Shirahase H, Uehara Y, Wada K, Shimaji H, Ishimitsu T, Hashizume Y, Kanda M, Nakamura S
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
J Hypertens. 1994 Feb;12(2):137-44.
To study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats.
Vehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks.
Systolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out.
NKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta.
NKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.
研究长期给予NKY - 722和尼卡地平对Dahl盐敏感（Dahl - S）大鼠肾功能以及肾脏和动脉形态学变化的影响。
给喂食高盐饮食的Dahl - S大鼠口服赋形剂、NKY - 722和尼卡地平，持续6周。
每周测量一次收缩压。在最后一周采集血液和尿液并进行尸检。
NKY - 722（每天1毫克/千克）可使血压持续降低6周，而尼卡地平（每天3毫克/千克）仅在第1周显示出类似效果。NKY - 722有降低血尿素氮的趋势，并显著降低血浆肌酐和肾素活性。NKY - 722增加尿量、尿钠、肌酐和蛋白质排泄，但对尿N - 乙酰 - β - D - 氨基葡萄糖苷酶活性无显著影响。NKY - 722增加肾小球滤过率，并在形态学上减轻肾小球硬化和肾动脉损伤。尼卡地平不影响血液或尿液参数，但显著减轻肾小球损伤。NKY - 722而非尼卡地平减轻脑动脉损伤。较低剂量的NKY - 722（每天0.3毫克/千克）不影响血压、血液或尿液参数，但显著减轻肾小球硬化和肾动脉损伤。NKY - 722（每天1毫克/千克）和尼卡地平（每天3毫克/千克）增加尿6 - 酮 - 前列腺素F1α（6 - 酮 - PGF1α）和PGE2。NKY - 722而非尼卡地平增加胸主动脉中6 - 酮 - PGF1α与血栓素B2的比值。
NKY - 722改善了Dahl - S大鼠的肾功能，并减轻了肾小球、肾脏和脑动脉损伤。NKY - 722对肾小球硬化和动脉损伤的作用至少部分独立于血压，可能与对类花生酸代谢的影响有关。
