Center for Cardiovascular Research, Charité Universitätsmedizin Berlin, Berlin, Germany.
J Hypertens. 2012 Nov;30(11):2182-91. doi: 10.1097/HJH.0b013e328357c049.
In subtotally nephrectomized rats, we studied to what extent high-dose calcitriol-induced cardiovascular disease can be modulated by almost complete suppression of parathyroid hormone (PTH), mediated by either cinacalcet (CINA) or parathyroidectomy (PTX).
Five groups were studied: sham-operated controls, uremic (U), uremic with calcitriol (U+1,25D), uremic and calcitriol with CINA (U+1,25D+CINA) and uremic and calcitriol with PTX (U+1,25D+PTX). Treatments lasted 14 weeks.
Compared with U group animals, PTH was significantly lower with calcitriol treatment and almost completely suppressed in animals treated with either PTX or CINA. Serum calcium and phosphorus levels were similarly elevated in all groups receiving calcitriol. Renal function in uremic animals was significantly more impaired in the U+1,25D group. Aortic calcifications were pronounced in U+1,25D animals and reduced by more than 50% by concomittant treatment with CINA or PTX. Chondrocytes were observed near areas of calcification (>90%) and endochondral bone formation was confirmed by positive immunofluorescence for chondrocytic transcription factor sox9 and matrix protein collagen X. Altered arterial (aneurysmatic) geometry with a significant increase in wall/lumen and lumen/body weight ratio was found only in the U+1,25D group. Myocardial fibrosis was present in all uremic groups with a significant increase in the U+1,25D group. Connective tissue growth factor messenger RNA was significantly upregulated only in the U+1,25D group.
Submaximal suppression of PTH by either CINA or PTX reduced vascular calcifications, arterial remodeling and myocardial fibrosis to a similar degree and independent of the serum calcium and phosphorus levels. These data do not indicate vasculotropic effects of calcimimetics independent of PTH suppression.
在次全肾切除大鼠中，我们研究了通过使用西那卡塞（CINA）或甲状旁腺切除术（PTX）几乎完全抑制甲状旁腺激素（PTH），多大程度上可以调节大剂量骨化三醇引起的心血管疾病。
研究了五组：假手术对照组、尿毒症组（U）、尿毒症加骨化三醇组（U+1,25D）、尿毒症加骨化三醇加 CINA 组（U+1,25D+CINA）和尿毒症加骨化三醇加 PTX 组（U+1,25D+PTX）。治疗持续 14 周。
与 U 组动物相比，骨化三醇治疗组的 PTH 显著降低，而接受 PTX 或 CINA 治疗的动物的 PTH 几乎完全被抑制。所有接受骨化三醇治疗的组的血清钙和磷水平均升高。尿毒症动物的肾功能在 U+1,25D 组显著受损。U+1,25D 动物的主动脉钙化明显，并用 CINA 或 PTX 联合治疗可减少 50%以上。在靠近钙化区域（>90%）观察到软骨细胞，并通过软骨细胞转录因子 Sox9 和基质蛋白胶原 X 的阳性免疫荧光证实了软骨内骨形成。仅在 U+1,25D 组发现动脉（动脉瘤样）几何形状改变，壁/腔和腔/体重比显著增加。所有尿毒症组均存在心肌纤维化，U+1,25D 组明显增加。结缔组织生长因子信使 RNA 仅在 U+1,25D 组显著上调。
通过 CINA 或 PTX 对 PTH 的亚最大抑制可将血管钙化、动脉重塑和心肌纤维化减少到相似程度，且与血清钙和磷水平无关。这些数据表明，钙敏感受体调节剂的血管作用不独立于 PTH 抑制。
