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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

Authors

Samantha L. Cooper

Julie March

Andrea R. Sabbatini

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

Manuela Jörg

Peter J. Scammells

JEANETTE ISAAC Jeanette.Woolard@nottingham.ac.uk
Professor of Cardiovascular Physiology and Pharmacology



Abstract

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.

Experimental Approach
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.

Key Results
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.

Citation

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
Publication Date 2020-01
Deposit Date Oct 15, 2019
Publicly Available Date Jan 16, 2020
Journal British Journal of Pharmacology
Print ISSN 0007-1188
Electronic ISSN 1476-5381
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 177
Issue 2
Pages 346-359
DOI https://doi.org/10.1111/bph.14870
Keywords Pharmacology
Public URL https://nottingham-repository.worktribe.com/output/2838182
Publisher URL https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.14870

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