Lopez J J, Lorell B H, Ingelfinger J R, Weinberg E O, Schunkert H, Diamant D, Tang S S
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts.
Am J Physiol. 1994 Aug;267(2 Pt 2):H844-52. doi: 10.1152/ajpheart.1994.267.2.H844.
To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 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 AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 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 AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 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 AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.
为了确定血管紧张素（ANG）II受体AT1和AT2亚型在左心室（LV）肥厚（LVH）中的分布及功能，将ANG II（10⁻⁸ M）注入因主动脉缩窄导致肥厚的离体大鼠心脏以及假手术对照组心脏。ANG II单独注入，或在存在AT1抑制剂[氯沙坦（10⁻⁵ M）或CL - 329167（10⁻⁷ M）]或AT2抑制剂[CG - 42112A（10⁻⁸ M）]的情况下注入。与对照心脏相比，单独注入ANG II时，LVH心脏的冠状动脉血管阻力（CVR）升高幅度较小（19%对39%；P < 0.01），尽管LVH心脏的基线CVR较高。AT1拮抗剂可预防这种情况，但AT2拮抗剂不能。ANG II还使LVH心脏的左心室舒张末期压力升高，表明舒张期松弛功能降低，AT1抑制可预防此情况，但AT2抑制不能。对LV膜制剂中ANG II结合位点的表征显示，各组之间的解离常数相似（1.6 ± 0.95对2.2 ± 2.0 nM；无显著差异），但LVH组的最大结合容量较低（21.1 ± 5.9对33.5 ± 3.0 fmol/mg蛋白；P < 0.05）。竞争试验表明，对照左心室主要含有AT1亚型（68.8 ± 20%），而LVH心室主要含有假定的AT2亚型（59.8% ± 10.8%；P < 0.05）。这表明在LVH中发生了受体亚型重新分布，AT1亚型下调。尽管如此，AT1亚型介导了ANG II对压力超负荷肥厚时冠状动脉张力和舒张功能障碍的影响。
