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Impaired Vascular Contractility to Uridine Adenosine Tetraphosphate (Up 4 A) in Angiotensin (Ang) II‐Induced Hypertensive Mice: The Receptor Desensitization?
Author(s) -
Zhou Zhichao,
Yadav Vishal R,
Sun Changyan,
Teng Bunyun,
Mustafa S. Jamal
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.942.10
Subject(s) - angiotensin ii , endocrinology , medicine , losartan , angiotensin ii receptor type 1 , contraction (grammar) , chemistry , stimulation , desensitization (medicine) , receptor , antagonist
We previously showed (Zhou et. al ., Vascular Pharmacol. 73:78–85, 2015) that Up 4 A‐mediated vascular contraction is partly through purinergic P2X 1 receptors (P2X 1 R). Since the plasma level of Up 4 A is elevated in hypertensives, which implies a crucial role for Up 4 A‐P2X 1 R signalling in hypertension. We investigated the vasoactive effect of Up 4 A in Ang II‐infused mice. Mean arterial blood pressure (MAP) was measured daily in saline or Ang II‐infused mice. Aortas were isolated for isometric tension measurement. Protein expression of Ang II type 1 receptor (AT1) and P2X 1 R was assessed by Western blot. MAP was elevated by ~50% in 3‐week Ang II‐infused mice indicating hypertension. Protein levels of both AT1 and P2X 1 R were upregulated in Ang II‐infused aortas. Surprisingly, Up 4 A (10 −9 –10 −5 M)‐induced concentration‐dependent contraction in saline‐infused aortas was significantly impaired in Ang II group. Both P2X 1 R antagonist MRS2159 and AT1 antagonist losartan attenuated Up 4 A‐induced aortic contraction in WT. However, Up 4 A‐induced aortic contraction with AT1 desensitization by the prior Ang II (100 nM) stimulation in WT was similar to that without the Ang II stimulation, while the second Up 4 A‐induced aortic contraction was markedly reduced as compared to the first exposure in the same preparation, suggesting a desensitization of P2R. This desensitization was further confirmed by P2X 1 R desensitizer α, β‐methylene ATP (10 μM). In conclusion, despite the upregulation of AT1 and P2X 1 R in hypertension, Up 4 A‐mediated aortic contraction was impaired in Ang II‐infused mice, which was likely through the desensitization of P2X 1 R but not AT1. This study implies that vascular P2R activity rather than plasma Up 4 A level may determine the role of Up 4 A in hypertension. Support or Funding Information Supported by HL02339, HL094447 from NIH and MEPSCKL201301 from Sichuan Medical University