Effects of an Adenosine Receptor Bitopic Ligand on The Cardiovascular System

Abstract

Adenosine regulates physiological and pathophysiological processes via the activation of four G‐protein coupled receptors identified as the A1, A2A, A2B and A3 receptors. All of these receptors are known to be involved in regulation of the cardiovascular system [1]. Recently, we described the effects of A1‐receptor selective agonists and the novel A1‐receptor bitopic ligand VCP746 on the rat cardiovascular system [2]. Here, we assess the haemodynamic responses of VCP746 in the presence and absence of selective A2A and A2B‐receptor antagonists (SCH58261 and PSB1115, respectively).As described previously [3], under anaesthetic, rats were instrumented with miniature pulsed Doppler flow probes for the measurement of vascular conductance at the renal, mesenteric and hindquarters vascular beds. Intra‐arterial and intra‐venous catheters were implanted for measurement of heart rate (HR) and mean arterial pressure (MAP), and drug administration, respectively. All procedures were carried out with approval of the University of Nottingham Animal Welfare Ethical Review Board, under Home Office Project and Personal License Authority.Experimental studies were conducted in conscious, freely‐moving rats. All compounds were prepared in a propylene glycol (PEG) buffer (5% PEG, 2% Tween, 0.9% saline). A 0.1ml bolus of SCH58261 (1.0 mg/kg), PSB1115 (10mg/kg) or vehicle was administered 10 minutes prior to increasing doses of VCP746 (6, 20, 60 μg/kg/min). Doses of VCP746 were administered as 3 minute infusions over a total of 9 minutes at an infusion rate of 0.1 ml/min.VCP746 produced tachycardic effects, which were associated with renal and mesenteric vasodilatations (Figure). There was little effect in the hindquarter vascular bed and MAP was not significantly affected (Figure). The haemodynamic effects of VCP746 were partially antagonised by SCH58261 and PSB1115 fully attenuated haemodynamic responses to VCP746.This study suggests that VCP746, the A1‐receptor bitopic ligand, mediates haemodynamic responses through the activation of the A2‐receptors, particularly the A2B‐receptor, rather than the A1‐receptor. This has implications for the design of bitopic ligands in the future.Support or Funding InformationWe would like to thank the BHF and COMPARE for funding.Cardiovascular responses to VCP746. Rats were dosed with either PSB1115 (0.1 ml bolus dose of 10 mg/kg i.v., n=8) or vehicle (0.1 ml bolus PEG buffer, n=8). Approximately 10 min later, all animals received an infusion of VCP746 (6, 20, and 60 μg/kg/min; each dose infused over 3 minutes). Data presented as mean ± SEM. *P < 0.05 versus baseline (Friedman test). A Wilcoxon test for integrated area under or above curve analysis was used for comparisons between groups (♯ P<0.05).Figure 1