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A tale of two receptors - Investigating how adenosine A2 receptors modulate adenosine A1 receptor-mediated cardioprotection
Abstract
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working relationships. The mutual reliance these health care providers demonstrated led to a great patient outcome a long way from a tertiary health care facility. The feasibility of replicating this model of health care in other sparsely resourced populations in Victoria is currently being examined. http://dx.doi.org/10.1016/j.hlc.2015.06.049 49 A tale of two receptors - Investigating how adenosine A2 receptors modulate adenosine A1 receptor-mediated cardioprotection E. Vecchio ∗ , A. TN Nguyen, C. Tan, P. White, L. May Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia Introduction: Adenosine, primarily through the activation of the adenosine A1 receptor (A1 AR), is a potent, endogenous cardioprotective agent that helps to limit myocardial damage post infarction. It has recently been identified that for full A1 AR-mediated cytoprotection, simultaneous activation of the adenosine A2 receptor (A2 AR) subtypes is required. The mechanism behind this phenomenon is unknown, with one possible explanation involving receptor dimerisation.
Aims: To determine the molecular basis for cardioprotective adenosine receptor interactions by examining binding and functional cooperativity. Methods: Functional adenosine receptor interactions were examined at the level of ERK1/2 phosphorylation by exposing isolated neonatal rat cardiomyocytes to a combination of adenosine receptor ligands. Cooperative interactions occurring across a dimeric (or higher order oligomeric) interface were assessed using radioligand [3 H]DPCPX dissociation kinetics. Results: Functional interactions at the level of ERK1/2 phosphorylation was observed for the non-selective adenosine receptor agonist NECA in the presence of the A2A AR and A2B AR selective antagonists, SCH 442416 or PSB 603 respectively. A change in [3 H]DPCPX dissociation kinetics from the A1 AR was observed in the presence of SCH 442416 or PSB 603 Discussion: Collectively, this data provides direct evidence for cooperative allosteric interactions occurring across adenosine heterodimers (or higher order oligomers) within cardiomyocytes and highlights the importance of all three adenosine receptors in cardioprotection. Further understanding of the adenosine heterodimeric complex provides a new
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strategy for the rational design of new cardioprotective agents. http://dx.doi.org/10.1016/j.hlc.2015.06.050 50 An audit of inter-hospital patient transfers for coronary angiography from a rural centre in Australia J. Janardan 1,∗ , K. Haji 2,3 , A. Al Alawi 1 , D. Wong 4,5,6 , H. Gibbs 1 , A. Soward 5,6 1 The
Alfred Hospital, Melbourne, Victoria, Australia 2 Epworth Hospital, Richmond, Victoria, Australia 3 Monash Medical Centre, Clayton, Victoria, Australia 4 MonashHeart, Monash Cardiovascular Research Centre, Melbourne, Victoria, Australia 5 Division of Medicine, Mildura Base Hospital, Mildura, Victoria, Australia 6 Mildura Cardiology, Mildura, Victoria, Australia Aim: To determine the characteristics and outcomes of patients transferred from a rural hospital for coronary angiography. Method: Retrospective audit of medical records of patients transferred from Mildura Base Hospital from 1st January to 31st December 2013 for coronary angiography. Demographic data, medical insurance, primary diagnosis, illness severity score, and transfer costs were recorded. Details regarding inpatient stay at the receiving hospitals were obtained from discharge summaries. Results: There were 114 transfers for coronary angiography which represented 41% of all medical inter-hospital transfers from this centre. Median age was 64 years, 36.9% were female. 42.9% had private insurance with 39.5% being transferred to private hospitals. The median Charlson comorbidity score was 1 and median Simple Clinical Score was 5 suggesting haemodynamically stable patients with low 24-hour and 30day mortality risk, suitable for transfer and advanced care. The principle diagnosis included non ST elevation (64%) and ST elevation myocardial infarction (14.9%), angina (11.4%), arrhythmias (6.1%), other chest pain (1.7%) and heart failure (1.7%). Angiography, performed in 95.6% of transfers (n=109), revealed significant coronary disease in 78 (71.5%) and resulted in revascularisation in 56 cases (coronary artery stenting in 40 and bypass grafting in 16), evidencing that transfer was clinically reasonable. In-hospital mortality was 2.6%. The cost of air ambulance transfer of 114 patients was $AU558,000. Conclusions: Coronary angiography is a common and appropriate reason for inter-hospital patient transfer. The cost of air transfer is significant and our study supports the development of cardiac catheterisation laboratories in selected large rural centres. http://dx.doi.org/10.1016/j.hlc.2015.06.051
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working relationships. The mutual reliance these health care providers demonstrated led to a great patient outcome a long way from a tertiary health care facility. The feasibility of replicating this model of health care in other sparsely resourced populations in Victoria is currently being examined. http://dx.doi.org/10.1016/j.hlc.2015.06.049 49 A tale of two receptors - Investigating how adenosine A2 receptors modulate adenosine A1 receptor-mediated cardioprotection E. Vecchio ∗ , A. TN Nguyen, C. Tan, P. White, L. May Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia Introduction: Adenosine, primarily through the activation of the adenosine A1 receptor (A1 AR), is a potent, endogenous cardioprotective agent that helps to limit myocardial damage post infarction. It has recently been identified that for full A1 AR-mediated cytoprotection, simultaneous activation of the adenosine A2 receptor (A2 AR) subtypes is required. The mechanism behind this phenomenon is unknown, with one possible explanation involving receptor dimerisation.
Aims: To determine the molecular basis for cardioprotective adenosine receptor interactions by examining binding and functional cooperativity. Methods: Functional adenosine receptor interactions were examined at the level of ERK1/2 phosphorylation by exposing isolated neonatal rat cardiomyocytes to a combination of adenosine receptor ligands. Cooperative interactions occurring across a dimeric (or higher order oligomeric) interface were assessed using radioligand [3 H]DPCPX dissociation kinetics. Results: Functional interactions at the level of ERK1/2 phosphorylation was observed for the non-selective adenosine receptor agonist NECA in the presence of the A2A AR and A2B AR selective antagonists, SCH 442416 or PSB 603 respectively. A change in [3 H]DPCPX dissociation kinetics from the A1 AR was observed in the presence of SCH 442416 or PSB 603 Discussion: Collectively, this data provides direct evidence for cooperative allosteric interactions occurring across adenosine heterodimers (or higher order oligomers) within cardiomyocytes and highlights the importance of all three adenosine receptors in cardioprotection. Further understanding of the adenosine heterodimeric complex provides a new
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strategy for the rational design of new cardioprotective agents. http://dx.doi.org/10.1016/j.hlc.2015.06.050 50 An audit of inter-hospital patient transfers for coronary angiography from a rural centre in Australia J. Janardan 1,∗ , K. Haji 2,3 , A. Al Alawi 1 , D. Wong 4,5,6 , H. Gibbs 1 , A. Soward 5,6 1 The
Alfred Hospital, Melbourne, Victoria, Australia 2 Epworth Hospital, Richmond, Victoria, Australia 3 Monash Medical Centre, Clayton, Victoria, Australia 4 MonashHeart, Monash Cardiovascular Research Centre, Melbourne, Victoria, Australia 5 Division of Medicine, Mildura Base Hospital, Mildura, Victoria, Australia 6 Mildura Cardiology, Mildura, Victoria, Australia Aim: To determine the characteristics and outcomes of patients transferred from a rural hospital for coronary angiography. Method: Retrospective audit of medical records of patients transferred from Mildura Base Hospital from 1st January to 31st December 2013 for coronary angiography. Demographic data, medical insurance, primary diagnosis, illness severity score, and transfer costs were recorded. Details regarding inpatient stay at the receiving hospitals were obtained from discharge summaries. Results: There were 114 transfers for coronary angiography which represented 41% of all medical inter-hospital transfers from this centre. Median age was 64 years, 36.9% were female. 42.9% had private insurance with 39.5% being transferred to private hospitals. The median Charlson comorbidity score was 1 and median Simple Clinical Score was 5 suggesting haemodynamically stable patients with low 24-hour and 30day mortality risk, suitable for transfer and advanced care. The principle diagnosis included non ST elevation (64%) and ST elevation myocardial infarction (14.9%), angina (11.4%), arrhythmias (6.1%), other chest pain (1.7%) and heart failure (1.7%). Angiography, performed in 95.6% of transfers (n=109), revealed significant coronary disease in 78 (71.5%) and resulted in revascularisation in 56 cases (coronary artery stenting in 40 and bypass grafting in 16), evidencing that transfer was clinically reasonable. In-hospital mortality was 2.6%. The cost of air ambulance transfer of 114 patients was $AU558,000. Conclusions: Coronary angiography is a common and appropriate reason for inter-hospital patient transfer. The cost of air transfer is significant and our study supports the development of cardiac catheterisation laboratories in selected large rural centres. http://dx.doi.org/10.1016/j.hlc.2015.06.051