Angiotensin II modulates renal sympathetic neurotransmission through nitric oxide in AT2 receptor knockout mice.
OBJECTIVE
Angiotensin (Ang) II enhances renal sympathetic neurotransmission and stimulates nitric oxide (NO) release. The present study investigates whether Ang II-mediated modulation of sympathetic neurotransmission is dependent on NO production in the kidney. AT2 -/y receptor-deficient mice are used to identify the Ang II receptor subtype involved.


METHODS
Mice kidneys were isolated and perfused with Krebs-Henseleit solution. Drugs were added to the perfusion solution in a cumulative manner. Release of endogenous noradrenaline (NA) was measured by high-performance liquid chromatography (HPLC). AT1 receptor expression was analysed by real-time polymerase chain reaction (PCR).


RESULTS
Ang II (0.01-30 nmol/l) dose dependently increased pressor responses in kidneys of AT2 -/y mice and wild-type (AT2 +/y) mice. Maximal pressor responses and EC50 values for Ang II was greater in AT2 -/y than in AT2 +/y mice. L-NAME (N(omega)-nitro-L-arginine methyl ester; 0.3 mmol/l) enhanced Ang II-induced pressor responses in both strains. In AT2 -/y mice, Ang II-induced facilitation of NA release was more pronounced than in AT2 +/y mice. L-NAME reduced Ang II-mediated facilitation of NA release in both strains. This reduction was more potent in AT2 -/y mice. In kidneys of AT2 -/y mice the AT1 receptor expression was significantly upregulated.


CONCLUSIONS
These results suggest that activation of AT1 receptors by Ang II releases NO in mouse kidney to modulate sympathetic neurotransmission. Since AT1 receptors are upregulated in AT2 -/y mice kidneys, NO-dependent effects were greater in these mice. Thus, NO seems to play an important modulatory role for renal sympathetic neurotransmission.
Stegbauer
Johannes
J
Department of Nephrology, Marienhospital Herne, Ruhr University Bochum, Hölkeskampring 40, D-44625 Herne, Germany.
Vonend
Oliver
O
Habbel
Sina
S
Quack
Ivo
I
Sellin
Lorenz
L
Gross
Volkmar
V
Rump
Lars Christian
LC
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000032:analysis / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000294:innervation*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010477:Perfusion; D016133:Polymerase Chain Reaction; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D015854:Up-Regulation; D014655:Vascular Resistance / Q000187:drug effects
D004791:Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester; D004837:Epinephrine