Blandford D E, Smyth D D
Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada.
J Pharmacol Exp Ther. 1988 Dec;247(3):1181-6.
In vitro studies have demonstrated an antagonism of the renal effects of vasopressin after alpha-2 adrenoceptor stimulation. Whether the effect of alpha-2 adrenoceptor stimulation in relation to sodium and water excretion in vivo is mediated through independent mechanisms is unclear. The dose-response relationship between renal alpha-2 adrenoceptor stimulation (clonidine) and water and electrolyte excretion was evaluated in anesthetized rats. Rats were nephrectomized unilaterally 7 to 10 days before the experimental day to allow isolation of renal function. A base-line level of sodium and water excretion was established by the infusion of saline (0.097 ml/min i.v.). In separate groups of rats, clonidine was infused directly into the renal artery at 0 (vehicle), 0.1, 0.3, 1 or 3 micrograms/kg/min at 0.0034 ml/min. The lower doses (0.1, 0.3 and 1 microgram/kg/min) produced a dose-related increase in urine volume and free water clearance and a decrease in urine osmolality. Electrolyte or solute excretion was not altered at these infusion rates even though urine volume increased 4-fold. The highest dose investigated (3 micrograms/kg/min) increased urine volume (9-fold) and sodium excretion (4-fold). Free water clearance and osmolar clearance were also increased. The effects of clonidine were attenuated by yohimbine but not prazosin indicating these effects were mediated by alpha-2 adrenoceptor stimulation. These results demonstrate a dose-related selectivity of alpha-2 adrenoceptor stimulation for water and sodium excretion. The increase in water excretion at the lower infusion rates would be consistent with the antagonism of the renal effects of vasopressin. The potent natriuresis observed only at higher doses indicates another mechanism may be involved.
体外研究表明，α-2肾上腺素能受体受刺激后对血管加压素的肾脏效应具有拮抗作用。α-2肾上腺素能受体受刺激对体内钠和水排泄的影响是否通过独立机制介导尚不清楚。在麻醉大鼠中评估了肾脏α-2肾上腺素能受体受刺激（可乐定）与水和电解质排泄之间的剂量反应关系。在实验日前7至10天对大鼠进行单侧肾切除术，以分离肾功能。通过静脉输注生理盐水（0.097 ml/分钟）建立钠和水排泄的基线水平。在不同组的大鼠中，以0.0034 ml/分钟的速度将可乐定以0（溶媒）、0.1、0.3、1或3微克/千克/分钟的剂量直接注入肾动脉。较低剂量（0.1、0.3和1微克/千克/分钟）使尿量和自由水清除率呈剂量相关增加，尿渗透压降低。尽管尿量增加了4倍，但在这些输注速率下电解质或溶质排泄未改变。所研究的最高剂量（3微克/千克/分钟）使尿量增加（9倍），钠排泄增加（4倍）。自由水清除率和渗透清除率也增加。育亨宾可减弱可乐定的作用，但哌唑嗪则不能，这表明这些作用是由α-2肾上腺素能受体受刺激介导的。这些结果证明了α-2肾上腺素能受体受刺激对水和钠排泄具有剂量相关的选择性。较低输注速率下的水排泄增加与血管加压素的肾脏效应拮抗作用一致。仅在较高剂量下观察到的强效利钠作用表明可能涉及另一种机制。
