title: Adenosine A₁-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment.
abstract: Adenosine mediates tubuloglomerular feedback responses via activation of A(1)-receptors on the renal afferent arteriole. Increased preglomerular reactivity, due to reduced nitric oxide (NO) production or increased levels of ANG II and reactive oxygen species (ROS), has been linked to hypertension. Using A(1)-receptor knockout (A(1)(-/-)) and wild-type (A(1)(+/+)) mice we investigated the hypothesis that A(1)-receptors modulate arteriolar and blood pressure responses during NO synthase (NOS) inhibition or ANG II treatment. Blood pressure and renal afferent arteriolar responses were measured in nontreated mice and in mice with prolonged N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or ANG II treatment. The hypertensive responses to L-NAME and ANG II were clearly attenuated in A(1)(-/-) mice. Arteriolar contractions to L-NAME (10(-4) mol/l; 15 min) and cumulative ANG II application (10(-12) to 10(-6) mol/l) were lower in A(1)(-/-) mice. Simultaneous treatment with tempol (10(-4) mol/l; 15 min) attenuated arteriolar responses in A(1)(+/+) but not in A(1)(-/-) mice, suggesting differences in ROS formation. Chronic treatment with L-NAME or ANG II did not alter arteriolar responses in A(1)(-/-) mice, but enhanced maximal contractions in A(1)(+/+) mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A(1)(+/+) mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A(1)-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A(1)-receptor signaling blunts l-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors: Xiang
authors: X
authors: Gao
authors: Andreas
authors: A
authors: Patzak
authors: Mauricio
authors: M
authors: Sendeski
authors: Peter G
authors: PG
authors: Scheffer
authors: Tom
authors: T
authors: Teerlink
authors: Johan
authors: J
authors: Sällström
authors: Bertil B
authors: BB
authors: Fredholm
authors: A Erik G
authors: AE
authors: Persson
authors: Mattias
authors: M
authors: Carlström
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D001160:Arterioles / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D043682:Receptor, Adenosine A1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D043682:Receptor, Adenosine A1; C487735:dimethylarginine; D000804:Angiotensin II; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester