Adenosine A1 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 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.

Conclusion: 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.