Hypotensive response to losartan in normal rats - Role of Ang II and the area postrema
Hypotensive response to losartan in normal rats - Role of Ang II and the area postrema
复制标题
DOI：
10.1161/01.hyp.27.3.598
复制
发表时间：
1996-03-01
期刊：
影响因子：
8.3
通讯作者：
Osborn, JW
中科院分区：
文献类型：
--
作者：
Collister, JP;Hornfeldt, BJ;Osborn, JW
我们已经报道了血管紧张素II (Ang II) AT(1)受体拮抗剂氯沙坦可以显著降低钠充血、血压正常的大鼠的动脉压。我们假设氯沙坦的这种作用是通过阻断内源性Ang II的作用介导的。为了验证这一假设，我们用动脉和静脉导管分别测量大鼠的动脉压和氯沙坦的输注。对照测量3天后，氯沙坦输注10天（10mg）。公斤(1)。d(-1))对正常日钠摄入量大鼠（NNa，约2 mmol/d， n=6）和高日钠摄入量大鼠（HNa，约15 mmol/d， n=7）抑制内源性Ang II的影响。尽管HNa大鼠的基础血浆肾素活性明显受到抑制（0.9+/-0.4 ng Ang I）。毫升(1)。h(-1))与NNa大鼠（4.0+/-0.3 ng Ang I）比较。毫升(1)。h(-1))，对照动脉压在NNa （113+/-4 mm Hg）和HNa （113+/-2 mm Hg）大鼠之间无差异。氯沙坦在给药第一天降低了NNa大鼠的动脉压（-12+/-2 mm Hg），但对HNa大鼠的动脉压没有影响（+4+/-4 mm Hg）。此外，到氯沙坦输注第10天，na大鼠的动脉压比对照组进一步下降（-32+/-2 mm Hg），但与对照组相比保持不变（+5+/-6 mm Hg）。第二项研究是为了验证后脑区（一种被认为可以调节Ang II的长期神经源性加压活性的心室周围器官）是氯沙坦的作用部位这一假设。在3个对照日之后，氯沙坦给区域残鼠（APx, n=11）或假性残鼠（n=10）服用NNa饮食，持续10天。假手术大鼠（95+/-3 mm Hg）和APx大鼠（96+/-2 mm Hg）的对照动脉压相似。各组之间的基础血浆肾素活性无差异（sham, 4.1+/-1.5 vs APx, 5.3+/-1.6 ng Ang I）。毫升(1)。h(1))。在氯沙坦治疗的第1天，假手术大鼠的动脉压（80+/-2 mm Hg）明显低于APx大鼠（90+/-3 mm Hg）。这种趋势持续到氯沙坦输注的第4天，假手术大鼠的动脉压（72+/-2 mm Hg）明显低于APx大鼠（83+/-4 mm Hg）。然而，在氯沙坦输注的其余时间里，除了第8天（假手术，72+/-2 mm Hg; APx, 84+/-2 mm Hg），各组之间没有显著差异。综上所述，这些结果支持氯沙坦在钠含量高、血压正常的大鼠中的降压作用是由于阻断内源性Ang II的生理作用。此外，在正常大鼠中，完整的后脑区对于氯沙坦降压作用的充分表达是必不可少的。
We have reported that the angiotensin II (Ang II) AT(1) receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg . kg(-1) . d(-1)) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9+/-0.4 ng Ang I . mL(-1) . h(-1)) compared with NNa rats (4.0+/-0.3 ng Ang I . mL(-1) . h(-1)), control arterial pressure was not different between NNa (113+/-4 mm Hg) and HNa (113+/-2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (-12+/-2 mm Hg) but had no effect on arterial pressure in HNa rats (+4+/-4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (-32+/-2 mm Hg) but remained unchanged compared with control in HNa rats (+5+/-6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic presser activity of Ang II, is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema-lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95+/-3 mm Hg) and APx (96+/-2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1+/-1.5 versus APx, 5.3+/-1.6 ng Ang I . mL(-1) . h(-1)). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80+/-2 mm Hg) compared with APx (90+/-3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72+/-2 mm Hg) was significantly lower than in APx rats (83+/-4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72+/-2 mm Hg; APx, 84+/-2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.