α2A-adrenoceptors regulate sympathetic transmitter release in mice kidneys

Background and purpose: In the present study, a rodent model was used to investigate whether the α2A-adrenoceptor (α2A) represents the presynaptic autoinhibitory receptor regulating sympathetic transmitter release in the kidney. Moreover, the potential role of α2A as a heteroceptor regulating adenosine triphosphate (ATP) release was tested. Experimental approach: Kidneys from wild-type (WT) and α2A-knockout (KO) mice were isolated and perfused. Renal nerves were stimulated with platinum-electrodes. Endogenously released noradrenaline (NA) was measured by HPLC. The perfusion pressure was monitored continuously. Key results: Renal nerve stimulation (RNS) induced a frequency (1,2,5,7.5,10,15 Hz)-dependent release of NA in WT mice (994±373, 2355±541, 6375±950, 11626±1818, 19138±2001 pg NA g-1 kidney (means±s.e.m.)). There was a 2.7-fold (5 Hz) increase of NA release in α2A-KO mice. In WT animals α-adrenoceptor blockade by phentolamine increased RNS-induced NA release in a concentration-dependent manner up to 350% of control. No facilitation by phentolamine was observed in α2A-KO mice. Pressor responses to 1 Hz and 2 Hz were resistant to α1-adrenoceptor blockade (0.03 μM prazosin) but abolished by P2 receptor blockade (5 μM PPADS). Blockade of α2-adrenoceptors (1 μM rauwolscine) increased these purinergic pressor responses to 296±112% (1 Hz) in WT but not in α2A-KO mice. Exogenous ATP (100 μM) increased basal but not RNS-induced NA release. Conclusions and Implications: α2A-Adrenoceptor-activation inhibits NA and ATP release from renal sympathetic nerves. Pressor responses to RNS at higher stimulation frequencies (>2 Hz) are mediated by NA. At lower frequencies neuronally released ATP seems to be the predominant transmitter mediating renovascular resistance. British Journal of Pharmacology (2007) 150, 121–127. doi:10.1038/sj.bjp.0706961