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.; J�rg, Manuela; Scammells, Peter J.; Woolard, Jeanette

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

Cooper, S. L., March, J., Sabbatini, A. R., Hill, S. J., Jörg, M., Scammells, P. J., & 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
• Contract Date: Oct 15, 2019