Adenosine A1-receptor deficiency diminishes afferent arteriolar and blood pressure responses during nitric oxide inhibition and angiotensin II treatment

Adenosine mediates tubuloglomerular feedback responses via activation of A1-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 A1-receptor knockout (A1−/−) and wild-type (A1+/+) mice we investigated the hypothesis that A1-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 Nω-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 A1−/− 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 A1−/− mice. Simultaneous treatment with tempol (10−4 mol/l; 15 min) attenuated arteriolar responses in A1+/+ but not in A1−/− mice, suggesting differences in ROS formation. Chronic treatment with l-NAME or ANG II did not alter arteriolar responses in A1−/− mice, but enhanced maximal contractions in A1+/+ mice. In addition, chronic treatments were associated with higher plasma levels of dimethylarginines (asymmetrical and symmetrical) and oxidative stress marker malondialdehyde in A1+/+ mice, and gene expression analysis showed reduced upregulation of NOS-isoforms and greater upregulation of NADPH oxidases. In conclusion, adenosine A1-receptors enhance preglomerular responses during NO inhibition and ANG II treatment. Interruption of A1-receptor signaling blunts l-NAME and ANG II-induced hypertension and oxidative stress and is linked to reduced responsiveness of afferent arterioles.