title: Adenosine A1 receptor-dependent and independent pathways in modulating renal vascular responses to angiotensin II.
abstract: OBJECTIVE
  Renal afferent arterioles are the effector site for autoregulation of glomerular perfusion and filtration. There is synergistic interaction between angiotensin II (ANG II) and adenosine (Ado) in regulating arteriolar contraction; however, the mechanisms are not clear. In this context, this study investigated the contribution of A1 receptor-dependent and independent signalling mechanisms.
  
  
  METHODS
  Isolated perfused afferent arterioles from transgenic mice (A1 (+/+) and A1 (-/-) ) were used for vascular reactivity studies. Cultured vascular smooth muscle cells (VSMC) were used for phosphorylation studies of signalling proteins that induce arteriolar contraction.
  
  
  RESULTS
  Maximal arteriolar contraction to ANG II was attenuated in A1 (-/-) (22%) compared with A1 (+/+) (40%). Simultaneous incubation with low-dose ado (10(-8)  mol L(-1) ) enhanced ANG II-induced contraction in A1 (+/+) (58%), but also in A1 (-/-) (42%). An ado transporter inhibitor (NBTI) abolished this synergistic effect in A1 (-/-) , but not in wild-type mice. Incubation with Ado + ANG II increased p38 phosphorylation in aortic VSMC from both genotypes, but treatment with NBTI only blocked phosphorylation in A1 (-/-) . Combination of ANG II + Ado also increased MLC phosphorylation in A1 (+/+) but not significantly in A1 (-/-) , and NBTI had no effects. In agreement, Ado + ANG II-induced phosphorylation of p38 and MLC in rat pre-glomerular VSMC was not affected by NBTI. However, during pharmacological inhibition of the A1 receptor simultaneous treatment with NBTI reduced phosphorylation of both p38 and MLC to control levels.
  
  
  CONCLUSIONS
  Interaction between ANG II and Ado in VSMC normally involves A1 receptor signalling, but this can be compensated by receptor independent actions that phosphorylate p38 MAPK and MLC.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: X
authors.initials: X
authors.lastname: Gao
authors.forename: M
authors.initials: M
authors.lastname: Peleli
authors.forename: C
authors.initials: C
authors.lastname: Zollbrecht
authors.forename: A
authors.initials: A
authors.lastname: Patzak
authors.forename: A E G
authors.initials: AE
authors.lastname: Persson
authors.forename: M
authors.initials: M
authors.lastname: Carlström
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D043682:Receptor, Adenosine A1; D000804:Angiotensin II; D048051:p38 Mitogen-Activated Protein Kinases; D000241:Adenosine
keywords: afferent arteriole; kidney; microcirculation; myosin light chain; p38 MAP kinase; vascular smooth muscle cell