Regulation of renal sympathetic neurotransmission by renal α 2A-adrenoceptors is impaired in chronic renal failure

Abstract

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 α 2-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 α 2-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 AT 1 receptors on noradrenaline release was markedly decreased in renal failure and depended on functioning α 2A- adrenoceptors. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.