Smith D E, Guillard S, Rodríguez C A
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
J Pharmacokinet Biopharm. 1992 Apr;20(2):195-207. doi: 10.1007/BF01071001.
Angiotensin II was used as a probe to study the effect of changes in perfusate flow rate on the renal clearance parameters of chlorothiazide in the isolated perfused rat kidney. Perfusion studies were performed in five rats with no angiotensin II present in the perfusate and in five rats with a 1-4 ng/min infusion of angiotensin II into the perfusate. Angiotensin II had a dramatic effect on the renal hemodynamics, resulting in a 43% decrease in perfusate flow, a 16% decrease in glomerular filtration rate (GFR), and a 45% increase in filtration fraction. Values for the fractional excretion of glucose were low and consistent, with or without angiotensin II. Although the unbound fraction (fu) of chlorothiazide was unchanged between treatments, the renal (CLr) and the secretion clearances were reduced by about 50% in the presence of angiotensin II; the excretion ratio [ER = CLr/(fu.GFR)] was reduced by 38% with angiotensin II present in the perfusate. Analysis of the data was complicated by the presence of a capacity-limited transport for renal tubular secretion. Transport parameters (+/- SD) were obtained and the corrected intrinsic secretory clearance [(Vmax/GFR)/Km] of chlorothiazide was 123 +/- 18 without angiotensin II vs. 72.8 +/- 30.0 with angiotensin II. These results demonstrate that alterations in organ perfusion can significantly reduce the clearance parameters of chlorothiazide in the rat IPK. These flow-induced changes in intrinsic secretory transport may reflect perturbations other than that of perfusion flow rate alone.
血管紧张素II被用作探针，以研究灌流液流速变化对氯噻嗪在离体灌流大鼠肾脏中肾清除参数的影响。对5只灌流液中无血管紧张素II的大鼠和5只灌流液中以1 - 4 ng/min输注血管紧张素II的大鼠进行了灌注研究。血管紧张素II对肾脏血流动力学有显著影响，导致灌流液流速降低43%，肾小球滤过率（GFR）降低16%，滤过分数增加45%。无论有无血管紧张素II，葡萄糖的分数排泄值都很低且一致。尽管氯噻嗪的未结合分数（fu）在不同处理之间没有变化，但在存在血管紧张素II的情况下，肾清除率（CLr）和分泌清除率降低了约50%；当灌流液中存在血管紧张素II时，排泄比[ER = CLr/(fu.GFR)]降低了38%。由于肾小管分泌存在容量限制转运，数据的分析变得复杂。获得了转运参数（±标准差），氯噻嗪的校正内在分泌清除率[(Vmax/GFR)/Km]在无血管紧张素II时为123±18，在有血管紧张素II时为72.8±30.0。这些结果表明，器官灌注的改变可显著降低氯噻嗪在大鼠离体灌流肾脏中的清除参数。这些由流速引起的内在分泌转运变化可能反映了除单纯灌流液流速之外的其他干扰因素。
