Exploring the Haemodynamic Effects of BAY60‐6583, in Conscious, Freely‐Moving Rats

The adenosine A 2B receptor (A 2B R) is a potential novel therapeutic target for cancer treatments, however, the effects of A 2B R ligands on the cardiovascular system have yet to be fully elucidated [1]. This project explored haemodynamic responses to a selective A 2B R agonist, BAY60‐6583, in conscious rats. Previous, unpublished studies have shown that BAY60‐6583 causes tachycardia and vasodilatations in the renal and mesenteric vascular beds, that are attenuated by the A 2B R selective antagonist, PSB1115, proving that the effects of BAY60‐6583 are caused by agonism of the A 2B R. It is not known, however, if the tachycardic response is caused directly by A 2B Rs situated on the heart, or by indirect catecholamine mediated homeostatic reflexes to maintain mean arterial pressure (MAP) in the presence of regional arterial vasodilatations. In this study, the haemodynamic response to BAY60‐6583 in the presence or absence of the beta‐adrenergic blocking agent propranolol was investigated to test if the tachycardic response is caused by catecholamine mediated reflexes. Methods Sprague‐Dawley rats were anaesthetised, before being implanted with pulsed Doppler flow probes for the measurement of vascular conductance in the renal, mesenteric, and hindquarter vascular beds. Subsequently, intra‐arterial and intra‐venous catheters were implanted, allowing measurements of heart rate (HR) and MAP, and drug administration, respectively. 24 hours after surgery, a bolus of either the beta‐blocker, propranolol (0.1 mL, 1.0 mg/kg), or vehicle (0.1 mL) was followed by infusion with either propranolol (0.5 mg/kg/hr) or vehicle, respectively. After 90 minutes, three doses (4, 13.3, 40 μg/kg/min) of BAY60‐6583 was consecutively infused, each for 3 minutes, respectively. Recordings were made for a further 4 hours after drug administration. BAY60‐6583 was administered on two separate experimental days, in the presence or absence of propranolol, with a washout day in between, allowing each rat to act as their control. Procedures were approved by the University of Nottingham Animal Welfare Ethical Review Board, under Home Office Project and Personal License Authority, and follow the FASEB statement of principles for the use of animals in research. Results Infusion of BAY60‐6583 (4, 13.3, 40 μg/kg/min) caused a dose‐dependent increase in HR, no significant change in MAP and was accompanied by an increase in renal and mesenteric vascular conductance, but no significant change in hindquarter vascular conductance (Figure 1). Treatment with propranolol attenuated the tachycardic effects of BAY60‐6583. Propranolol caused no changes to the effects of BAY60‐6583 on regional vascular beds (Figure 1). Conclusions The tachycardia caused by BAY60‐6583 administration can be attenuated by beta‐blockade, suggesting that BAY60‐6583 may cause catecholamine mediated reflex countermeasures to maintain MAP in the presence of vasodilatations in the renal and mesenteric vascular beds, in conscious rats. Support or Funding Information This work was funded by The Centre of Membrane Proteins and Receptors (COMPARE).Responses to BAY60‐6583, ± propranolol, in conscious rats. A 0.1 mL bolus of propranolol (1.0 mg/kg) or vehicle was administered, before a 90‐minute infusion of either propranolol (0.5 mg/kg/hr) or vehicle, respectively. After infusion, three doses (4, 13.3, 40 μg/kg/min, each for 3 minutes) of BAY60‐6583 was administered. *Friedman’s test, P<0.05 accepted for significance versus baseline. #Wilcoxon test, P<0.05 accepted for significance between conditions. Data: mean ± SEM, n=8.References. [1] 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 .