Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats
Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats
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DOI：
10.1007/s00467-009-1153-6
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发表时间：
2009-07-01
影响因子：
3
通讯作者：
Schmitt, Claus Peter
中科院分区：
文献类型：
--
作者：
Nakagawa, Kumiko;Parekh, Niru;Schmitt, Claus Peter
拟钙剂可增加钙敏感受体 (CaSR) 对钙离子 (Ca2+) 的敏感性，并可有效控制尿毒症甲状旁腺功能亢进症。最近的研究表明有额外的降血压作用，但其潜在机制尚不清楚。我们将 R-568 及其对映体 S-568（其对 CaSR 几乎没有活性）注入麻醉大鼠体内。测量股动脉的平均动脉血压（MAP）和心率（HR）；局部测量肾血流量（RBF）和肠系膜血流量（MBF）。每 10 分钟按 0.7 mg/kg 的剂量向股静脉输注 R-568，该剂量已知可降低血浆中甲状旁腺激素 (PTH) 和 Ca2+ 的水平，但不会影响血压或心率。每 3 分钟 2.1 mg/kg 的 R-568 和 S-568 输注到股静脉中，显着降低 MAP 26 +/- 4.5 和 23.7 +/- 3.1%，HR 分别显着降低 7.8 +/- 2.9 和 5.8 +/- 2.0%。动脉内输注 R-568 以剂量依赖性方式增加血流量。在血浆浓度为 70 A mumol/l 时，R-568 和 S-568 使 RBF 增加 17 A +/- 3 和 15 A +/- 3%，使 MBF 增加 28 A +/- 5 和 29 A +/- 5%。对肠系膜动脉血流的影响大于肾动脉，但两种化合物之间没有差异。拟钙剂 R-568 在浓度超过调节 PTH 分泌所需的浓度时，通过血管舒张和负变时性发挥急性、不依赖 CaSR 的降血压作用。
Calcimimetics increase the sensitivity of the calcium sensing receptor (CaSR) to calcium ions (Ca2+) and allow for efficient control of uraemic hyperparathyroidism. Recent studies suggested an additional blood pressure-lowering action, the underlying mechanisms are as yet unknown. We infused R-568 and its enantiomer S-568, which has little activity at the CaSR, in anaesthetized rats. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in the femoral artery; renal blood flow (RBF) and mesenteric blood flow (MBF) were measured locally. Infusion of R-568 at 0.7 mg/kg per 10 min into the femoral vein, a dose known to reduce levels of parathyroid hormone (PTH) and Ca2+ in plasma, did not affect blood pressure or heart rate. Infusion of 2.1 mg/kg per 3 min of R-568 and S-568 into the femoral vein significantly reduced MAP by 26 +/- 4.5 and 23.7 +/- 3.1% and HR by 7.8 +/- 2.9 and 5.8 +/- 2.0%, respectively. Intra-arterial infusions of R-568 increased blood flow in a dose-dependent fashion. At plasma concentrations of 70 A mu mol/l R-568 and S-568 increased RBF by 17 A +/- 3 and 15 A +/- 3% and MBF by 28 A +/- 5 and 29 A +/- 5%. The effects on blood flow were greater in the mesenteric artery than in the renal artery, but not different between both compounds.The calcimimetic R-568 exerts acute, CaSR-independent, hypotensive effects via vasodilation and negative chronotropy at concentrations exceeding those required for modulation of PTH secretion.