Functional and in situ hybridization evidence that preganglionic sympathetic vasoconstrictor neurons express ghrelin receptors

doi:10.1016/j.neuroscience.2010.01.001

Neuroscience

Volume 166, Issue 2, 17 March 2010, Pages 671-679

https://doi.org/10.1016/j.neuroscience.2010.01.001 Get rights and content

Abstract

Agonists of ghrelin receptors can lower or elevate blood pressure, and it has been suggested that the increases in blood pressure are caused by actions at receptors in the spinal cord. However, this has not been adequately investigated, and the locations of neurons in the spinal cord that express ghrelin receptors, through which blood pressure increases may be exerted, are not known. We investigated the effects within the spinal cord of two non-peptide ghrelin receptor agonists, GSK894490 and CP464709, and two peptide receptor agonists, ghrelin and des-acyl ghrelin, and we used polymerase chain reaction (PCR) and in situ hybridization to examine ghrelin receptor expression. I.v. application of the non-peptide ghrelin receptor agonists caused biphasic changes in blood pressure, a brief drop followed by a blood pressure increase that lasted several minutes. The blood pressure rise, but not the fall, was antagonized by i.v. hexamethonium. Application of these agonists or ghrelin peptide directly to the spinal cord caused only a blood pressure increase. Des-acyl ghrelin had no significant action. The maximum pressor effects of agonists occurred with application at spinal cord levels T9 to T12. Neither i.v. nor spinal cord application of the agonists had significant effect on heart rate or the electrocardiogram. Ghrelin receptor gene expression was detected by PCR and in situ hybridization. In situ hybridization localized expression to neurons, including autonomic preganglionic neurons of the intermediolateral cell columns at all levels from T3 to S2. The numbers of ghrelin receptor expressing neurons in the intermediolateral cell columns were similar to the numbers of nitric oxide synthase positive neurons, but there was little overlap between these two populations. We conclude that activation of excitatory ghrelin receptors on sympathetic preganglionic neurons increases blood pressure, and that decreases in blood pressure caused by ghrelin agonists are mediated through receptors on blood vessels.

Section snippets

Physiological studies

A total of 98 male Sprague–Dawley rats with an average weight of 350 g and average age of 60 days were supplied with food and water ad libitum prior to experiments. The procedures were approved by the University of Melbourne Animal Experimentation Ethics Committee and the Animal Care Committee of the School of Veterinary Sciences, Gifu University. Rats were sedated with ketamine hydrochloride (50–60 mg/kg i.m.) and anesthesia was induced with α-chloralose (60 mg/kg i.v.). Following

Effects of intravenous administration of ghrelin receptor agonists

I.v. administration of either ghrelin receptor agonist, at doses ranging from 2.5–10 mg/kg (CP464709) and 0.5–1.5 mg/kg (GSK894490), gave a characteristic blood pressure response, consisting of a rapid initial blood pressure decrease, followed by a longer lasting rise in blood pressure (Fig. 1). The decrease was dose-dependent, with a larger fall with increasing agonist concentration (Table 1), whereas the blood pressure increases to each drug were similar at doses in the range tested. The

Discussion

The present study provides evidence that autonomic preganglionic neurons in the spinal cord express the ghrelin receptor and that ghrelin receptor agonists can activate some of these neurons to increase blood pressure. By contrast, activation of peripheral ghrelin receptors caused blood pressure to decrease, probably by a direct action on blood vessels.

Conclusion

We conclude that ghrelin receptors are expressed by sympathetic preganglionic neurons of vasoconstrictor pathways and that their activation increases blood pressure. Thus it may be feasible to target ghrelin receptors to control blood pressure.

Acknowledgments

This work was supported by a grant from the National Health and Medical Research Council of Australia (Grant number 508947). We thank Zhengdong Qu for assistance with in situ hybridization. Microscope facilities were provided by the Australian Phenomics Network Histopathology and Organ Pathology Node.

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Systems NeuroscienceResearch PaperFunctional and in situ hybridization evidence that preganglionic sympathetic vasoconstrictor neurons express ghrelin receptors

Abstract

Section snippets

Physiological studies

Effects of intravenous administration of ghrelin receptor agonists

Discussion

Conclusion

Acknowledgments

Peptides

Neuron

Regul Pept

Mol Brain Res

Trends Pharmacol Sci

Peptides

Biochem Biophys Res Commun

Trends Genet

A quantitative approach to recording peristaltic activity from segments of rat small intestine in vivo

Neurogastroenterol Motil

Postprandial response of plasma ghrelin levels to various test meals in relation to food intake, plasma insulin, and glucose

J Clin Endocrinol Metab