Integrative Cardiovascular Pharmacology

Group head

• Associate Professor Robert Widdop

Background

The renin angiotensin system is one of the major hormonal systems regulating the cardiovascular status of the body, with respect to both pharmacodynamic blood pressure regulation and trophic influences on the heart and vasculature. Increased activity of the renin angiotensin system is likely to contribute to a range of cardiovascular diseases including hypertension, heart failure, atherosclerosis and stroke. There are a number of angiotensin receptor subtypes that are activated by endogenous angiotensin peptides as well as by synthetic compounds. The AT₁ receptor subtype mediates most of the classical effects of angiotensin II. Blockade of AT₁ receptors by sartan-type compounds has proven very successful in the treatment of diseases such as hypertension. However, other non-AT₁ receptors have been less well investigated, and this is a major focus of the Integrated Cardiovascular Pharmacology Laboratory.

In particular, the AT₂ receptor exerts counterregulatory effects to the AT₁ receptor and we are interested in the functional effects of acute and chronic AT₂ receptor stimulation per se, on pharmacodynamic status (blood pressure and flow) and on cardiovascular remodelling (heart and blood vessel antihypertrophic and antifibrotic effects etc.) in a range of models of hypertension, atherosclerosis and stroke, as well as aging. In addition, the role of shorter angiotensin peptide fragments (e.g. Ang 1-7, Ang III, Ang IV) under normal and pathological settings are also under investigation.

Our laboratory incorporates a wide range of both in vitro and in vivo techniques under both acute and chronic treatment conditions, such that we are able to study blood vessel and heart function from a cellular level through to an integrated haemodynamic level that closely mimics the clinical setting. These techniques are also coupled with ex vivo histopathological assessment of cardiovascular tissues to inform on structural changes associated with cardiovascular remodelling.

Current research

Current projects are concerned with the following general areas:

• Effects of AT₂ receptor stimulation in hypertension and aging.
• Effects of manipulating AT₁ receptors and AT₂ receptors in stroke.
• Functional cardiovascular effects of angiotensin peptides in cardiovascular diseases such as atherosclerosis and hypertension

Many of our projects are concerned with the functional interactions between AT₁ and AT₂ receptors in normal and pathological cardiovascular disease models, and how different angiotensin peptide fragments exert unique effects.

Staff list

• A/Prof Robert Widdop, BSc(Hons), PhD; Associate Professor
• Dr Tracey Gaspari, BSc(Hons), PhD; Research Fellow
• Dr Emma Jones, BSc(Hons), PhD, Research Fellow
• Ms Iresha Welungoda, BSc(Hons); Graduate Research Assistant
• Mr Antony (Bill) Vinh, PhD Student
• Ms Jennifer Irvine, PhD Student
• Ms Claudia McCarthy, PhD student
• Ms Damie Phua, PhD student
• Ms Sonja Tesanovic, PhD student
• Ms Sanja Bosnyak, BSc(Hons) Student

Funding support

Key publications

1. Paull, J.R.A., Li, X.C., Sampey, D.B. and Widdop, R.E. (2001).  Pharmacodynamic contribution to the vasodilator effect of chronic AT1 receptor blockade in SHR.  Hypertension, 37, 91-98.
2. Paull, J.R.A. and Widdop, R.E. (2001).  Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult SHR. J. Hypertension, 19, 1393-1402.
3. Widdop, R.E., Matrougui, K., Levy, B.I. and Henrion, D. (2002).  AT2 receptor-mediated relaxation is preserved after long-term AT1 receptor blockade. Hypertension, 40, 516-520.
4. Duke L.M., Eppel G.A., Widdop R.E. & Evans R.G. (2003).  Disparate roles of AT2 receptors in the renal cortical and medullary circulations of anaesthetized rabbits.  Hypertension, 42, 200-205.
5. Zulli A., Widdop R.E., Hare D.L., Buxton B.F. & Black M.J. (2003). High methionine and cholesterol diet abolishes endothelial relaxation.  Arterioscler. Thromb. Vasc. Biol., 23, 1358-1363.
6. Widdop R.E., Jones E.S., Hannan R.E. & Gaspari T. (2003).  Angiotensin AT2 receptor: cardiovascular hope or hype? (Review).  Brit. J. Pharmacol., 140, 809-824.
7. Hannan R.E., Davis E.A. & Widdop R.E. (2003).  Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide.  Brit. J. Pharmacol., 140, 987-995.
8. Li X.C. & Widdop R.E. (2004) AT2 receptor-mediated vasodilatation is unmasked by AT1 receptor blockade in conscious SHR.  Brit. J. Pharmacol., 142, 821-830.
9. Jones E. S., Black M.J. & Widdop R.E. (2004).  Angiotensin AT2 receptor contributes to cardiovascular remodelling of aged rats during chronic AT1 receptor blockade.  J. Mol. Cell. Cardiol., 37(5): 1023-1030.
10. Duke L.M., Evans RG & Widdop R.E. (2005). AT2 receptors contribute to acute blood pressure-lowering and vasodilator effects of AT1 receptor antagonism in conscious normotensive but not hypertensive rats. Am. J. Physiol. (Heart. Circ. Physiol.). 288, H2289-H2297
11. You D., Loufrani L., Baron C., Levy B.I., Widdop R.E. & Henrion D. (2005). High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats. Circulation, 111, 1006-1111.
    (see accompanying Editorial: Circulation, 111, 956-957)
12. Walters P.E., Gaspari T.A. & Widdop R.E. (2005). Angiotensin-(1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats. Hypertension, 45, 960-966.