Regulation of renal sympathetic neurotransmission by renal α2A‐adrenoceptors is impaired in chronic renal failure

BACKGROUND AND PURPOSE: The mechanisms underlying increased renal noradrenaline in renal failure are still unclear. In this study, the role of α(2A)-adrenoceptors in controlling sympathetic neurotransmission in chronic renal failure was evaluated in a subtotal nephrectomy model. Also, the influence of this receptor subtype on angiotensin II (Ang II)-mediated noradrenaline release was evaluated. EXPERIMENTAL APPROACH: α(2A)-adrenoceptor-knockout (KO) and wild-type (WT) mice underwent subtotal (5/6) nephrectomy (SNx) or SHAM-operation (SHAM). Kidneys of WT and KO mice were isolated and perfused. Renal nerves were stimulated with platinum electrodes and noradrenaline release was measured by HPLC. KEY RESULTS: Noradrenaline release induced by renal nerve stimulation (RNS) was significantly increased in WT mice after SNx. RNS-induced noradrenaline release was significantly higher in SHAM-KO compared with SHAM-WT, but no further increase in noradrenaline release could be observed in SNx-KO. α-adrenoceptor antagonists increased RNS-induced noradrenaline release in SHAM-WT but not in SHAM-KO. After SNx, the effect of α₂-adrenoceptor blockade on renal noradrenaline release was attenuated in WT mice. The mRNA expression of α(2A)-adrenoceptors was not altered, but the inhibitory effect of α₂-adrenoceptor agonists on cAMP formation was abolished after SNx. Ang II facilitated RNS-induced noradrenaline release in SHAM-WT but not in SHAM-KO and SNx-WT. CONCLUSION AND IMPLICATIONS: In our model of renal failure autoregulation of renal sympathetic neurotransmission was impaired. Presynaptic inhibition of noradrenaline release was diminished and the facilitatory effect of presynaptic angiotensin AT₁ receptors on noradrenaline release was markedly decreased in renal failure and depended on functioning α(2A)-adrenoceptors.