Samantha L. Cooper
The effect of two selective A1-receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats
Cooper, Samantha L.; March, Julie; Sabbatini, Andrea R.; Hill, Stephen J.; Jörg, Manuela; Scammells, Peter J.; Woolard, Jeanette
Andrea R. Sabbatini
STEPHEN HILL email@example.com
Professor of Molecular Pharmacology
Peter J. Scammells
JEANETTE ISAAC Jeanette.Woolard@nottingham.ac.uk
Professor of Cardiovascular Physiology and Pharmacology
Background and purpose
Adenosine is a local mediator that regulates physiological and pathological processes via activation of four G protein‐coupled receptors (A1, A2A, A2B, A3). We have investigated the effect of two A1‐receptor selective agonists and the novel A1‐receptor bitopic ligand VCP746 on the rat cardiovascular system.
To investigate the effect of these A1‐agonists on the cardiovascular system, we evaluated their regional haemodynamic responses in conscious rats. Male Sprague Dawley rats (350–450g) were chronically implanted with pulsed Doppler flow probes (positioned around the renal and mesenteric arteries, and the descending abdominal aorta) and catheters (jugular vein and caudal artery). Cardiovascular responses were measured following i.v. infusion (3 min each dose) of CCPA (120, 400, 1200 ng.kg‐1.min‐1), capadenoson or adenosine (30, 100, 300 μg.kg‐1.min‐1) or VCP746 (6, 20, 60 μg.kg‐1.min‐1) following pre‐dosing with DPCPX (0.1 mg.kg‐1 i.v.) or vehicle.
CCPA produced a significant A1‐receptor‐mediated decrease (p less than 0.05) in heart rate that was accompanied by vasoconstrictions in the renal and mesenteric vascular beds but an increase in hindquarters vascular conductance. The partial agonist capadenoson also produced an A1‐receptor‐mediated bradycardia. In contrast, VCP746 produced increases in heart rate and renal and mesenteric vascular conductance that were not mediated by A1‐receptors. In vitro studies confirmed that VCP746 had potent agonist activity at both A2A and A2B receptors.
Conclusions and Implications
These results suggest VCP746 mediates its cardiovascular effects via activation of A2 rather than A1 adenosine receptors. This has implications for the design of future bitopic ligands that incorporate A1 allosteric ligand moieties.
Scammells, P. J., Cooper, S. L., March, J., Sabbatini, A. R., Hill, S. J., Jörg, M., …Woolard, J. (2020). The effect of two selective A1-receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats. British Journal of Pharmacology, 177(2), 346-359. https://doi.org/10.1111/bph.14870
|Journal Article Type||Article|
|Acceptance Date||Sep 16, 2019|
|Online Publication Date||Oct 9, 2019|
|Deposit Date||Oct 15, 2019|
|Publicly Available Date||Jan 16, 2020|
|Journal||British Journal of Pharmacology|
|Peer Reviewed||Peer Reviewed|
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