The effect of two selective A₁-receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats

Background and Purpose: Adenosine is a local mediator that regulates physiological and pathological processes via activation of four GPCRs (A₁, A_2A, A_2B, and 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: The regional haemodynamic responses of these agonist was investigated in conscious rats. Male Sprague–Dawley rats (350–450 g) were chronically implanted with pulsed Doppler flow probes on the renal, mesenteric arteries and the descending abdominal aorta and the jugular vein and caudal artery catheterized. Cardiovascular responses were measured following intravenous infusion (3 min each dose) of CCPA (120, 400, and 1,200 ng·kg⁻¹·min⁻¹), capadenoson or adenosine (30, 100, and 300 μg·kg⁻¹·min⁻¹), or VCP746 (6, 20, and 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 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 A_2A- and A_2B-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.