title: Impaired Aortic Contractility to Uridine Adenosine Tetraphosphate in Angiotensin II-Induced Hypertensive Mice: Receptor Desensitization?
abstract: OBJECTIVE
  We previously showed that uridine adenosine tetraphosphate (Up4A)-mediated aortic contraction is partly mediated through purinergic P2X1 receptors (P2X1R). It has been reported that the plasma level of Up4A is elevated in hypertensive patients, implying a potential role for Up4A-P2X1R signaling in hypertension. This study investigated the vasoactive effect of Up4A 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 ~50% in Ang II-infused mice. Protein levels of both AT1R and P2X1R were upregulated in Ang II-infused aortas. Surprisingly, Up4A (10-9-10-5 M)-induced concentration-dependent contraction was significantly impaired in Ang II-infused mice. Studies in control mice revealed that both P2X1R (MRS2159) and AT1R (losartan) antagonists significantly attenuated Up4A-induced aortic contraction. In addition, desensitization of AT1R by prior Ang II (100 nM) exposure had no effect on Up4A-induced aortic contraction. However, subsequent serial exposure responses to Up4A-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 P2X1R desensitizer α, β-methylene ATP (10 μM).
  
  
  CONCLUSIONS
  Despite upregulation of AT1R and P2X1R in hypertension, Up4A-mediated aortic contraction was impaired in Ang II-infused mice, likely through the desensitization of P2X1R but not AT1R. This implies that vascular P2X1R activity, rather than plasma Up4A level, may determine the role of Up4A in hypertension.
authors.affiliation: Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, West Virginia, USA.|Present address: Division of Cardiology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Yadav
authors.affiliation: Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, West Virginia, USA.|Present address: Molecular Vascular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Changyan
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Bunyen
authors.initials: B
authors.lastname: Teng
authors.affiliation: Department of Physiology and Pharmacology, Center for Cardiovascular and Respiratory Sciences, Clinical and Translational Science Institute, West Virginia University, Morgantown, West Virginia, USA.
authors.forename: Jamal S
authors.initials: JS
authors.lastname: Mustafa
mesh_terms: D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D062186:Arterial Pressure; D001794:Blood Pressure; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D007537:Isometric Contraction / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D058474:Receptors, Purinergic P2X1 / Q000187:drug effects*; D014662:Vasoconstrictor Agents
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015226:Dinucleoside Phosphates; D044140:Receptor, Angiotensin, Type 1; D058474:Receptors, Purinergic P2X1; D014662:Vasoconstrictor Agents; C529314:uridine adenosine tetraphosphate; D000804:Angiotensin II; D019808:Losartan
keywords: P2X1R; Up4A.; angiotensin II; blood pressure; contraction; hypertension; receptor desensitization