Nakagawa Kumiko, Parekh Niru, Koleganova Nadezda, Ritz Eberhard, Schaefer Franz, Schmitt Claus Peter
Division of Paediatric Nephrology, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
Pediatr Nephrol. 2009 Jul;24(7):1385-9. doi: 10.1007/s00467-009-1153-6. Epub 2009 Mar 12.
Calcimimetics increase the sensitivity of the calcium sensing receptor (CaSR) to calcium ions (Ca(2+)) 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 Ca(2+) 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 micromol/l R-568 and S-568 increased RBF by 17 +/- 3 and 15 +/- 3% and MBF by 28 +/- 5 and 29 +/- 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.
钙敏感受体激动剂可提高钙敏感受体（CaSR）对钙离子（Ca(2+)）的敏感性，从而有效控制尿毒症性甲状旁腺功能亢进。最近的研究表明其具有额外的降压作用，但其潜在机制尚不清楚。我们在麻醉大鼠中输注R-568及其对映体S-568，后者对CaSR几乎没有活性。在股动脉测量平均动脉血压（MAP）和心率（HR）；局部测量肾血流量（RBF）和肠系膜血流量（MBF）。以每10分钟0.7mg/kg的剂量将R-568输注到股静脉中，该剂量已知可降低血浆中甲状旁腺激素（PTH）和Ca(2+)的水平，但不影响血压或心率。以每3分钟2.1mg/kg的剂量将R-568和S-568输注到股静脉中，可使MAP分别显著降低26±4.5%和23.7±3.1%，使HR分别降低7.8±2.9%和5.8±2.0%。动脉内输注R-568可使血流量呈剂量依赖性增加。在血浆浓度为70μmol/l时，R-568和S-568使RBF分别增加17±3%和15±3%，使MBF分别增加28±5%和29±5%。对肠系膜动脉血流量的影响大于肾动脉，但两种化合物之间没有差异。钙敏感受体激动剂R-568在浓度超过调节PTH分泌所需浓度时，通过血管舒张和负性变时作用发挥急性、不依赖CaSR的降压作用。
