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


METHODS
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.


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.


CONCLUSIONS
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.
Department of Nephrology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany. henning.hoch@med.uni-duesseldorf.de
Henning
H
Hoch
Johannes
J
Stegbauer
Sebastian A
SA
Potthoff
Lutz
L
Hein
Ivo
I
Quack
Lars Christian
LC
Rump
Oliver
O
Vonend
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004558:Electric Stimulation; D007668:Kidney / Q000294:innervation / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000235:genetics / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D009435:Synaptic Transmission
C547769:Adra2a protein, mouse; C547772:Adra2b protein, mouse; C547775:Adra2c protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D044140:Receptor, Angiotensin, Type 1; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D000804:Angiotensin II; D000242:Cyclic AMP; D009638:Norepinephrine
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