posted on 2017-03-20, 00:03authored byChung Hui Chuo
Ischaemic heart
disease, in particular myocardial infarction and resultant heart failure,
places a significant burden on society. The adenosine receptor is a potent
mediator of cardioprotection. Adenosine receptor signalling within
cardiomyocytes during ischaemia and reperfusion injury reduces infarct size and
improves post-ischemic heart function. However, the transition of adenosine
receptor agonists into the clinic as a cardioprotective therapy has been
hampered by significant on-target side effects such as bradycardia,
atrioventricular block and hypotension. As such, while higher adenosine
receptor agonist concentrations are likely to be more therapeutically
effective, they cannot be trialled due to the likelihood of detrimental effects
in patients with acute coronary occlusion. The failure of cardioprotective therapies
in the clinic is also likely due to the relative inability of most drug
candidates to control the remodelling process following myocardial infarction
which leads to heart failure. VCP746, a novel A1/A2B adenosine receptor
agonist, was previously shown to display biased agonism in Chinese hamster
ovary cells stably expressing A1 adenosine receptors and furthermore,
cytoprotection without bradycardia in native systems. A strong body of evidence
also supports a role for adenosine receptor agonists in regulating cardiac
remodelling processes such as cardiac hypertrophy and fibrosis. This project
therefore aims to further explore the ability of VCP746 to confer
cardioprotection in the absence of haemodynamic adverse effects in more
physiologically relevant systems. In addition, the potential for VCP746 to
reduce cardiac remodelling will also be investigated for the first time in
cell-based and whole animal studies.