THE AUTONOMIC AND SENSORY NEUROBIOLOGY LABORATORY

The Research

Nervous Control of Blood Pressure
The Noradrenaline Transporter and the Adrenal Gland
Complex Regional Pain Syndrome
Publications

Nervous Control of Blood Pressure

Blood pressure readings from a normal rat (top) and a rat with hypertension (bottom)

High blood pressure, or hypertension, is a major risk factor for heart attack and stroke and affects up to 17% of the Australian adult population. In nearly 90% of these people, the cause is unknown (essential hypertension) while for others, the high blood pressure may be related to other disease processes such as kidney failure. Much of the work in our laboratory aims to further our understanding of how nerves in the brain, that normally play a crucial role in keeping blood pressure at a regular level, may become over-active and contribute to hypertension.

We do this by looking at these nerves and the genes and proteins they express. Our goal is to determine the role played by these specialised groups of nerves and their contribution in changes to blood pressure. We are studying animals with essential hypertension (the spontaneously hypertensive rat; SHR) and also rats that kidney failure due to a genetic condition called polycystic kidney disease (PKD). We hope that our work will form the basis for development of new treatment for high blood pressure.

In collaboration with the Assoc. Prof. Paul Pilowsky and Dr Anne Goodchild from the Stroke and Hypertension Laboratory at Royal North Shore Hospital, Sydney NSW, we have been looking at the specific clusters of nerves in the brainstem and spinal cord which act specifically to control blood pressure.

Cells in the spinal cord labelled for the enzyme nitric oxide synthase that is responsible for making nitric oxide.

One region of the brain we are interested in is the rostral ventrolateral medulla (RVLM), which is considered the final output centre for sympathetic control of vascular tone. We are looking at the types of neurotransmitters and receptors expressed by these nerves and their projections pathways. Another region of the brain that we are studying in collaboration with Prof. Javier Stern (Department of Physiology, Medical College of Georgia) is the paraventricular nucleus of the hypothalamus.

Another project, performed in collaboration with Prof. Leonard Arnolda, Dr Doug McKitrick and Dr Vasyl Holobottsky from the Departments of Cardiology and Medicine at Royal Perth Hospital WA, involves looking at blood pressure control but this time the role of the spinal cord and its ability to change, both over the short and long term. We are interested in how nitric oxide, cGMP and NMDA receptors work in these different brain regions to control blood pressure.

Polycystic Kidney Disease

In the healthy body, the kidney and the sympathetic nervous system work together to keep our blood pressure in the normal range. When people have kidney disease this system fails and people can develop high blood pressure. High blood pressure can lead to heart attack and stroke, and so is a serious complication for people who already have kidney disease. We are examining the role of the sympathetic nervous system using different models of kidney disease. One of these models is a new Lewis rat model of polycystic kidney disease (PKD), which is the fourth most important cause of kidney disease in Australia. This work will not only help us understand how the brain and kidney communicate with each other, but will also have the potential to improve quality of treatment for people with kidney disease. This work is done in collaboration with Dr Gopala Rangan (University of Sydney) and Dr Deborah Hopwood (Animal Resources Centre).

New Studies are currently being undertaken with Murdoch researchers at the Centre for Comparative Genomics and Separation Science Laboratory to understand the genetic and metablolic feature of this new PKD model.

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The Noradrenaline Transporter and the Adrenal Gland

Sections of the adrenal medulla showing labelling for tyrosine hydroxylase and the noradrenaline transporter and how they overlap

Chromaffin cells of the adrenal medulla function to secrete adrenaline and noradrenaline into the circulation, playing a role in the stress response and rapid changes in blood pressure. On the basis of the type of hormone released, these cells are divided into two sub populations, adrenergic and noradrenergic. Our research, performed in our collaborators Prof. Janusz Lipski and Assoc. Prof. David Christie, at The University of Auckland, and has focused on the role of the Noradrenaline Transporter (NAT) in the adrenal gland.
NAT belongs to a family of proteins that control the amount of neurotransmitters and hormones after their release. Pheochromocytoma is a tumour of the adrenal medulla. These patients suffer from an excessive secretion of catecholamines and often present with hypertension. We are also studying pheochromocytoma, looking at the molecular mechanisms that may underlie the development of these tumours. This work is being performed in collaboration with Dr Graeme Eisenhofer, (University Hospital Carl Gustav Carus Dresden) and Dr Karel Pacak from the NIH, Bethesda USA.

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Complex Regional Pain Syndrome

Complex regional pain syndrome (CRPS) starts after various types of injury, sometimes quite minor, with or without obvious nerve trauma. The syndrome can develop after a seemingly insignificant injury that would normally heal within a few days. Sometimes, the limb may swell, sweat excessively, and be either warmer or cooler than the unaffected limb. The pain and sensory disturbances are often so severe that they lead to profound disability that neither resolves spontaneously nor responds to treatment. In collaboration with Professor Peter Drummond, (Psychology, Murdoch University) and Dr Phil Finch, a specialist pain physician, we are looking at the innervation pattern of skin from patients with CRPS to identify abnormalities that may cause this painful condition to develop. We hope our work can lead to establishment the efficacy of a promising new approach to treatment.

Publications

Powers-Martin, K, Phillips, JK, Biancardi, VC, and Stern, JE. Heterogeneous distribution of basal cyclic guanosine monophosphate (cGMP) within distinct neuronal populations in the hypothalamic paraventricular nucleus, Am. J. Physiol. Regul. Integr. Comp. Physiol. (2008) (In press)

Powers-Martin, K, Barron, AM, Auckland, CH, McCooke, JK, McKitrick, DJ, Arnolda, LF, and Phillips, JK. Immunohistochemical assessment of cyclic guanosine monophosphate (cGMP) and soluble guanylate cyclase (sGC) within the rostral ventrolateral medulla, J Biomed Sci.(2008).

Cleary S, Phillips JK, Huynh TT, Pacak K, Fliedner S, Elkahloun AG, Munson P, Worrell RA and Eisenhofer G. Chromogranin A. (2008) Expression in Phaeochromocytomas Associated with von Hippel-Lindau Syndrome and Multiple Endocrine Neoplasia Type 2. Horm Metab Res. (2007) 39(12): 876-883.

Gibbs GF, Drummond PD, Finch PM and Phillips JK. (2008). Unravelling the Pathophysiology of Complex Regional Pain Syndrome: Focus on Sympathetically Maintained Pain. Clin Exp Pharmacol Physiol  (2008).

Edwards MA, Loxley RA, Williams AJ, Connor M and Phillips JK. Lack of functional expression of NMDA receptors in PC12 cells. Neurotoxicology  (2007) 28(4): 876-885.

Malik V, Holobotovskyy VV, Phillips JK, McKitrick DJ and Arnolda LF. Intrathecal cGMP elicits pressor responses and maintains mean blood pressure during haemorrhage in anaesthetized rats. J Physiol  (2007) 581(Pt 2): 543-552.

Cleary S, Phillips JK, Huynh TT, Pacak K, Elkahloun AG, Barb J, Worrell RA, Goldstein DS and Eisenhofer G. Neuropeptide Y expression in phaeochromocytomas: relative absence in tumours from patients with von Hippel-Lindau syndrome. J Endocrinol  (2007) 193(2): 225-233.

Phillips JK, Hopwood D, Loxley RA, Ghatora K, Coombes JD, Tan YS, Harrison JL, McKitrick DJ, Holobotvskyy V, Arnolda LF and Rangan GK. Temporal Relationship between Renal Cyst Development, Hypertension and Cardiac Hypertrophy in a New Rat Model of Autosomal Recessive Polycystic Kidney Disease. Kidney Blood Press Res  (2007) 30(3): 129-147.

Cleary S, Phillips JK. the norepinephrine transporter and pheochromocytoma. Annals N.Y. Acad. Sci. (2006) [Review] 1073:263-269.

Powers-Martin K, McKitrick DF, Arnolda LF, Phillips JK. Distinct Subpopulations of Cyclic Guanosine Monophosphate (cGMP) and Neuronal Nitric Oxide Synthase (nNOS) Containing Sympathetic Preganglionic Neurons in Spontaneously Hypertensive and Wistar-Kyoto Rats. J. Comp. Neurol. (2006) 497(4): 566-574.

Reja V, Phillips JK, Goodchild AK, Pilowsky PM. Upregulated gene expression of the AT1 receptor and intracellular kinase gene expression in hypertensive rats. Clin. Exp. Pharm. Physiol. (2006) 33(8): 690-695.

Fuller PF, Reddrop C, Rodger J, Bellingham M, Phillips JK. Differential expression of the NMDA NR2B Receptor Subunit in Motoneuron Populations Susceptible and Resistant to Amyotrophic Lateral Sclerosis. Neuroscience Letters (2006) 399: 157-161.

Heidari M, Rice, KL, Phillips JK, Kees UR, Greene WK. The nuclear oncoprotein TLX1/HOX11 associates with pericentromeric satellite 2 DNA in leukemic T-cells. Leukemia (2006) 20 (2): 304-312.

Cleary S, Brouwers FM, Eisenhofer G, Pacak K, Christie DL, Lipski J, McNeil AR, Phillips JK. Expression of the Noradenaline Transporter and Phenylethanolamine N-Methyltransferase in Normal Human Adrenal Gland and Phaeochromocytoma. Cell Tissue Res.(2005) 27: 1-11.

Dixon DN, Loxley RA, Barron A, Cleary S, Phillips JK. Comparative studies of PC12 and MPC pheochromocytoma derived rodent cell lines as models for the study of neuroendocrine systems. In Vitro Cell Dev. Biol. Anim. (2005) 41: 197-206.

Springall DA, Powers-Martin K, Phillips JK, Pilowsky PM, Goodchild AK. Phosphorylated ERK1/2 immunoreactivity identifies a novel population of sympathetic preganglionic neurons. Neuroscience (2005). In Press

Edwards, M.A. Loxley, R.A., Powers-Martin K., Lipski, J., McKitrick, D.J., Arnolda L.F., & Phillips J.K. Unique Levels of Expression of N-Methyl-D-Aspartate Receptor Subunits and Neuronal Nitric Oxide Synthase in the Rostral Ventrolateral Medulla of the Spontaneously Hypertensive Rat. Molecular Brain Research (2004) 129: 33-43.

Phillips JK, Arnolda LF. BK channels, baroreflex sensitivity and genetic markers. J Hypertens (2002) 20(5): 825-7.

Reja V, Goodchild AK, Phillips JK, Pilowsky PM. Tyrosine hydroxylase gene expression in ventrolateral medulla oblongata of WKY and SHR: a quantitative real time polymerase chain reaction study. Auton Neurosci (2002) 98: 79-84.

Takeda M, Dubey R, Phillips JK, Lipski J. Effects of vasopressin on isolated rat adrenal chromaffin cells Regul Pept (2002) 106: 55-65.

Goodchild AK, Phillips JK, Lipski J, Pilowsky PM. Differential expression of catecholamine synthetic enzymes in the caudal ventral pons J Comp Neurol (2001) 438: 457-467.

Phillips JK, Dubey R, Sesiashvili E, Takeda M, Christie DL, Lipski J. Differential expression of the noradrenaline transporter in adrenergic chromaffin cells, ganglion cells and nerve fibres of the rat adrenal medulla J Chem Neuroanat (2001a) 21: 95-104.

Phillips JK, Goodchild AK, Dubey R, Sesiashvili E, Takeda M, Chalmers J, Pilowsky PM, Lipski J. Differential expression of catecholamine biosynthetic enzymes in the rat ventrolateral medulla J Comp Neurol (2001b) 432: 20-34.

Hill CE, Phillips JK, Sandow SL. Heterogeneous control of blood flow amongst different vascular beds [Review] Med Res Rev (2001) 21:1-60.

Takeda M, Phillips JK, Dubey R, Polson JW, Lipski J. Modulation of ACh?induced currents in rat adrenal chromaffin cells by ligands of a2-adrenergic and imidazoline receptors Auton Neurosci (2001) 88: 151-159.

Phillips JK, Hickey H, Hill CE. Heterogeneity in mechanisms underlying vasodilatory responses in small arteries of the rat hepatic mesentery Auton Neurosci (2000) 83: 159-170.

Phillips JK, Lipski J. Single cell RT-PCR as a tool to study gene expression in central and peripheral autonomic neurons [Review] Auton Neurosci (2000) 86: 1-12.

Hill CE, Phillips JK, Sandow SL. Development of peripheral autonomic synapses: Neurotransmitter receptors, neuroeffector associations and neural influences [Review] Clin Exp Pharmacol Physiol (1999) 26: 581-590.

Phillips JK, Hill CE. Neuroreceptor mRNA expression in the rat mesenteric artery develops independently of innervation Int J Dev Neurosci (1999) 17: 377-386.

Phillips JK, McLean AJ, Hill CE. Receptors involved in nerve-mediated vasoconstriction in small arteries of the rat hepatic mesentery Br J Pharmacol (1998) 124: 1403-1412.

Phillips JK, Vidovic M, Hill CE. Variation in mRNA expression of alpha-adrenergic, neurokinin and muscarinic receptors amongst four arteries of the rat J Auton Nerv Syst (1997) 62: 85-93.

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