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Integrative Cardiovascular Pharmacology Laboratory

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 Integrative 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 integrative 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 projects

Current research is focussed on the following areas:

  • Effects of AT2 receptor stimulation in cardiovascular diseases, such as hypertension, atherosclerosis and cardiac remodelling.
  • Effects of AT2 receptor stimulation and interactions with AT1 receptors in stroke.
  • Cardiovascular effects of angiotensin peptide fragments in cardiovascular diseases such as hypertension, atherosclerosis and cardiac remodelling.
  • Design, synthesis and function of novel AT2 receptor ligands 

 

Click on figure for larger image

To discuss projects please contact Professor Robert Widdop

Personnel

  • Professor Robert Widdop
  • Dr Emma Jones (Lecturer)
  • Dr Tracey Gaspari (Postdoctoral Fellow)
  • Dr Antony (Bill) Vinh (Monash University Larkins Fellow & National Heart Foundation Fellow)
  • Ms Iresha Welungoda (Graduate Research Assistant)
  • Ms Sanja Bosnyak (PhD student)
  • Ms Damie Phua (PhD student)
  • Mr Antony Sutherland (Honours student)
  • Mr Tyrone Barnes (Honours student)

Collaborators

  • Dr Jennifer Callaway (Department of Pharmacology, University of Melbourne)
  • A/Professor Kate Denton (Department of Physiology, Monash University)
  • Professor Mibel Aguilar (Department of Biochemistry & Molecular Biology, Monash University)
  • Professor Patrick Perlmutter (School of Chemistry, Monash University)
  • Dr Siew Yeen Chai (Department of Physiology, Monash University)
  • Dr Barb Kemp-Harper (Department of Pharmacology, Monash University)
  • Dr Anthony Dear (ECRU Biotechnology Group, Australian Centre for Blood Diseases)
  • Professor Arthur Christopoulos (Department of Pharmacology & MIPS, Parkville, Monash University)
  • Professor Walter Thomas (School of Biomedical Science, University of Queensland)
  • Professor Jaye Chin-Dusting (BakerIDI Heart & Diabetes Institute, Melbourne)
  • Dr Jennifer Irvine (BakerIDI Heart & Diabetes Institute, Melbourne)
  • Professor Geoff Head (BakerIDI Heart & Diabetes Institute, Melbourne)
  • Dr Daniel Henrion (University of Angers, France)
  • Dr Muscha Steckelings (Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Germany)

Publications (2005-present)

Steckelings UM, Larhed M, Hallberg A, Widdop RE, Jones ES, Wallinder C, Namsolleck P, Dahlöf B, Unger T. Non-peptide AT2-receptor agonists. Curr Opin Pharmacol. 2010 Dec 15. [Epub ahead of print].

Irvine J, Kemp-Harper BK, Widdop RE. Chronic administration of the HNO donor, Angeli's salt does not lead to tolerance, cross-tolerance or endothelial dysfunction: comparison with GTN and DEA/NO. Antioxid Redox Signal. 2010 Sep 19. [Epub ahead of print].

Jones ES, Del Borgo MP, Kirsch JF, Clayton D, Bosnyak S, Welungoda I, Hausler N, Unabia S, Perlmutter P, Thomas WG, Aguilar MI, Widdop RE (2011). A Single β-Amino Acid Substitution to Angiotensin II Confers AT2 Receptor Selectivity and Vascular Function. Hypertension, 57, 570-576.

Hilliard LM, Nematbakhsh M, Kett MM, Teichman E, Sampson AK, Widdop RE, Evans RG, Denton KM (2011). Gender differences in pressure-natriuresis and renal autoregulation: role of the Angiotensin type 2 receptor. Hypertension, 57, 275-82.

Clayton D, Hanchapola I, Hausler N, Unabia S, Lew RA, Widdop RE, Smith AI, Perlmutter P, Aguilar MI. (2011) β-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2). J Mol Recognit., 24, 235-244.

Steckelings UM, Widdop RE, Paulis L, Unger T (2010). The angiotensin AT2 receptor in left ventricular hypertrophy. J Hypert., 28 Suppl 1, S50-S55.

Tesanovic S, Vinh A, Gaspari TA, Casley D, Widdop RE (2010) Vasoprotective and atheroprotective effects of angiotensin (1-7) in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol., 30, 1606-1613.

Bosnyak S, Welungoda IK, Hallberg A, Alterman M, Widdop RE, Jones ES. (2010) Stimulation of angiotensin AT2 receptors by the non-peptide agonist, Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats. Brit. J. Pharmacol., 159, 709-716.

Libinaki R, Tesanovic S, Heal A, Nikolovski B, Vinh A, Widdop RE, Gaspari TA, Devaraj S, Ogru E. (2010) The Effect of Tocopheryl Phosphate on Key Biomarkers of Inflammation: Implication in the reduction of atherosclerosis progression in a hypercholesterolemic rabbit model. Clin Exp Pharmacol Physiol., 37, 587-592.

Porrello ER, Meeker WF, Thomas WG, Widdop RE, Delbridge LM (2010) Glucocorticoids Suppress Growth in Neonatal Cardiomyocytes Co-Expressing AT(2) and AT(1) Angiotensin Receptors. Neonatology, 97, 257-265.

McCarthy CA, Vinh A, Callaway JK, Widdop RE. (2010) Angiotensin AT2 receptor mediated neuroprotection and nitric oxide bioavailability in stroke. Stroke 40, e94

McCarthy CA, Vinh A, Callaway JK, Widdop RE. (2009) Angiotensin AT2 Receptor Stimulation Causes Neuroprotection in a Conscious Rat Model of Stroke. Stroke 40, 1482-1490

Vinh A, Gaspari TA, Jones ES and Widdop RE. (2009) Functional cardiovascular effects of angiotensin peptides: focus on atherosclerosis and hypertension. Curr Hypertens Rev., 5, 227-36.

Irvine JC, Ritchie RH, Favaloro JL, Andrews KL, Widdop RE, Kemp-Harper BK (2008). Nitroxyl (HNO): the Cinderella of the nitric oxide story. Trends Pharmacol Sci., 29, 601-8.

Jones ES, Vinh A, McCarthy C, Gaspari TA & Widdop RE (2008). AT2 receptors: functional relevance in cardiovascular disease (Review). Pharmacology & Therapeutics, 120, 292-316.

Porrello ER, Widdop RE, Delbridge LM (2008). Early origins of cardiac hypertrophy: does cardiomyocyte attrition programme for pathological 'catch-up' growth of the heart? Clin Exp Pharmacol Physiol., 35, 1358-64.

Sampson AK, Moritz KM, Jones EM, Flower RL, Widdop RE, Denton KM (2008).  Can the Study of Female Rats Help Our Understanding of Women? Response. Hypertension, 52, e43-e44.

Sampson AK, Moritz KM, Jones ES, Flower RL, Widdop RE, Denton KM (2008). Enhanced angiotensin II type 2 receptor mechanisms mediate decreases in arterial pressure attributable to chronic low-dose angiotensin II in female rats. Hypertension, 52, 666-71.

Widdop RE, Vinh A, Henrion D & Jones ES (2008).  Vascular angiotensin AT2 receptors in hypertension and aging (Review). Clin Exp Pharmacol Physiol., 35, 386-90.

Sampson A, Widdop RE & Denton K (2008)  Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats. Clin Exp Pharmacol Physiol., 35, 391-5.

Vinh A, Widdop RE, Chai SY & Gaspari TA (2008). Angiotensin IV-evoked vasoprotection is conserved in advanced atheroma.  Atherosclerosis, 200, 37-44.

Vinh A, Widdop RE*, Drummond GR & Gaspari TA (2008).  Chronic angiotensin IV treatment reverses endothelial dysfunction in ApoE-deficient mice. Cardiovasc Res., 77, 178-87.

Vinh A, Gaspari TA, Liu HB, Dousha LF, Widdop RE & Dear AE (2008).  A Novel Histone Deacetylase Inhibitor Reduces Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice. J Vasc Res., 45, 143-152.

Irvine JC, Favaloro JL, Widdop RE & Kemp-Harper BK (2007)Nitroxyl Anion Donor, Angeli's Salt, Does Not Develop Tolerance in Rat Isolated Aortae. Hypertension 49, 885-92.

Rajapakse NW, Eppel GA, Widdop RE & Evans RG (2006). Ang II type 2 receptors and neural control of intrarenal blood flow. Am J Physiol Regul Integr Comp Physiol., 291, R1669-76.

Zulli A., Burrell L.M., Widdop R.E., Black M.J., Buxton B.F., Hare D.L. (2006). Immunolocalization of ACE2 and AT2 Receptors in Rabbit Atherosclerotic Plaques. J Histochem Cytochem. 54, 147-50.

McDougall SJ, Widdop RE & Lawrence AJ (2005). Central autonomic integration of psychological stressors: focus on cardiovascular modulation. Auton Neurosci., 123, 1-11.

Roulston C.L., Lawrence A.J., Widdop R.E., Jarrott B. (2005). Minocycline treatment attenuates microglia activation and non-angiotensin II [(125)I] CGP42112 binding in brainstem following nodose ganglionectomy. Neuroscience 135, 1241-1253.

Walters P, Gaspari TA & Widdop RE (2005) Angiotensin-(1-7) acts as a vasodepressor agent via AT2 receptors in conscious rats. Hypertension, 45, 960-966.

You D, Loufrani L, Baron C, Levy BI, Widdop RE & 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.

Duke LM, Evans RG & Widdop RE (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.

Duke LM, Widdop RE, Kett MM & Evans RG (2005)  AT2 receptors mediate tonic renal medullary vasoconstriction in renovascular hypertension.  Brit. J. Pharmacol., 144, 486-492.

McDougall S.J., Lawrence A.J. & Widdop R.E. (2005).  Differential cardiovascular responses to stressors in hypertensive and normotensive rats.  Exp. Physiol, 90, 141-150.

McDougall S.J., Widdop R.E. &Lawrence A.J. (2005). Gene expression in WKY and SHR brain following acute and chronic air-puff stress. Molecular Brain Research, 133, 329-336.