by intraperitoneal injection of pentobarbital sodium (50 mg/kg). A 24-gauge stainless-steel guide cannula (length, 19 mm) was positioned 2.5 mm from the cortex surface and 1 mm above the left lateral cerebroventricle through a burr hole located stereotaxically 0.8 mm posterior and 1.5 mm

Results

Intracerebroventricularly administered neuromedin U resulted in a rapid and progressive increase in MAP and HR at 0.5 and 0.05 nmol, respectively (Fig. 1). Increases in arterial pressure were significantly larger at 0.5 than at 0.05 nmol. However, there was no significant difference in the increase in heart rate between 0.05 and 0.5 nmol. These MAP and HR effects were observed within 10 min of the injection and lasted approximately 90 min before returning to the baseline at 0.05 nmol. However,

Discussion

This study is the first to demonstrate that NMU can influence central cardiovascular control as a result of its actions on the central nervous system (CNS). Intracerebroventricular administration of NMU (0.5 and 0.05 nmol) resulted in a progressive increase in MAP with an associated increase in HR. The BP and HR responses in this study are similar to those arising from microinjection of other neuropeptides, such as orexin [12], leptin [11], and neuropeptide Y [19]. These results further

Acknowledgements

We appreciate Kumiko Iki's technical assistance. This work was supported in part by grants-in-aid for scientific Research (10557009 and 11470019) from the Ministry of Education, Science, Sports, and Culture, Japan. This study was carried out as a part of “Ground Research Announcement for Space Utilization” by the Japan Space Forum.

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