Adenosine receptor regulation of coronary blood flow in Ossabaw miniature swine

Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A(1), A(2A), A(2B), A(3)) to CBF in swine have not been determined. ARs generally decrease (A(1), A(3)) or increase (A(2A), A(2B)) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A(1) antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A(1)/A(2A) expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A(2)-nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A(1)-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A(2) antagonist 3,7-dimethyl-1-propargylxanthine and A(2A)-selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A(2B) and A(3) antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ∼70%, whereas A(1), A(2A), and A(2B) mRNA were up-regulated in dyslipidemic versus control >5-fold and there was no change in the ratio of A(1)/A(2A) protein in microvessels distal to the stent. In control Ossabaw swine A(1) antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A(1) and A(2A) signaling, not receptor expression.