Abstract

Introduction.
The
adenosine A_2B receptor (A_2BR) has been shown to have roles
in pathological conditions involving the cardiovascular system, including
ischaemia-reperfusion injury and cancer [1]. Thus, there is an interest in targeting
the A_2BR for potential novel therapeutics [2]. However, the systemic
effects of A_2BR ligands on the cardiovascular system have not been
determined. This project explored the systemic and regional haemodynamic
responses to A_2BR ligands in conscious, freely moving rats.

Methods.
Adult, male, Sprague-Dawley rats were anaesthetised, before implantation with pulsed Doppler
flow probes to facilitate the measurement of vascular conductance in
mesenteric, renal, and hindquarter vascular beds. Subsequently, intra-arterial and
intra-venous catheters were implanted, allowing measurements of heart rate (HR)
and mean arterial pressure (MAP), and drug administration, respectively. Compounds
were prepared in propylene glycol buffer (5% PEG, 2% Tween, 0.9% saline). Twenty-four
hours after surgery, a bolus of either the A_2BR antagonist PSB1115
(10 mg/kg) or vehicle was administered. Ten minutes later, a low, medium and
high dose of the A_2BR-selective agonist BAY60-6583, was infused,
each for three minutes, respectively, and recordings made for a further 4 hours.
Each rat was administered the A_2BR agonist on two separate experimental
days, in the presence or absence of PSB1115, allowing each rat to act as their
control. A group size of 8 was required. Procedures were approved by the
University of Nottingham Animal Welfare Ethical Review Board, under Home Office
Project and Personal License Authority.

Results.
Infusion
of BAY60-6583 (4, 13.3, 40 μg/kg/min)
caused a dose-dependent increase in HR, but no significant change to MAP. This
was accompanied by a dose-dependent increase in renal and mesenteric vascular
conductance, but no significant change in hindquarter vascular conductance. The observed effects were attenuated
by PSB1115 (10 mg/kg), confirming the responses are caused by agonism of A_2BR.

Conclusions.
BAY60-6583
caused a dose-dependent increase in HR and an increase in renal and mesenteric
vascular conductance. However, no changes to MAP was observed. This
tachycardic response could be indicative of baroreceptor reflex mediated
countermeasures to maintain MAP in the presence of vasodilatations in the renal
and mesenteric vascular beds.

Funding. This work was supported financially by the Centre of Membrane Proteins and Receptors (COMPARE), a collaboration between the Universities of Nottingham and Birmingham.

References

[1] Vecchio EA, White PJ, May LT (2019)
The adenosine A_2B G protein-coupled receptor: Recent advances and
therapeutic implications. Pharmacol Ther, 198, 20-33.

[2] Sorrentino C, Morello S (2017) Role of
adenosine in tumor progression: focus on A_2B receptor as potential
therapeutic target. Journal of Cancer Metastasis and Treatment, 3, 127-38.