Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats
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ORIGINAL ARTICLE
Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats Kumiko Nakagawa & Niru Parekh & Nadezda Koleganova & Eberhard Ritz & Franz Schaefer & Claus Peter Schmitt
Received: 29 December 2008 / Revised: 6 February 2009 / Accepted: 9 February 2009 / Published online: 12 March 2009 # IPNA 2009
Abstract 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 pressurelowering 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 S568 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 K. Nakagawa : F. Schaefer : C. P. Schmitt (*) Division of Paediatric Nephrology, Centre for Paediatric and Adolescent Medicine, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany e-mail: [email protected] N. Parekh Institute of Physiology, University of Heidelberg, Heidelberg, Germany N. Koleganova Institute of Pathology, University of Heidelberg, Heidelberg, Germany E. Ritz Department of Internal Medicine, Division of Nephrology, University of Heidelberg, Heidelberg, Germany
flow in a dose-dependent fashion. At plasma concentrations of 70 µmol/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. Keywords Calcimimetic agents . Blood pressure . Vasodilation . Stereoselectivity . Hyperparathyroidism
Introduction Calcimimetic agents bind in a stereospecific way to the parathyroid calcium sensing receptor (CaSR), increase its sensitivity to ionized calcium, efficiently reduce parathyroid hormone (PTH) secretion from the parathyroid gland and improve the calcium phosphate product in patients with uraemic hyperparathyroidism [1]. They constitute a major breakthrough in the therapy of secondary hyperparathyroidism and are likely to improve clinical outcome [2]. Experimental studies furthermore suggest beneficial effects beyond the control of bone and mineral homeostasis, i.e. renoprotection [3, 4] and a blood pressure-lowering action [5, 6].
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