Cerebrovascular Pharmacology

Group Head

Associate Professor Chris Sobey

Background

Factors regulating blood flow to the brain are numerous and complex. Under normal conditions, brain blood flow is maintained at the appropriate level through fine adjustments to the diameter of the supplying arteries. A “stroke” occurs when a portion of brain tissue is deprived of blood due to blockage or rupture of a cerebral artery, resulting in death of the most severely affected brain cells. Cardiovascular disorders such as atherosclerosis, hypertension, diabetes and brain haemorrhages are associated with an increased risk of stroke. A common factor in these disorders is the breakdown of mechanisms that act to dilate cerebral arteries. Thus, advances in our understanding of abnormal regulation of cerebral arteries in disease states is likely to lead to better treatments to minimize brain damage caused by strokes, or even to prevent strokes from occurring.

The Cerebrovascular Pharmacology Laboratory uses a variety of techniques to study brain artery function in the living body (in vivo), as well as in isolated tissue preparations (in vitro). We are concerned with increasing our understanding of mechanisms that maintain cerebral arteries open under normal conditions, and in various diseases models to identify potentially important abnormalities in brain blood flow regulation. If successful, this research may lead to important advances in stroke therapy.

Current research

Reactive oxygen species (ROS), also known as “oxygen-derived free radicals”, are normally thought of as toxic by-products of metabolism, but our work has found that ROS production – at least at low levels – is a critical part of the normal dilator response of cerebral arteries to some stimuli.

Our studies are designed to identify the enzymatic sources of ROS in cerebral arteries and to better understand their regulatory roles in cerebral vascular physiology and pathology. Much of our work in this area focuses on the role of NADPH oxidase, an enzyme which is now known to be a major source of ROS in blood vessels. We are also focusing on the endogenous nitric oxide receptor (NOGC) and how it is functionally altered by ROS-induced oxidative mechanisms in cardiovascular disease. Some of our funded work is geared towards development and commercialization of drugs that inhibit or reverse the detrimental effects of excessive ROS production in disease.

Currently, specific projects are investigating the roles of different isoforms of NADPH oxidase in cerebral artery function under normal conditions and in disease states such as subarachnoid haemorrhage, chronic hypertension, cerebral ischaemia (stroke) and ageing. In addition, we have found that gender is an important modifying factor in many of these settings, and so it is also of major interest to clarify these effects and their underlying mechanisms.

Staff list

• A/Prof. Christopher Sobey, BSc(Hons), PhD; NHMRC Senior Research Fellow
• Dr. Alyson Miller, BSc(Hons), PhD; Research Fellow
• Ms Anja Mast, BSc PostGrad Dip Biotech; Graduate Research Assistant
• Ms Katherine Jackman, PhD Student
• Ms Ravina Ravi, PhD Studen
• Mr Michael De Silva, BSc(Hons) Student

Key publications list

1. Sobey, C.G., Heistad, D.D. and Faraci, F.M. (1996).  Effect of subarachnoid hemorrhage on dilatation of rat basilar artery in vivo.  American Journal of Physiology 271: H126-H132.
2. Sobey, C.G. and Faraci, F.M. (1997).  Effects of a novel inhibitor of guanylyl cyclase on dilator responses of mouse cerebral arterioles.  Stroke 28:837-843.
3. Sobey, C.G., Heistad, D.D and Faraci, F.M (1997).  Mechanisms of bradykinin-induced cerebral vasodilatation in rats. Evidence that reactive oxygen species activate K+ channels.  Stroke 28:2290-2295.
4. Sobey, C.G. and Faraci, F.M. (1998). Subarachnoid haemorrhage: What happens to the cerebral arteries?  Clinical and Experimental Pharmacology and Physiology 25:867-876.
5. Chrissobolis, S., Ziogas, J., Chu, Y., Faraci, F.M. and Sobey, C.G. (2000).  Role of inwardly rectifying K+ channels in K+-induced cerebral vasodilatation in vivo.  American Journal of Physiology 279:H2704-H2712.
6. Chrissobolis, S. and Sobey, C.G. (2001).  Evidence that rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C.  Circulation Research 88:774-779.
7. Chrissobolis, S., Ziogas, J. Anderson, C.R., Chu, Y., Faraci, F.M. and Sobey, C.G. (2002).  Neuronal NO mediates cerebral vasodilator responses to K+ in hypertensive rats. Hypertension 39:880-885.
8. Paravicini, T.M., Drummond, G.R. and Sobey, C.G. (2004). Reactive oxygen species in the cerebral circulation: physiological roles and therapeutic implications for hypertension and stroke. Drugs 64:2143-2157.<
9. Paravicini, T.M., Chrissobolis, S., Drummond, G.R. and Sobey, C.G. (2004). Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 35:584-589.
10. Sobey, C.G., Weiler, J.M., Boujaoude, M. and Woodman, O.L. (2004). Effect of short-term phytoestrogen treatment in male rats on nitric oxide-mediated responses of carotid and cerebral arteries: comparison with 17b-estradiol.  Journal of Pharmacology and Experimental Therapeutics 310:135-140.
11. Budzyn, K., Marley, P.D. and Sobey, C.G. (2004).  Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS deficient mice.  American Journal of Physiology (Regul Integr Comp Physiol) 287:R342–R348.
12. Miller, A.A., Drummond, G.R., Schmidt, H.H.H.W. and Sobey, C.G. (2005). NADPH-oxidase activity and function are profoundly greater in cerebral versus systemic arteries. Circulation Research 97:1055-1062.
13. Paravicini, T.M., Miller, A.A., Drummond, G.R. and Sobey, C.G. (2006).  Flow-induced cerebral vasodilatation in vivo involves activation of phosphatidylinositol-3-kinase, NADPH-oxidase, and nitric oxide synthase. Journal of Cerebral Blood Flow and Metabolism 26:836-845.
14. Budzyn, K., Marley, P.D. and Sobey, C.G. (2006). Targeting Rho and Rho-kinase in the treatment of cardiovascular disease.  Trends in Pharmacological Sciences 27:97-104.
15. Miller, A.A., Drummond, G.R. and Sobey, C.G. (2006).  Reactive oxygen species in the cerebral circulation: are they all bad? Antioxidants and Redox Signaling 8:1113-1120.
16. Patent: “Therapeutic Compositions”.  Inventors: GR Drummond, GJ Dusting & CG Sobey. WO2004075884, Published: Sep 10, 2004;

Funding support