Divergent coronary flow responses to uridine adenosine tetraphosphate in atherosclerotic ApoE knockout mice

Uridine adenosine tetraphosphate (Up 4 A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up 4 A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up 4 A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X 1 receptor (P2X 1 R) expression in isolated mouse coronary arteries. In vivo effects of Up 4 A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up 4 A (10 −9 –10 −5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X 1 R antagonist MRS2159 restored Up 4 A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X 1 R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X 1 R in ApoE KO + HFD mice. In contrast, Up 4 A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up 4 A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X 1 R. In contrast, Up 4 A increases CBF in vivo regardless of the atherosclerotic model.