氫氯噻嗪的利尿與抗利尿作用致大鼠尿量及組織含水量的變化

【摘要】  　　目的：探討藥物氫氯噻嗪對健康機體的利尿作用與抗利尿作用間的規(guī)律關(guān)系。方法：對應(yīng)用氫氯噻嗪健康大鼠組和無藥對照鼠組，分別采用自由飲水、少量清水灌胃（4h:125mL·kg-1)、和較大量清水灌胃（4h:175mL·kg-1)及超量清水灌胃（4h:260mL·kg-1)的“清水利尿”條件時，觀察給水量不同條件時大鼠6h尿量的變化，及超量水灌胃后大鼠血漿滲透壓、腦組織含水量及腎組織病理切片水腫情況。結(jié)果：自由飲水和少量水灌胃條件時，用藥鼠的6h尿量多于未用藥鼠（P＜0.01）；在較多水灌胃和超量水灌胃條件時，用藥鼠的6h尿量少于未用藥鼠（P＜0.01）；在超量水灌胃（4h:260mL·kg-1)后，用藥鼠血漿滲透壓比未用藥鼠低，而用藥鼠腦組織含水量比未用藥組鼠多（P＜0.01），用藥組鼠腎組織病理切片出現(xiàn)明顯的水腫，未用藥組鼠無明顯水腫。結(jié)論：氫氯噻嗪本身具有利尿作用與抗利尿作用并存，即當(dāng)尿量不多時顯現(xiàn)出利尿效應(yīng)，當(dāng)尿量過多（如水利尿）時顯現(xiàn)出抗利尿效應(yīng)；且若進(jìn)入機體水量過多，該藥可致水中毒。

【關(guān)鍵詞】  氫氯噻嗪；抗利尿作用；水中毒；血漿滲透壓；腦組織含水量

　　［ABSTRACT］ Objective: To explore diuretic and relative anti�瞕iuretic effect of hydrochlorothiazide on various water intake patterns. Methods: Rats were randomly divided into hydrochlorothiazide administration group (group A) and non�瞐dministration group (group B). Two rats were raised in one metabolic cage, and six cages were comprised in each group. Free water intake (feeding, p.o.), controlled water intake with low volume (intragastric administration with 125 mL/kg in 4hrs, i.g.125), medium volume (175 mL/kg in 4 hrs, i.g.175) and excessive water intake (260 mL/kg in 4 hrs, i.g.260) were employed to each group( group A and B, respectively). In first round, quantities of urine volume in the first 6 hrs (Vol6), plasma osmolality (Posmol) and cerebral tissue content of water (CH2O) were calculated by hydrochlorothiazide administration for 3 days (or placebo) in groups. Controlled water intake with i.g.175 and i.g.260 were employed in the second and the third round in group A and B, Vol6 and CH2O were calculated, respectively. Results: A significantly high urine volumes in the first 6 hrs were observed in group A (P＜0.01) from p.o. and i.g.125 rats, but significantly low in i.g.175 and i.g.260 rats (P＜0.01). It showed the lower plasma osmolality level in group A i.g.260 rats, while the cerebral tissue content of water were significantly high (P＜0.01). A clearly histological edema changes could be found in group A i.g.260 rats. Conclusions: Hydrochlorothiazide has diuretic and anti�瞕iuretic effects. Functional shift from diuresis to antidiuresis is depending on urine formation, which means diuretic effect combined with low urine formation, while antidiuresis effect combines with high urine formation. It is demonstrated that hydrochlorothiazide administration has the risk to water intoxication under the excessive water intake condition.
   
　　［KEY WORDS］ Hydrochlorothiazide; Anti�瞕iuretic effect; Water intoxication; Plasma osmotic pressure；Brain water content

　　氫氯噻嗪（hydrochlorothiazide HCTZ）是經(jīng)典的排鈉利尿藥，該藥作用與機制早已明確，但HCTZ又能夠使尿崩癥者的尿量減少，是治療腎性尿崩癥的首選有效藥。但是對健康機體，迄今尚缺資料顯示該藥又使尿量增多（利尿）同時又使尿量減少（抗利尿）的兩種相反效應(yīng)［1］。因而該藥使尿崩癥者的尿量減少的主要機制，通常認(rèn)為由該藥的排鈉作用致尿崩癥者體液滲透壓下降——患者渴感消失而飲水減少——尿量減少［2］。本研究試圖通過氫氯噻嗪影響健康大鼠，分別在自由飲水、少量被動清水灌胃和較大量及超量清水灌胃的“水利尿”［3］條件時，觀察鼠排尿量及其組織含水量的變化，以探明該藥本身是否具有抗利尿的藥理作用，以及其利尿和抗利尿的作用規(guī)律。

　　1  材料與方法

　　1.1  材料

　　1.1.1  主要材料

　　氫氯噻嗪片(山西利豐華瑞制藥有限責(zé)任公司生產(chǎn)，批號20080507)，注射用水溶解后灌胃；雙蒸水（自制；用作大量灌胃造成水利尿）；清潔級SD雄性大鼠，200～250g（購自中山大學(xué)實驗動物中心）。

教育核心期刊論文發(fā)表 　　

　  1.1.2  實驗設(shè)備

  大白鼠代謝籠［4］、冰點滲透壓計(Beokman Coulter Lx．USA)、電熱恒溫箱、萬分之一電子分析天平、普通電子秤。

　　1.2  方法

　　1.2.1  篩選與分組

　　將大鼠自由飲水，禁食18h后，38℃雙蒸水，25mL·kg-1灌胃，裝進(jìn)大鼠代謝籠收集2h尿量，尿量達(dá)灌水量40%以上者入選［4］；隨機分成A、B組，每組各12只。A組氫氯噻嗪溶液灌胃給藥，25mg·kg－1·d－1，分2次，連續(xù)7d。B組不給藥。非收集尿量期間兩組均自由飲水，不禁食。

　　1.2.2  收集尿量

　　分別將同組2鼠放入1個代謝籠，均收集6h尿