Madeddu P, Varoni M V, Palomba D, Emanueli C, Demontis M P, Glorioso N, Dessì-Fulgheri P, Sarzani R, Anania V
Clinica Medica, University of Sassari, Italy.
Circulation. 1997 Nov 18;96(10):3570-8. doi: 10.1161/01.cir.96.10.3570.
To evaluate the role of kinins in the regulation of cardiovascular function, we studied the phenotype of a mouse strain with disruption of the bradykinin B2-receptor gene (Bk 2r-/-).
Under basal conditions, tail-cuff blood pressure was higher in Bk2r-/- than in wild-type Bk2r+/+ and heterozygous Bk2r+/- mice (124+/-1 versus 109+/-1 and 111+/-2 mm Hg, respectively; P<.01 for both comparisons), a difference that was confirmed by measurements of intra-arterial blood pressure in unanesthetized mice. Heart weight was greater in Bk2r-/- than in Bk2r+/+ and Bk2r+/- mice (505+/-10 versus 449+/-12 and 477+/-10 mg/100 g body wt, P<.05). Chronic blockade of B2-receptors by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice. Compared with the wild-type strain, both Bk2r-/- and Bk2r+/- mice showed exaggerated vasopressor responses to angiotensin II. In addition, chronic administration of an angiotensin AT1-receptor antagonist reduced the basal blood pressure of Bk2r-/- by 21+/-3 mmHg (P<.05) to the levels of Bk2r+/+. No difference was detected between strains as far as plasma renin activity and the expression of renin and AT1-receptor genes are concerned. Chronic salt loading (0.84 mmol/g chow for 15 days) increased the blood pressure of Bk2r-/- and Bk2r+/- by 34+/-3 and 14+/-6 mm Hg, respectively, whereas it was ineffective in Bk2r+/+.
Our results suggest that a normally functioning B2-receptor is essential for the maintenance of cardiovascular homeostasis in mice. Dysfunction of the kallikrein-kinin system could contribute to increase blood pressure levels by leaving the activity of vasoconstrictor agents unbalanced.
为评估激肽在心血管功能调节中的作用，我们研究了缓激肽B2受体基因敲除小鼠品系（Bk 2r-/-）的表型。
在基础条件下，Bk2r-/-小鼠的尾套血压高于野生型Bk2r+/+和杂合子Bk2r+/-小鼠（分别为124±1 mmHg与109±1 mmHg和111±2 mmHg；两组比较P均<0.01），这一差异在未麻醉小鼠的动脉内血压测量中得到证实。Bk2r-/-小鼠的心脏重量大于Bk2r+/+和Bk2r+/-小鼠（505±10 mg/100 g体重与449±12 mg/100 g体重和477±10 mg/100 g体重，P<0.05）。用伊卡替班（50 nmol/100 g体重，皮下注射，每日两次）慢性阻断B2受体或用硝基-L-精氨酸甲酯（0.14 mmol/100 g体重，口服）抑制一氧化氮合酶可使Bk2r+/+小鼠的血压升高至Bk2r-/-小鼠的水平。与野生型品系相比，Bk2r-/-和Bk2r+/-小鼠对血管紧张素II的升压反应均增强。此外，长期给予血管紧张素AT1受体拮抗剂可使Bk2r-/-小鼠的基础血压降低21±3 mmHg（P<0.05）至Bk2r+/+小鼠的水平。就血浆肾素活性以及肾素和AT1受体基因的表达而言，各品系之间未检测到差异。长期高盐饮食（0.84 mmol/g饲料，持续15天）可使Bk2r-/-和Bk2r+/-小鼠的血压分别升高34±3 mmHg和14±6 mmHg，而对Bk2r+/+小鼠无效。
我们的结果表明，正常功能的B2受体对于维持小鼠心血管稳态至关重要。激肽释放酶-激肽系统功能障碍可能通过使血管收缩剂活性失衡而导致血压升高。
