Iyer S N, Ferrario C M, Chappell M C
Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1095, USA.
Hypertension. 1998 Jan;31(1 Pt 2):356-61. doi: 10.1161/01.hyp.31.1.356.
Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT1) antagonist losartan augments circulating levels of the bioactive peptide angiotensin-(1-7) [Ang-(1-7)]. Hence, we determined whether Ang-(1-7) contributes to the hypotensive effects produced by the combined administration of lisinopril and losartan in spontaneously hypertensive rats by blocking the peptide's synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisinopril and losartan elicited an elevation of mean arterial pressure that was sustained throughout the infusion period and for 20 minutes thereafter. The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1-7) and no change in plasma angiotensin II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar1,Thr8]-Ang II abolished any additional pressor effects of either neprilysin inhibitor in spontaneously hypertensive rats treated with lisinopril or losartan. However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inhibition of Ang-(1-7) formation in rats exposed to the combined blockade of Ang II production and activity is associated with a reversal of the antihypertensive actions produced by these therapies. Thus, endogenous Ang-(1-7) functions as a vasodilator hormone in this form of genetic hypertension.
单独使用血管紧张素转换酶（ACE）抑制剂或与血管紧张素I型受体（AT1）拮抗剂氯沙坦联合使用，均可提高生物活性肽血管紧张素-（1-7）[Ang-（1-7）]的循环水平。因此，我们通过用两种结构不同的中性内肽酶抑制剂之一阻断该肽的合成，来确定Ang-（1-7）是否有助于赖诺普利和氯沙坦联合给药对自发性高血压大鼠产生的降压作用。对接受赖诺普利和氯沙坦治疗9天血压已恢复正常的大鼠静脉注射CGS 24592（30 mg/kg），可引起平均动脉压升高，在整个输注期间以及输注后20分钟内持续存在。高血压反应与Ang-（1-7）循环水平降低62%相关，而血浆血管紧张素II（Ang II）无变化。静脉输注另一种中性内肽酶抑制剂（SCH 39370，30 mg/kg）使平均血压升高幅度与CGS 24592相似。用非选择性拮抗剂[Sar1，Thr8]-Ang II预处理可消除中性内肽酶抑制剂对接受赖诺普利或氯沙坦治疗的自发性高血压大鼠的任何额外升压作用。然而，内皮素A拮抗剂BQ123和缓激肽B2拮抗剂HOE 140对基础血压均无影响，也未改变中性内肽酶抑制剂的升压或心率作用。这些数据表明，在暴露于Ang II生成和活性联合阻断的大鼠中，抑制Ang-（1-7）的形成与这些治疗产生的降压作用的逆转相关。因此，内源性Ang-（1-7）在这种遗传性高血压中起血管舒张激素的作用。
