Regionally selective cardiovascular responses to adenosine A2A and A2B receptor activation

Abstract

Adenosine is a local mediator that regulates changes in the cardiovascular system via activation of four G protein-coupled receptors (A₁ , A_2A , A_2B , A₃ ). Here, we have investigated the effect of A_2A and A_2B -selective agonists on vasodilatation in three distinct vascular beds of the rat cardiovascular system. NanoBRET ligand binding studies were used to confirm receptor selectivity. The regional hemodynamic effects of adenosine A_2A and A_2B selective agonists were investigated in conscious rats. Male Sprague-Dawley rats (350-450 g) were chronically implanted with pulsed Doppler flow probes on the renal artery, mesenteric artery, and the descending abdominal aorta. Cardiovascular responses were measured following intravenous infusion (3 min for each dose) of the A_2A -selective agonist CGS 21680 (0.1, 0.3, 1 µg kg^-1 min^-1 ) or the A_2B -selective agonist BAY 60-6583 (4,13.3, 40 µg kg^-1 min^-1 ) following predosing with the A_2A -selective antagonist SCH 58261 (0.1 or 1 mg kg^-1 min^-1 ), the A_2B /A_2A antagonist PSB 1115 (10 mg kg^-1 min^-1 ) or vehicle. The A_2A -selective agonist CGS 21680 produced a striking increase in heart rate (HR) and hindquarters vascular conductance (VC) that was accompanied by a significant decrease in mean arterial pressure (MAP) in conscious rats. In marked contrast, the A_2B -selective agonist BAY 60-6583 significantly increased HR and VC in the renal and mesenteric vascular beds, but not in the hindquarters. Taken together, these data indicate that A_2A and A_2B receptors are regionally selective in their regulation of vascular tone. These results suggest that the development of A_2B receptor agonists to induce vasodilatation in the kidney may provide a good therapeutic approach for the treatment of acute kidney injury.

Keywords: A2 receptor activation; Doppler flow; adenosine; hemodynamics.