DISTRIBUTION AND FUNCTION OF CARDIAC ANGIOTENSIN AT(1)-RECEPTOR AND AT(2)-RECEPTOR SUBTYPES IN HYPERTROPHIED RAT HEARTS
DISTRIBUTION AND FUNCTION OF CARDIAC ANGIOTENSIN AT(1)-RECEPTOR AND AT(2)-RECEPTOR SUBTYPES IN HYPERTROPHIED RAT HEARTS
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DOI：
10.1152/ajpheart.1994.267.2.h844
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发表时间：
1994-08-01
影响因子：
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通讯作者：
TANG, SS
中科院分区：
文献类型：
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作者：
LOPEZ, JJ;LORELL, BH;TANG, SS
为探讨心脏血管紧张素Ⅱ受体AT（1）和AT（2）亚型在左心室肥厚（LVH）中的分布和功能，将10（-8）M的血管紧张素Ⅱ（ANG Ⅱ）灌注到主动脉缩窄引起的肥厚大鼠心脏和假手术对照组。ANG II单独输注或与ATL抑制剂[氯沙坦（10（-5）M）或CL-329167（10（-7）M）]或AT（2）抑制剂[CG-42112A（10（-8）M）]联合输注。ANG II单独引起的LVH冠状动脉血管阻力（CVR）增加较少。对照心脏（19 vs. 39%; P <0.01），尽管LVH心脏的基线CVR更高。AT（1）拮抗剂可阻止这种作用，而AT（2）拮抗剂则不能。血管紧张素II还增加了左室肥厚心脏的左室舒张末期压，表明AT（1）抑制剂可阻止舒张期舒张功能下降，而AT（2）抑制剂则不能阻止舒张期舒张功能下降。LV膜制备物中ANG II结合位点的表征显示两组之间的解离常数相似（1.6 +/-0.95 vs. 2.2 +/-2.0 nM;不显著），但LVH组的最大结合能力较低（21.1 +/-5.9 vs. 33.5 +/-3.0 fmol/mg蛋白; P <0.05）。竞争试验表明对照组左心室主要含有AT（1）亚型（68.8 ± 20%），而LVH心室主要含有假定的AT（2）亚型（59.8% ± 10.8%; P <0.05）。这表明在AT（1）亚型下调的LVH中发生受体亚型再分布。尽管如此，AT（1）亚型介导ANG II对压力超负荷性肥大的冠状动脉张力和舒张功能障碍的影响。
To determine distribution and function of cardiac angiotensin (ANG) II receptor AT(1) and AT(2) subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of ATL inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT(2) inhibitor [CG-42112A (10(-8) M)]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with. control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT(1) but not AT(2) antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT(1) but not AT(2) inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT(1) subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT(2) subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT(1) subtype downregulation. Nonetheless, the AT(1) subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.