Heather Macarthur, Ph.D.
Pharmacological and Physiological Science
Ph.D., William Harvey Research Institute, Saint Bartholomew's Medical College (London), 1994
A consequence of living in an oxygen rich environment is dealing with the production of reactive radical species (including nitric oxide, superoxide and peroxynitrite) within and around our cells, either as a result of inflammation or as a byproduct of cellular respiration. Systems that depend on catecholamines as major biological mediators are particularly vulnerable to reactive species since catecholamines are very sensitive to oxidative reactions.
Our laboratory is interested in the interactions between reactive species and catecholamines and the consequences these interactions have for health and disease.
The control of vascular tone is vital to maintaining blood pressure and adequate organ perfusion. Mediators released from sympathetic nerves that innervate the exterior blood vessel wall, as well as mediators released from the interior endothelial lining of the blood vessel, are major contributors to the preservation of normal vascular tone. A major focus of our laboratory has been to investigate “cross-talk” between these two important systems. Evidence exists for the modulation of sympathetic neurotransmission by endothelial cell mediators. Nitric Oxide (NO), in particular, has been implicated in a number of studies. We have shown that NO released from the endothelium of the blood vessel interacts with and deactivates norepinephrine, the catecholaminergic portion of sympathetic neurotransmission (1). This modulation is in play under normal conditions and is diminished in models of hypertension as oxidative stress increases (2, 3). Not surprisingly there are also indirect consequences for co-transmission from the sympathetic nerves as a result of the modulation of norepinephrine by NO (2, 3).
Vascular dysfunction is also a characteristic of septic shock. In the case of this disease there is a loss of vascular reactivity to catecholamines coupled with the development of hypotension that is often irreversible. We have determined that increased oxidative stress caused by systemic inflammation in this disease, deactivates both norepinephrine and epinephrine contributing to the vascular crisis and further exacerbating inflammation as the negative modulation of immune cells by these catecholamines is lost (4, 5).
In addition to the importance of catecholamine deactivation in the periphery, central catecholamine deactivation also appears to play a role in neurodegenerative diseases such as Parkinson’s disease. There is increasing evidence that oxidative stress plays an important role in the pathogenesis of this disease. We have determined that dopamine, the major neuronal mediator that controls movement, is deactivated by reactive species produced by oxidative stress. The resultant product of this oxidative reaction is dopaminochrome. Using a novel sensitive HPLC assay for dopaminochrome (6) we have found this product to be present in animal models of neurodegeneration (7). Furthermore we have also found that dopaminochrome causes apoptosis in cellular models of sympathetic neurons, leading us to hypothesize that dopaminochrome plays a role in the degeneration of neurons such as occurs in Parkinson’s disease (8, 9).
Kolo LL, Westfall TC and Macarthur H. Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed. Am J Physiol Heart Circ Physiol. 2004;286(1):H296-303.
Kolo LL, Westfall TC and Macarthur H. Modulation of neurotransmitter release by NO is altered in mesenteric arterial bed of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2004;287(4):H1842-1847.
Macarthur H, Westfall TC and Wilken GH. Oxidative stress attenuates NO-induced modulation of sympathetic neurotransmission in the mesenteric arterial bed of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2008;294(1):H183-189.
Macarthur H, Couri DM, Wilken GH, Westfall TC, Lechner AJ, Matuschak GM, Chen Z and Salvemini D. Modulation of serum cytokine levels by a novel superoxide dismutase mimetic, M40401, in an Escherichia coli model of septic shock: correlation with preserved circulating catecholamines. Crit Care Med. 2003;31(1):237-245.
Macarthur H, Westfall TC, Riley DP, Misko TP and Salvemini D. Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock. Proc Natl Acad Sci U S A. 2000;97(17):9753-9758. PMCID: 16937.
Ochs SD, Westfall TC and Macarthur H. The separation and quantification of aminochromes using high-pressure liquid chromatography with electrochemical detection. J Neurosci Methods. 2005;142(2):201-208.
Mallajosyula JK, Kaur D, Chinta SJ, Rajagopalan S, Rane A, Nicholls DG, Di Monte DA, Macarthur H and Andersen JK. MAO-B elevation in mouse brain astrocytes results in Parkinson's pathology. PLoS One. 2008;3(2):e1616. PMCID: 2229649.
Linsenbardt AJ, Wilken GH, Westfall TC and Macarthur H. Cytotoxicity of dopaminochrome in the mesencephalic cell line, MN9D, is dependent upon oxidative stress. Neurotoxicology. 2009;30(6):1030-1035. PMCID: 2789849.
Linsenbardt AJ, Wilken GH, Westfall TC and Macarthur H. Dopaminochrome induces apotosis in the mesencephalic cell line, MN9D, in a caspase-independent manner. J. Neurochemistry. 2010 (submitted).
NIH/NHLBI R01 HL61836
Deactivation of Catecholamines by NO, O-2 and Peroxynitrite
Principal Investigator, 2000-2004
NIH/NHLBI R01 HL60260
NPY Induced Regulation of Sympathetic Neurotransmission
NIH/NIDA R01 DA024074
Role of peroxynitrite in morphine hyperalgesia and tolerance
Research Grant from G.D. Searle/Monsanto
The Role of Catecholamines in Sepsis and Pain - Effects of Superoxide Dismutase mimics
Principal Investigator, 1998-2000.
Honors and Awards
1992 Young Investigator Travel Award, British Society of Thrombosis and Haemostasis
1995-1997 Postdoctoral Research Fellowship, American Heart Association (Missouri Affiliate)
1998 Saint Louis University, Office of Multicultural Affairs, Award of Appreciation: In recognition of your contribution to a positive learning environment
1997‑1999 Visiting Research Scientist with G.D. Searle & Co
Lecturer in Graduate Education, Saint Louis University School of Medicine.
Lecturer in Human Systems Physiology for Certificate in Anatomy & Physiology, Saint Louis University School of Medicine
Lecturer in Cardiovascular Module, Saint Louis University School of Medicine.
Small Group Leader for Pharmacology Module, Saint Louis University School of Medicine.
Lecturer in Physiology, Saint Louis University School of Nursing and Allied Health Professionals.
Instructor and Tutor in Physiology and Supplemental Instructor in Pharmacology, Department of Multicultural Affairs, Saint Louis University School of Medicine.
Instructor for Drug Abuse Course for FBI
Exploring the consequence of the oxidation of catecholamines by reactive species in
normal and pathophysiological conditions (e.g. neurodegeneration, hypertension).
Experimental models used – cell culture (neuronal and microglial cell lines), isolated tissue preparations, whole animal models.
Techniques – HPLC, ELISA, cell based assays, fluorescence imaging, Western analysis and physiological recording.
Professional Organizations and Associations
Society for Neuroscience