Impaired Aortic Contractility to Uridine Adenosine Tetraphosphate in Angiotensin II-Induced Hypertensive Mice: Receptor Desensitization?

OBJECTIVE We previously showed that uridine adenosine tetraphosphate (Up(4)A)mediated aortic contraction is partly mediated through purinergic P2X(1) receptors (P2X(1)R). It has been reported that the plasma level of Up(4)A is elevated in hypertensive patients, implying a potential role for Up(4)A-P2X(1)R signaling in hypertension. This study investigated the vasoactive effect of Up(4)A in aortas isolated from angiotensin (Ang) II-infused (21 days) hypertensive mice. METHODS Blood pressure was measured by tail cuff plethysmography. Aortas were isolated for isometric tension measurements, and protein expression was analyzed by western blot. RESULTS Mean and systolic arterial pressures were elevated by similar to 50% in Ang II-infused mice. Protein levels of both AT1R and P2X(1)R were upregulated in Ang II-infused aortas. Surprisingly, Up(4)A (10(-9)-10(-5) M)-induced concentration-dependent contraction was significantly impaired in Ang II-infused mice. Studies in control mice revealed that both P2X(1)R (MRS2159) and AT1R (losartan) antagonists significantly attenuated Up(4)A-induced aortic contraction. In addition, desensitization of AT1R by prior Ang II (100 nM) exposure had no effect on Up(4)A-induced aortic contraction. However, subsequent serial exposure responses to Up(4)A-induced aortic contraction were markedly reduced, suggesting a desensitization of purinergic receptors. This desensitization was further confirmed in control mice by prior exposure of aortas to the P2X(1)R desensitizer alpha, beta-methylene ATP (10 mu M). CONCLUSION Despite upregulation of AT1R and P2X(1)R in hypertension, Up(4)A-mediated aortic contraction was impaired in Ang II-infused mice, likely through the desensitization of P2X(1)R but not AT1R. This implies that vascular P2X(1)R activity, rather than plasma Up(4)A level, may determine the role of Up4A in hypertension.