莫索尼定与可乐定对肾性高血压大鼠动脉压及心率作用的比较

背景莫索尼定是高选择性的第二代中枢性降压药,而可乐定是第一代中枢降压药,用于临床治疗高血压,但副作用较多.目的比较莫索尼定与可乐定对肾性高血压大鼠的作用特点.设计随机对照动物实验.单位南通大学医学院药理学教研室.材料实验于2004-09/12在南通医学院完成.选择SD大鼠110只,鼠龄60 d,体质量(180±30)g.方法SD大鼠左侧肾动脉用0.2 mm或0.25 mm内径的银夹狭窄,右侧肾脏不触及,造成二肾一夹型(two-kidney one-clip,2K-IC)肾性高血压模型.①采用尾动脉间接测压法,一次或连续口服给药,分别测定清醒肾性高血压大鼠血压及其心率变化.一次口服给药的降压实验大鼠随机分成5组,每组10只,盐酸莫索尼定1 mg/kg组、3 mg/kg组、10 mg/kg组、盐酸可乐定(1 mg/kg)组作阳性对照、生理盐水组作阴性对照.根据盐酸莫索尼定对血压作用特点,测定给药后1,4,24,48,72 h时间点的血压,分别与给药前或生理盐水作用相比较.连续每天1次口服给药降压实验分组同上,连续给药7 d,1次/d,测定每天给药前、给药后1 h血压及心率的变化,停药后观察3 d.人拟推荐剂量为盐酸莫索尼定0.4 mg/kg左右,按动物体表面积换算,大鼠口服剂量约为0.04 mg/kg左右.②采用颈动脉插管直接测压法测定麻醉肾性高血压大鼠血压及其心率变化以0.2mg/kg的药液灌胃,大鼠随机分5组,每组10只,分别为盐酸莫索尼组、0.13 mg/kg组、0.4 mg/kg组、1.3 mg/kg组、盐酸可乐定0.13 mg/kg组及生理盐水对照组,测定给药前及给药后不同时间的平均动脉压.主要观察指标一次或连续口服给药情况下清醒和麻醉肾性高血压大鼠血压及其心率变化.结果在实验过程中,各组大鼠无脱失,全部进入结果分析.①清醒肾性高血压大鼠一次大剂量口服莫索尼定降压与心率减慢作用呈剂量依赖性,其10倍剂量与可乐定作用相近;连续小剂量口服莫索尼定降压百分率与可乐定相仿,心率减慢作用弱而短暂.②麻醉肾性高血压大鼠,一次口服莫索尼定降压作用与剂量相关;莫索尼定3～10倍剂量与可乐定降压百分率差异无显著性意义(P＞0.05).结论大剂量一次口服给药,莫索尼定对清醒肾性高血压大鼠的降压作用呈剂量依赖性,其10倍剂量与可乐定作用相当;对麻醉肾性高血压大鼠莫索尼定3～10倍剂量与可乐定降压相当.小剂量连续口服给药,莫索尼定和可乐定等剂量对肾性高血压大鼠的降压作用相当.

Effects of moxonidine versus clonidine on arterial pressure and heart rate in renal-hypertensive rats

BACKGROUND: Moxonidine is the second-generation high-selective central antihypertensive drug, while clonidine is the first-generation antihypertensive drug that is used in clinic with many side effects.OBJECTIVE: To compare the characteristics between moxonidine and clonidine in renal-hypertensive rats.DESIGN: Randomized controlled animal experiment.SETTING: Department of Pharmacology, Medical College, Nantong University.MATERIALS: The experiment was conducted in Medical College, Nantong University between September and December 2004. Totally 110 SD rats aged 60 days with the body mass of (180±30) g were used in the study.METHODS: Left renal artery stenosis in SD rats was established by inserting silver clip with the inner diameter of 0.2 mm or 0.25 mm, while the right renal artery was not received, so as to establish two-kidney one-clip(2K-1C) renal hypertensive models. ①Changes of blood pressure and heart rate in awake rats with renal hypertension were determined with arteria caudilis indirect manometric method, oral administration once or consecutively. The experiment of depressurization with once oral administration:The rats were randomly assigned into 5 groups with 10 rats in each group:1 mg/kg, 3 mg/kg, 10 mg/kg moxonidine hydrochloride groups, 1 mg/kg clonidine hydrochloride group were considered as positive control group,while saline group as negative control group. On the basis of the effect of moxonidine hydrochloride on blood pressure, blood pressure was measured at 1, 4, 24, 48, 72 hours after moxonidine administration, and compared with that before administration or the effect of saline. The experiment of depressurization with consecutively oral administration once a day. The grouping was the same to above-mentioned. Successive administration was for 7 days, once a day. The blood pressure and heart rate were determined at 1 hour before and after administration, and observed for 3 days after drug withdrawal. Recommended dose of moxonidine hydrochloride for human was about 0.4 mg/kg, while the oral dose for rats were around 0.04 mg/kg based on the animals' surface area. ②Changes of blood pressure and heart rate in anaesthesia rats with renal hypertension with a catheter on the carotid artery directly: 0.2 mg/kg drug liquor was given with gastric perfusion. The rats were randomly divided into 5 groups with 10 ones in each group: 0.13,0.4, 1.3 mg/kg moxonidine hydrochloride groups, 0.13 mg/kg clonidine hydrochloride group and saline control group. Mean arterial pressure was determined before and after administration at different time.MAIN OUTCOME MEASURES: Changes of blood pressure and heart rate in conscious and anesthetized renal-hypertensive rats before and after being administrated orally once or consecutively.RESULTS: All the rats were involved in the result analysis, without drop out during the trial. ①Moxonidine showed a dose-dependent effect on depressurization and descent of heart rate after once large dose oral administration in conscious renal-hypertensive rats. The 10-fold higher doses of moxonidine caused the same effects of clonidine. The decreasing of heart rate was little and short after consecutively small dose of oral administration of moxonidine, and which was similar to clonidine in percentage of depressurization. ②In anesthetized renal-hypertensive rats, moxonidine showed a dose-dependent effect on depressurization after once oral administration. There was no significant difference between moxonidine and clonidine in percentage of depressurization after 3 to 10-fold higher dose administration (P ＞ 0.05).CONCLUSION: The once higher dose oral administration of moxonidine has dose-dependent effect on depressurization for renal-hypertensive awake rats. Anesthesia. The effect of 10-fold dosage of moxonidine is equal to that of clonidine. The effect of 3-10-fold dosage of moxonidine is equal to that of clonidine in anesthesia renal-hypertensive rats. The small dose oral administration continuously of both moxonidine and clonidine with the same volume has the same depressurization effect in renal-hypertensive rats.