Intengan H D, He G, Schiffrin E L
Medical Research Council Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
Hypertension. 1998 Oct;32(4):770-7. doi: 10.1161/01.hyp.32.4.770.
The structural and mechanical properties of small arteries are altered in rat models of hypertension. The precise role of humoral factors in these changes has not been determined. In deoxycorticosterone acetate (DOCA) salt hypertension, endothelin-1 (ET-1) peptide content and gene expression are enhanced in mesenteric resistance arteries. These vessels also present augmented vasoconstrictor responsiveness to vasopressin versus control uninephrectomized rats. To determine whether an interaction exists between vasopressin and ET-1 in the pathogenesis of small-artery structural alterations in DOCA-salt rats, we examined the effect of chronic V1 vasopressin receptor antagonism (OPC-21268, 30 mg/kg BID) on the structure and mechanical properties of mesenteric resistance arteries using a pressure myograph and the effect on preproendothelin-1 (preproET-1) gene expression, determined by Northern blot analysis of preproET-1 mRNA. Tail-cuff systolic pressures were elevated in DOCA-salt (200+/-11 mm Hg) versus uninephrectomized rats (109+/-4 mm Hg) and decreased slightly but significantly by OPC-21268 to 187+/-7 mm Hg (P<0.01). Treatment with DOCA-salt increased vascular media-lumen ratios and media cross-sectional areas and reduced both stress and incremental elastic modulus for a given pressure. However, there was no change in distensibility or incremental elastic modulus versus media stress. OPC-21268 partially attenuated the vascular growth in DOCA-salt rats. PreproET-1 mRNA was increased 2-fold in mesenteric arteries of DOCA-salt rats versus uninephrectomized rats, an effect abrogated by OPC-21268. Thus, DOCA-salt hypertension is associated with altered morphology of the small-arterial wall, without altering stiffness of the arterial wall components. OPC-21268 regressed in part these changes, suggesting the involvement of vasopressin. The concomitant attenuation of enhanced ET-1 expression by OPC-21268 suggests that ET-1 may be involved in mediating in part the vascular effects of vasopressin in DOCA-salt hypertensive rats.
在高血压大鼠模型中，小动脉的结构和力学特性会发生改变。体液因子在这些变化中的确切作用尚未确定。在醋酸脱氧皮质酮（DOCA）盐性高血压模型中，肠系膜阻力动脉中的内皮素-1（ET-1）肽含量和基因表达增强。与对照单肾切除大鼠相比，这些血管对血管加压素的血管收缩反应性也增强。为了确定血管加压素和ET-1在DOCA盐大鼠小动脉结构改变的发病机制中是否存在相互作用，我们使用压力肌动描记法研究了慢性V1血管加压素受体拮抗作用（OPC-21268，30mg/kg，每日两次）对肠系膜阻力动脉结构和力学特性的影响，以及对前内皮素-1（preproET-1）基因表达的影响，通过对preproET-1 mRNA进行Northern印迹分析来确定。DOCA盐大鼠（200±11mmHg）的尾袖收缩压高于单肾切除大鼠（109±4mmHg），OPC-21268使其略有但显著降低至187±7mmHg（P<0.01）。DOCA盐处理增加了血管中膜与管腔的比值和中膜横截面积，并降低了给定压力下的应力和增量弹性模量。然而，与中膜应力相比，血管扩张性或增量弹性模量没有变化。OPC-21268部分减弱了DOCA盐大鼠的血管生长。与单肾切除大鼠相比，DOCA盐大鼠肠系膜动脉中的preproET-1 mRNA增加了2倍，OPC-21268消除了这一效应。因此，DOCA盐性高血压与小动脉壁形态改变有关，而不改变动脉壁成分的硬度。OPC-21268部分逆转了这些变化，提示血管加压素参与其中。OPC-21268同时减弱了ET-1表达的增强，提示ET-1可能部分介导了血管加压素在DOCA盐性高血压大鼠中的血管效应。
