Madeddu P, Milia A F, Salis M B, Gaspa L, Gross W, Lippoldt A, Emanueli C
From the Clinica Medica and Terapia Medica, Medical Schoo , and the Department of Animal Biology, Section of Pharmacology , University of Sassari, Sassari, Italy.
Hypertension. 1998 Sep;32(3):503-9. doi: 10.1161/01.hyp.32.3.503.
We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B2 receptor in the contralateral kidney. BK B2-receptor knockout (B2-/-), wild-type (B2+/+), and heterozygous (B2+/-) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B2-/- mice than in B2+/- or B2+/+ mice (121+/-2 versus 113+/-2 and 109+/-1 mm Hg; P<0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B2-/- mice than in B2+/- or B2+/+ mice (28+/-2 versus 14+/-2 and 14+/-2 mm Hg, respectively, at 2 weeks; P<0.05 for both comparisons). Blockade of the BK B2 receptor by Icatibant enhanced the pressure response to clipping in B2+/+ mice (29+/-2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B2-/- mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B2+/+ mice given Icatibant (30 and 32 mm Hg) than in B2+/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B2-/- and B2+/- mice, but this effect was delayed in B2+/+ mice. However, the HR response to clipping in B2+/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B2-/-: 5.7+/-0.1 versus 5.2+/-0.1; B2+/+: 5.1+/-0.1 versus 4.5+/-0.1; P<0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.
我们评估了激肽是否对两肾一夹（2K1C）高血压的发展具有保护作用，该模型的特征是缺血性肾脏中的肾素 - 血管紧张素系统激活以及对侧肾脏中缓激肽（BK）B2受体表达增加。将BK B2受体敲除（B2 - / - ）、野生型（B2 + / + ）和杂合子（B2 + / - ）小鼠的左肾动脉进行夹闭，另一肾保持未处理状态。B2 - / - 小鼠的基础收缩压（SBP，通过尾套体积描记法测量）高于B2 + / - 或B2 + / + 小鼠（分别为121±2与113±2和109±1 mmHg；两组比较P均<0.05）。假手术后SBP未从基础值改变，但在接受夹闭的小鼠中升高。2K1C B2 - / - 小鼠中SBP的升高大于B2 + / - 或B2 + / + 小鼠（2周时分别为28±2与14±2和14±2 mmHg；两组比较P均<0.05）。艾替班特阻断BK B2受体增强了B2 + / + 小鼠对夹闭的压力反应（2周时为29±2 mmHg）。2K1C小鼠的动脉内平均血压（MBP）高于各自的假手术小鼠，B2 - / - 小鼠的MBP差值更高（2周和4周时分别为32和38 mmHg），给予艾替班特的B2 + / + 小鼠的MBP差值高于未给予艾替班特的B2 + / + 小鼠（分别为30和32 mmHg与17和18 mmHg）。在4周时，急性注射血管紧张素1型受体拮抗剂使2K1C高血压小鼠的MBP恢复正常。在B2 - / - 和B2 + / - 小鼠夹闭后1周观察到心动过速反应，但在B2 + / + 小鼠中这种效应延迟出现。然而，艾替班特增强了B2 + / +小鼠对夹闭的心率反应。在每个品系中，2K1C高血压小鼠的心脏重量与体重之比大于假手术对照动物（B2 - / - ：5.7±0.1与5.2±0.1；B2 + / + ：5.1±0.1与4.5±0.1；两组比较P均<0.01）。2K1C高血压小鼠中夹闭肾重量与未夹闭肾重量之比持续降低。我们的结果表明，作用于BK B2受体的激肽在2K1C高血压早期阶段对过度血压升高具有保护作用。
