Smyth D D, Pirnat D, Forzley B, Penner S B
Department of Pharmacology Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
Ann N Y Acad Sci. 2003 Dec;1009:288-95. doi: 10.1196/annals.1304.059.
Imidazoline receptor agonists such as moxonidine and rilmenidine increase sodium excretion whether administered within the central nervous system, intravenously, or directly into the renal artery. To determine if this natriuresis was mediated by a direct renal effect and was independent of the renal sympathetic nerves, we used two different preparations in the pentobarbital-anesthetized rat. In the first series of studies, rats were unilaterally nephrectomized 7 to 10 days before the experiment. On the day of the experiment, the remaining kidney was denervated (surgical and 10% phenol/ 95% ethyl alcohol) or sham treated. The effect of an intravenous infusion of rilmenidine was determined. Rilmenidine (10 nmol/kg/minute) decreased blood pressure and increased urine flow rate and sodium excretion in the sham- but not the denervation-treated rats. The response to furosemide (5.05 nmol/kg/minute) remained intact following denervation. We then used a two-kidney rat model that allowed for separate urine collection from each ureter. We used low infusion rates of moxonidine directly into the left renal artery. An increase in urine flow rate from the left but not the right kidney would suggest a direct renal action. Low infusion rates of moxonidine (10, 30 nmol/kg/minute) increased urine flow rate similarly from both ureters. A low infusion rate of furosemide (9.1 nmol/kg/minute) into the left renal artery increased urine flow rate only from the left ureter. The failure of moxonidine to increase urine flow rate selectively only in the left kidney indicated the agonist acts at an extrarenal site to increase urine flow rate from both kidneys equally. The complete attenuation of the response to rilmenidine indicates the importance of the renal nerves and suggests that the extrarenal site is most probably the central nervous system. Collectively, these studies do not support a direct renal action of imidazoline agonists in producing natriuresis.
莫索尼定和利美尼定等咪唑啉受体激动剂，无论经中枢神经系统给药、静脉注射还是直接注入肾动脉，均可增加钠排泄。为了确定这种利钠作用是否由直接的肾脏效应介导且独立于肾交感神经，我们在戊巴比妥麻醉的大鼠中使用了两种不同的制备方法。在第一系列研究中，大鼠在实验前7至10天进行单侧肾切除术。在实验当天，对剩余的肾脏进行去神经支配（手术和10%苯酚/95%乙醇）或假处理。测定静脉输注利美尼定的效果。利美尼定（10 nmol/kg/分钟）可降低假处理大鼠的血压，并增加其尿流率和钠排泄，但对去神经支配处理的大鼠无此作用。去神经支配后，对呋塞米（5.05 nmol/kg/分钟）的反应保持不变。然后我们使用了双肾大鼠模型，该模型允许从每个输尿管分别收集尿液。我们将低输注速率的莫索尼定直接注入左肾动脉。左肾而非右肾的尿流率增加将提示直接的肾脏作用。低输注速率的莫索尼定（10、30 nmol/kg/分钟）使两侧输尿管的尿流率同样增加。将低输注速率的呋塞米（9.1 nmol/kg/分钟）注入左肾动脉仅使左输尿管的尿流率增加。莫索尼定未能仅选择性地增加左肾的尿流率，表明该激动剂作用于肾外部位，使两侧肾脏的尿流率同等增加。对利美尼定反应的完全减弱表明肾神经的重要性，并提示肾外部位很可能是中枢神经系统。总体而言，这些研究不支持咪唑啉激动剂在产生利钠作用时有直接的肾脏作用。
