Sharifi A M, Schiffrin E L
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montréal, University of Montréal, Québec, Canada.
J Hypertens. 1997 Dec;15(12 Pt 1):1441-8. doi: 10.1097/00004872-199715120-00011.
Apoptosis or programmed cell death could be greater than normal in various cardiovascular disorders, particularly in the heart. Apoptosis might contribute to remodeling of blood vessels in hypertension and could participate in regulation of vascular hypertrophy/hyperplasia.
To investigate apoptosis in deoxycorticosterone acetate (DOCA)-salt hypertension and to determine whether endothelin-1, whose expression is enhanced in these rats, plays a role in apoptosis.
We administered two orally active endothelin-A (ET[A])-selective receptor antagonists, A-127,722.5 (30 mg/kg per day) and LU 135,252 (50 mg/kg per day), to establish whether antigrowth effects of these ET(A) antagonists are in part mediated through apoptosis. Apoptosis was evaluated by radiolabeling of 3' OH ends of fragmented DNA, extracted from aortas, using terminal deoxynucleotidyl transferase, to show the presence of internucleosomal DNA splicing as 'DNA laddering'. Its presence was confirmed by in-situ end-labeling.
Systolic blood pressure was slightly but significantly lower in treated than it was in untreated DOCA-salt hypertensive rats by a mean of 26 mmHg (P < 0.01) after 4 weeks of treatment with A-127,722.5 and by 19 mmHg (P < 0.01) in rats treated with LU 135,252. Aortic cross-sectional area (CSA) was significantly greater (P < 0.001) in DOCA-salt rats than it was in uninephrectomized controls. This increased CSA was normalized by both ET(A) antagonists. DOCA-salt rats exhibited a greater degree of apoptosis (evaluated by DNA 'laddering') in aorta (353 +/- 14 pixels/microg DNA) than did control rats (232 +/- 10 pixels/microg DNA, P < 0.01). The magnitude of apoptosis was significantly greater (P < 0.01) in aorta of endothelin-antagonist-treated than it was in aorta of untreated DOCA-salt hypertensive rats. In-situ end-labeling confirmed that more apoptosis had occurred in the media of aorta from DOCA-salt hypertensive rats and the further increase found after treatment with the ET(A) antagonists.
An increase in apoptosis occurs in aorta of DOCA-salt hypertensive rats, probably as a physiologic counterpart of growth in this hypertensive model. ET(A) antagonists may act in part by accentuating the apoptosis, thereby inducing a blunting of vascular growth, which could also contribute to their antihypertensive effects.
在各种心血管疾病中，尤其是在心脏中，细胞凋亡或程序性细胞死亡可能比正常情况更严重。细胞凋亡可能有助于高血压患者血管的重塑，并可能参与血管肥大/增生的调节。
研究醋酸脱氧皮质酮（DOCA）-盐性高血压中的细胞凋亡，并确定在这些大鼠中表达增强的内皮素-1是否在细胞凋亡中起作用。
我们给予两种口服活性内皮素-A（ET[A]）选择性受体拮抗剂，A-127,722.5（每天30mg/kg）和LU 135,252（每天50mg/kg），以确定这些ET(A)拮抗剂的抗生长作用是否部分通过细胞凋亡介导。通过使用末端脱氧核苷酸转移酶对从主动脉提取的片段化DNA的3'OH末端进行放射性标记来评估细胞凋亡，以显示存在核小体间DNA剪接，即“DNA梯状条带”。通过原位末端标记证实其存在。
在用A-127,722.5治疗4周后，治疗组的收缩压比未治疗的DOCA-盐性高血压大鼠略低但显著降低，平均降低26mmHg（P<0.01），在用LU 135,252治疗的大鼠中降低19mmHg（P<0.01）。DOCA-盐性大鼠的主动脉横截面积（CSA）比单侧肾切除的对照组显著更大（P<0.001）。两种ET(A)拮抗剂均使这种增加的CSA恢复正常。DOCA-盐性大鼠主动脉中的细胞凋亡程度（通过DNA“梯状条带”评估）（353±14像素/μg DNA）比对照大鼠（232±10像素/μg DNA，P<0.01）更大。内皮素拮抗剂治疗组主动脉中的细胞凋亡程度比未治疗的DOCA-盐性高血压大鼠主动脉中的显著更大（P<0.01）。原位末端标记证实，DOCA-盐性高血压大鼠主动脉中膜发生了更多的细胞凋亡，并且在用ET(A)拮抗剂治疗后发现凋亡进一步增加。
DOCA-盐性高血压大鼠主动脉中细胞凋亡增加，这可能是该高血压模型中生长的生理对应物。ET(A)拮抗剂可能部分通过加剧细胞凋亡起作用，从而导致血管生长的减弱，这也可能有助于它们的降压作用。
