Adenosine A 1 receptor‐dependent and independent pathways in modulating renal vascular responses to angiotensin II

Aim 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 A 1 receptor‐dependent and independent signalling mechanisms. Methods Isolated perfused afferent arterioles from transgenic mice (A 1 +/+ and A 1 −/− ) 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 A 1 −/− (22%) compared with A 1 +/+ (40%). Simultaneous incubation with low‐dose ado (10 −8  mol L −1 ) enhanced ANG II ‐induced contraction in A 1 +/+ (58%), but also in A 1 −/− (42%). An ado transporter inhibitor ( NBTI ) abolished this synergistic effect in A 1 −/− , 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 A 1 −/− . Combination of ANG II  + Ado also increased MLC phosphorylation in A 1 +/+ but not significantly in A 1 −/− , 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 A 1 receptor simultaneous treatment with NBTI reduced phosphorylation of both p38 and MLC to control levels. Conclusion Interaction between ANG II and Ado in VSMC normally involves A 1 receptor signalling, but this can be compensated by receptor independent actions that phosphorylate p38 MAPK and MLC .