Shimizu T, Nakamura M, Imai M
Department of Pharmacology, National Cardiovascular Center Research Institute, Suita, Japan.
Tohoku J Exp Med. 1991 Aug;164(4):293-8. doi: 10.1620/tjem.164.293.
S-8666, [6, 7-dichloro-5-(N, N-dimethylsulfamoyl)-2, 3-dihydrobenzofurancarboxylic acid] is a potent diuretic with uricosuric action. Although the major site of action of S-8666 has been proven by the in vitro microperfusion study to be the thick ascending limb of Henle's loop, clearance studies in the rat suggested that this drug has an additional thiazide-like action. To provide direct evidence that S-8666 acts also on distal nephron segments, we examined effect of S-8666 on Cl- flux across the rabbit connecting tubule perfused in vitro. The drug suppressed the lumen-to-bath Cl- flux by 96 +/- 41 (S.E.)pmol.mm-1.min-1 (n = 9) without affecting transmural voltage. To demonstrate that S-8666 acts on the connecting tubule cell, the target of thiazide diuretics, we compared effects of S-8666 and trichlormethiazide on the basolateral membrane voltage of the connecting tubule cell. Both drugs added to the lumen caused a small but significant hyperpolarization of the basolateral membrane without affecting transmural voltage. We conclude that S-8666 is a unique uricosuric diuretic having actions on both thick ascending limb of Henle's loop and connecting tubule.
S-8666，即[6,7-二氯-5-(N,N-二甲基氨磺酰基)-2,3-二氢苯并呋喃羧酸]，是一种具有促尿酸排泄作用的强效利尿剂。尽管体外微灌注研究已证实S-8666的主要作用部位是髓袢升支粗段，但大鼠的清除率研究表明，该药物还具有类似噻嗪类的作用。为了提供直接证据证明S-8666也作用于远端肾单位节段，我们检测了S-8666对体外灌注的兔连接小管中氯离子通量的影响。该药物使管腔至浴液的氯离子通量降低了96±41（标准误）pmol·mm⁻¹·min⁻¹（n = 9），而不影响跨膜电压。为了证明S-8666作用于连接小管细胞（噻嗪类利尿剂的作用靶点），我们比较了S-8666和三氯噻嗪对连接小管细胞基底外侧膜电压的影响。两种药物加入管腔后均引起基底外侧膜轻微但显著的超极化，而不影响跨膜电压。我们得出结论，S-8666是一种独特的促尿酸排泄利尿剂，对髓袢升支粗段和连接小管均有作用。
