The Cardiovascular Therapeutics Unit
The Cardiovascular Therapeutics Unit has been formed by the collaboration from two laboratories – Integrated Pharmacology and Human Cardiovascular Research - which share a common focus in cardiovascular pharmacology and translation research. Although each laboratory has special interests and individual projects, the unit structure allows a project-driven approach utilising the diverse research techniques and expertise within the group. These strengths enable exciting collaborative partnerships with the pharmaceutical industry and/or contract projects with early start-up and Biotech companies eager to establish safety pharmacology and mechanism of action of novel lead compounds.
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Key Research Areas
Investigation of novel angiotensin II receptor antagonists for the treatment of vascular disease
A major risk factor for cardiovascular disease is atherosclerosis whereby plaques eventually affect blood supply to the heart leading to ischaemic events such as angina and myocardial infarction. Antihypertensive drugs such as the sartan class of angiotensin AT1 receptor antagonists may also suppress atherosclerotic plaque formation. The effectiveness of the sartans may not just be due to inhibition of the renin-angiotensin system. Pathological events central to vascular disease progression include oxidative stress and subsequent inflammatory events at the site of atherosclerotic plaque formation. Over-expression of AT1 receptors contributes to the atherosclerotic process, which includes vascular remodelling in conditions of hypercholesterolaemia. In this project, within the ARC Centre of Excellence for Free Radical Chemistry and Biotechnology, novel AT1 receptor antagonists have been modified chemically to possess additional antioxidant and cellular protection properties. These will be investigated in bioassays, in vitro and in vivo, of acute and chronic vascular disease and atherosclerosis.
The cardiovascular pharmacology of the venom from the jellyfish Malo maxima and its relation to Irukandji syndrome in Western Australia
Irukandji syndrome is caused by small Irukandji jellyfish and is typified by nausea, profuse vomiting, severe muscle spasms and excruciating back pain. Only a single species – Carukia barnesi – has been definitively linked with Irukandji syndrome, however it is likely that other species may also cause forms of this syndrome. Malo maxima – a jellyfish found in the Broome region of Western Australia – has been implicated in cases of severe Irukandji syndrome which is a major occupational health and safety hazard for the pearling industry, as well as locals and tourists. This project is investigating the cardiovascular pharmacology of the venom of Malo maxima in order to characterise its effects, compare them with Carukia barnesi and inform the treatment of this syndrome.
Local anaesthetic agents and cardiovascular toxicity
In the clinic, local anaesthetic toxicity may occur due to a variety of reasons, however it is typified by central nervous system signs and may lead to cardiovascular collapse unresponsive to traditional cardiac resuscitation techniques. This project will examine and compare the effects of several commonly used local anaesthetic agents on the cardiovascular system in experimental animals. Cardiac and vascular function will be assessed in vitro and in vivo and the potential for “rescue” by a lipid emulsion – Intralipid – will be tested.
Acute and chronic effects of methadone and buprenorphine on QTc prolongation and cardiac function
Methadone has been used since the 1960s in the management of opioid dependence. Although there were early reports of cardiac electrocardiogram (ECG) abnormalities amongst heroin users and methadone patients, there had been little research and no case reports of ECG abnormalities or cardiac toxicity in methadone patients until recently. Concerns regarding opioid agonists, prolonged QTc intervals and the potentially fatal ventricular arrhythmia, Torsade de Pointes (TdP), emerged following case reports of methadone patients developing TdP, as well as evidence of QTc prolongation and related cardiotoxicity. This project is examining cardiac function and cardiovascular variables in experimental animals treated with methadone or other opioid agonists.
Cannabinoid receptor ligands and modified morphine derivatives in acute and neuropathic pain
Many patients with terminal cancer, other illnesses or injuries suffer chronic intractable pain. These patients may be unable to receive relief with currently available pain-relieving (anti-nociceptive) drugs, such as morphine, due to problems of dependence and tolerance. Our research is directed at the discovery of novel therapeutic agents for the treatment of chronic (neuropathic) pain. The effectiveness of novel cannabinoid CB1 and CB2 receptor ligands or modified morphine-like compounds, administered via intrathecal or peripheral routes, are being examined in the treatment of allodynia in a neuropathic pain model, as well as in acute and inflammatory pain.
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Key References
Tham SM, Angus JA, Tudor EM and Wright CE. Synergistic and additive interactions of the cannabinoid agonist CP55,940 with µ opioid receptor and a2-adrenoceptor agonists in acute pain models in mice. Br J Pharmacol 2005; 144: 875-884.
Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD and Salem HH. PI 3-kinase p110g: a new target for antithrombotic therapy. Nature Med 2005; 11: 507-514.
Winkel KD, Tibballs J, Molenaar P, Lambert G, Coles P, Ross-Smith M, Wiltshire C, Fenner PJ, Gershwin LA, Hawdon GM, Wright CE and Angus JA. The cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: effects in human, rat and guinea-pig tissues in vitro and in pigs in vivo. Clin Exp Pharmacol Physiol 2005; 32: 777-788.
Daykin HJ, Sturgeon SA, Jones C and Wright CE. Arterial antithrombotic effects of aspirin, heparin, enoxaparin and clopidogrel alone, or in combination, in the rat. Thromb Res 2006; 118: 755-762.
Morritt AN, Bortolotto SK, Dilley RJ, Han XL, Kompa AR, McCombe D, Wright CE, Itescu S, Angus JA and Morrison WA. Cardiac tissue engineering in an in vivo vascularized chamber. Circulation 2007; 115: 353-360. Royse CF, Royse AG, Rohrlach R, Wright CE and Angus JA. The cardiovascular effects of adrenaline, dobutamine and milrinone in rabbits using pressure-volume loops and guinea pig isolated atrial tissue. Anaes Intensive Care 2007; 35: 180-188.
Soeding PE, Royse CF, Wright CE, Royse AG and Angus JA. Inoprotection: the perioperative role of levosimendan. Anaesth Intensive Care 2007; 35: 845-862.
Royse CF, Liew DFL, Wright CE, Royse AG and Angus JA. Persistent depression of contractility and vasodilation with propofol but not with sevoflurane or desflurane in rabbits. Anesthesiology 2008; 108: 87-93.
Sturgeon SA, Jones C, Angus JA and Wright CE. Advantages of a selective b-isoform phosphoinositide 3-kinase antagonist, an anti-thrombotic agent devoid of other cardiovascular actions in the rat. Eur J Pharmacol 2008; 587: 209-215.
Wafai R, Angus JA and Wright CE. Adaptation of hindquarter vascular reactivity to femoral artery ligation and hypercholesterolemia in the rabbit. J Vasc Res 2008; 45: 279-294.
Wafai R, Tudor EM, Angus JA and Wright CE. Vascular effects of FGF-2 and VEGF-B co-administration in rabbits with bilateral hindlimb ischemia. J Vasc Res 2009; 46: 45-54.
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HUMAN CARDIOVASCULAR RESEARCH
Website:http://www.heartweb.com.au & Anaesthesia & Pain Management Unit (AMPU)
This laboratory forms part of the Cardiovascular Therapeutics Unit (see group above). In addition to the common CTU projects outlined above, there are animal-based projects looking at post-operative cognitive decline and anaesthesia, organ protection using anaesthesia agents and novel inotropes, and novel approaches to end the vascular treatment of atherosclerotic lesions. A number of human studies are also currently underway that will be described in the “anaesthesia and pain management unit” section below
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Key References
Alsaddique AA, Royse AG, Royse CF, Fouda MA. Management of diastolic heart failure following cardiac surgery. Eur J Cardiothorac Surg. 2009 Feb;35(2):241-9.
Canty DJ, Royse CF. Audit of anaesthetist-performed echocardiography on perioperative management decisions for non-cardiac surgery. Br J Anaesth. 2009 Jun 23.
Hebbard P, Royse C. Audit of transverse abdominus plane block for analgesia following caesarean section. Anaesthesia. 2008 Dec;63(12):1382.
Royse AG, Chang GS, Nicholas DM, Royse CF. No late ulnar artery atheroma after radial artery harvest for coronary artery bypass surgery. Ann Thorac Surg. 2008 Mar;85(3):891-4.
Royse C. Ultrasound education in anaesthesia: turning the tables on convention. Ann Card Anaesth. 2008 Jul-Dec;11(2):77-9.
Royse CF. High thoracic epidural anaesthesia for cardiac surgery. Curr Opin Anaesthesiol. 2009 Feb;22(1):84-7.
Royse CF, Bird H, Royse AG. Routine assessment of coeliac axis and renal artery flow is not feasible with transoesophageal echocardiography. Anaesthesia. 2009 Jan;64(1):103-4.
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