Bianciotti L G, de Bold A J
Cardiovascular Endocrinology Laboratory, University of Ottawa Heart Institute, Ottawa, Ont., Canada.
Cardiovasc Res. 2001 Mar;49(4):808-16. doi: 10.1016/s0008-6363(00)00311-4.
Increased expression of the cardiac natriuretic peptides (NP), atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) is observed during chronic hemodynamic overload. The mechanisms underlying this process are not fully understood. In vitro, endothelin 1 (ET-1) is a powerful stimulator of cardiac NP and, therefore, has been assumed to be one possible mediator of increased NP gene expression following chronic pressure or volume overload. In the present work we investigated the possible role of ET-1 in mediating the observed upregulation of cardiac NP in two kidney-one clip (2K-1C) Goldblatt hypertensive rats treated for 6 weeks with the ET-1 type A (ET(A)) receptor subtype receptor antagonist ABT-627.
2K-1C hypertension was induced in male Sprague-Dawley rats weighing 100-125 g by placing a silver clip (internal diameter 0.25 mm) around the left renal artery through a flank incision. The right kidney was left undisturbed. Sham operated rats underwent the same experimental procedures but no clip was placed on the left renal artery. ABT-627 was administered (10 mg/kg per day) in the drinking water for 6 weeks.
In hypertensive rats, ABT-627 prevented a further rise in blood pressure beginning at 3 weeks after clipping and reduced the ventricular hypertrophy observed at the end of the experiment. ET(A) blockade prevented enhanced NP gene expression in the right ventricle and partially prevented it in the left ventricle. No modifications in atrial NP gene expression were observed in either control or 2K-1C animals. ET(A) blockade decreased BNP circulating levels but did not affect ANF plasma levels in clipped rats. ABT-627 increased alpha-myosin heavy chain gene expression and decreased the abundance of the beta isoform transcript.
The results obtained in the present investigation show the participation of ET-1 in the increased expression of ventricular NP in 2K-1C renovascular hypertension and an apparent lack of effect of ET(A) blockade on atrial NP gene expression in both control and hypertensive animals thus showing that in vivo, atrial and ventricular NP gene expression are differentially regulated.
在慢性血流动力学负荷增加期间，观察到心脏利钠肽（NP）、心房利钠因子（ANF）和脑利钠肽（BNP）的表达增加。这一过程的潜在机制尚未完全了解。在体外，内皮素1（ET-1）是心脏NP的强力刺激物，因此被认为是慢性压力或容量负荷增加后NP基因表达增加的一种可能介质。在本研究中，我们研究了ET-1在介导用ET-1 A型（ET(A)）受体亚型拮抗剂ABT-627治疗6周的二肾一夹（2K-1C）戈德布拉特高血压大鼠中观察到的心脏NP上调中的可能作用。
通过经侧腹切口在100 - 125 g雄性斯普拉格-道利大鼠的左肾动脉周围放置一个银夹（内径0.25 mm）诱导2K-1C高血压。右肾未受干扰。假手术大鼠接受相同的实验程序，但左肾动脉未放置夹子。ABT-627以10 mg/kg/天的剂量加入饮用水中给予6周。
在高血压大鼠中，ABT-627从夹闭后3周开始阻止血压进一步升高，并减少实验结束时观察到的心室肥厚。ET(A)阻断可防止右心室中NP基因表达增强，并部分防止左心室中NP基因表达增强。在对照或2K-1C动物中均未观察到心房NP基因表达的改变。ET(A)阻断降低了夹闭大鼠的BNP循环水平，但不影响ANF血浆水平。ABT-627增加了α-肌球蛋白重链基因表达并降低了β同工型转录本的丰度。
本研究获得的结果表明ET-1参与了2K-1C肾血管性高血压中心室NP表达的增加，并且ET(A)阻断对对照和高血压动物的心房NP基因表达明显没有影响，从而表明在体内，心房和心室NP基因表达受到不同的调节。
