AngⅡ受体阻断剂与ACEI对肾性高血压大鼠血以及血浆和组织AngⅡ含量变化的影响

Effects of angiotensin Ⅱ receptor antagonist and angiotensin converting enzyme inhibitor on blood pressure and angiotesin Ⅱ contents in plasma and renal tissue of renovascular hypertensive rats

目的明确血管紧张素转换酶抑制剂(ACEI)卡托普利与血管紧张素Ⅱ(AngⅡ)受体阻断剂洛沙坦二类药物的药效和作用特点。方法本实验采用①离体血管环微量生物反应测定法检测AngⅡ引起的血管收缩反应;②建立两肾一夹型高血压大鼠模型;利用颈动脉插管法和鼠尾测压计检测血压,观测急性与慢性血压的变化;③用放射免疫法检测高血压大鼠血浆与肾组织中的AngⅡ含量。结果①离体血管环实验:AngⅡ能引起剂量依赖性的血管收缩反应,卡托普利(0.1 mg/kg)对低剂量AngⅡ收缩反应有轻度的抑制效应;随着外源性AngⅡ量增多,其抑制血管收缩作用明显减弱。同样条件下洛沙坦却能完全抑制AngⅡ所引起的血管收缩反应。②在体急性降压实验:最大有效剂量的卡托普利使模型鼠的平均动脉压由(18.4±3.9)kPa降为(8.7±1.2)kPa,降压幅度达到9.6 kPa,之后给洛沙坦最大降压有效剂量(2 mg/kg),血压未再下降;改变给药顺序,平均动脉压由(16.8±1.1)kPa降为(11.4±2.4)kPa,降压幅度为5.30 kPa,然后给最大有效降压剂量的卡托普利,血压持续降为(9.3±1.8)kPa,幅度达2.12 kPa,差异具有明显的统计学意义(P<0.05)。③慢性降压实验:高血压大鼠模型给予实验因素干预后,卡托普利组平均动脉压由(18.9±2.5)kPa降为(11.8±1.6)kPa,洛沙坦平均动脉压由(19.7±2.4)kPa降为(11.7±2.0)kPa,降压幅度分别为7.19 kPa和7.93 kPa,与对照组比较差异无统计学意义。④放射免疫实验:血浆中AngⅡ含量卡托普利组为(376±72)ng/L,明显低于对照组的(526±77)ng/L,而洛沙坦组为(1 036±159)ng/L,明显高于对照组(P<0.01),二者差异具有统计学意义。肾组织中AngⅡ含量,卡托普利组(392±81)pg/g,较对照组的(431±80)pg/g降低8.9%,洛沙坦组为(294±86)pg/g,较对照组降低32.4%(P<0.05)。结论①洛沙坦是通过阻断AngⅡ受体而发挥作用,而卡托普利只能够减少内源性AngⅡ的生成,离体状态下药效弱于洛沙坦。②急性在体实验卡托普利的最大降压效应强于洛沙坦;慢性在体实验二者药效差异无统计学意义。③长期作用下,肾组织的AngⅡ水平对调节血管张力起主要的作用,血浆中AngⅡ辅助起作用。

Objective To study the therapeutic effects and characteristics of ACEI and Ang Ⅱ receptor antagonist. Methods The 2K1C hypertensive rat model was made. Vascular ring was isolated to assess the Ang Ⅱ -induced vasoconstriction. Blood pressure was measured through carotid canula and tail-cuff manometer. The plasma and renal tissue Ang Ⅱ contents were determined using radioimmunoassay kit. Results Olsolated vascular ring study：Ang Ⅱ induced a dose-dependent vasoconstriction response. Losartan （1 × 10^-6 mol/L） could completely block the Ang Ⅱ -induced vasoconstriction, while captopfil （1 × 10^-6 mol/L） did not show effects on Ang Ⅱ -induced vasoconstriction except a slight inhibitory action at small doses of Ang Ⅱ. ②Acute depressor effects： captopfil of 0.1 mg/kg （the maximal effective dosage） decreased the mean blood pressure （MAP） from control value of （ 18.4 ± 3.9） kPa to （8.7 ± 1.2） kPa （decrease by 9.6 kPa）, whereas losartan 2 mg/kg （the maximal effective dosage） decreased the MAP from （ 16.8 ± 1.1 ）kPa （contol） to （ 11.4 ± 2.4） kPa （decrease by 5.30 kPa）. Following the first administration of captopril,reapplication of losartan could not further decrease the MAP; However, after the first administration of losartan, reapplication of captopril could still further decrease the MAP by 2.12 kPa （P 〈 0.05）. ③Chronic depressor effects： after gavage administration of the agent for four weeks, captopril and losartan decreased the MAP from （ 18.9 ± 2.5） kPa to （ 11.8 ± 1.6） kPa and from （ 19.7 ± 2.4） kPa to （ 11.7 ± 2, 0） kPa respectively, with no significant differences between two groups. Radioimmunoassay： after the four-week gavage administration, the plasma Ang Ⅱ content was （376 ± 72） ng/L, which was significantly lower than control value （526± 78） ng/L in captopril group,and the plasma Ang Ⅱ content was （1 036±159） ng/L in losartan group which was significantly higher than control value. The renal tissue Ang Ⅱ content was （392±81） pg/g in captopfil group and （294 ± 86） pg/g in losartan group,both were significantly lower than control value （431 ± 80） pg/g. Conclusion The acute depressor effects of captopril are larger than that of losartan, while the chronic depressor effects are no significant differences between the two agents, indicating that the plasma AngⅡ contents are unrelated to the maintenance of hypertension, while the renal tissue Ang ± contents are responsible for the chronic hypertension.