Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats

Nakagawa, Kumiko; Parekh, Niru; Koleganova, Nadezda; Ritz, Eberhard; Schaefer, Franz; Schmitt, Claus Peter

doi:10.1007/s00467-009-1153-6

Cited by 16 publications

(21 citation statements)

References 16 publications

(27 reference statements)

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“…[23] have shown acute cardiovascular effects in rats by the type II agonist calcimimetic R-568, and its enantiomer S-568. Since this molecule has no or very little activity on the CaSR, the hypotensive effect of R-568 was most likely not mediated via CaSR.…”

Section: Introductionmentioning

confidence: 99%

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

et al. 2012

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BackgroundCalcimimetics, such as R-568, are thought to activate G protein-linked Ca2+-sensing receptor (CaSR) by allosterically increasing the affinity of the receptor for Ca2+ allowing for efficient control of uremic hyperparathyroidism. Several recent studies suggest they possess additional vascular actions. Although it has been postulated that calcimimetics may have a direct effect on CaSR in the blood vessels, further studies are needed to elucidate their vascular CaSR-dependent versus CaSR-independent effects.Methodology/Principal FindingsFocusing on human umbilical vein endothelial cells (HUVECs), we studied the CaSR expression and distribution by Immunofluorescence and Western Blot analysis. CaSR function was evaluated by measuring the potential effect of calcimimetic R-568 and its enantiomer S-568 upon the modulation of intracellular Ca2+ levels (using a single cell approach and FURA-2AM), in the presence or absence of Calhex-231, a negative modulator of CaSR. To address their potential vascular functions, we also evaluated R- and S-568-stimulated enzymatic release of Nitric Oxide (NO) by DAF-2DA, by Nitric Oxide Synthase (NOS) radiometric assay (both in HUVECs and in Human Aortic Endothelial Cells) and by measuring eNOS-ser1177 phosphorylation levels (Immunoblotting). We show that, although the CaSR protein was expressed in HUVECs, it was mainly distributed in cytoplasm while the functional CaSR dimers, usually localized on the plasma membrane, were absent. In addition, regardless of the presence or absence of Calhex-231, both R- and S-568 significantly increased intracellular Ca2+ levels by mobilization of Ca2+ from intracellular stores, which in turn augmented NO release by a time- and Ca2+-dependent increase in eNOS-ser1177 phosphorylation levels.Conclusions/SignificanceTaken together, these data indicate that in human endothelium there is no stereoselectivity in the responses to calcimimetics and that CaSR is probably not involved in the action of R- and S-568. This suggests an additional mechanism in support of the CaSR-independent role of calcimimetics as vasculotrope agents.

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Section: Introductionmentioning

confidence: 99%

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

et al. 2012

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“…In patients with chronic kidney disease (60), and in a rat model of surgically induced chronic kidney disease (39), calcimimetic treatment is associated with antihypertensive effects. However, because calcimimetics are phenylalkylamine derivatives, their ability to reduce blood pressure has been ascribed to potential off-target effects on L-type Ca 2ϩ channels (37,52). Given the importance of the CaSR in many physiological processes (43), the aim of this study was to determine whether the CaSR in VSMC contributes directly to blood pressure regulation.…”

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confidence: 99%

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

Schepelmann

Yarova

Lopez-Fernandez

et al. 2016

American Journal of Physiology-Cell Physiology

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-The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22␣ promoter (SM22␣-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Crepositive SM22␣ CaSR ⌬flox/⌬flox [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca 2ϩ ) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-L-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca 2ϩ concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR. calcium-sensing receptor; CaSR; vascular smooth muscle cells; blood pressure regulation; G protein-coupled receptor; blood vessel tone regulation THE EXTRACELLULAR CALCIUM -sensing receptor CaSR was the first G protein-coupled receptor identified that has an ion, Ca 2ϩ

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“…Similarly, the protection of podocyte damage by the calcimimetic was shown without lowering blood pressure. Although calcimimetics have been shown to decrease blood pressure (14,15), this effect has been observed in animals with increased blood pressure and more extensive kidney damage. The indirect method of blood pressure measurement is a limitation of this study.…”

Section: Discussionmentioning

confidence: 97%

The calcimimetic R-568 prevents podocyte loss in uninephrectomized ApoE^−/−mice

Gut

Piecha

Pradel

et al. 2013

American Journal of Physiology-Renal Physiology

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Calcimimetics are indicated for secondary hyperparathyroidism in chronic kidney disease, and some data have suggested their protective role for progression of renal damage. We aimed to evaluate whether a calcimimetic can slow the progression of kidney damage in uninephrectomized apolipoprotein E (ApoE)-deficient (ApoE-/-) mice. To this end, we compared its effect with that of calcitriol. Male ApoE-/- mice (12 wk old) were randomized to undergo sham operation (sham) or unilateral nephrectomy (UNX) and subsequently received the calcimimetic R-568 (4 μg·kg⁻¹·day⁻¹), calcitriol (0.03 μg·kg⁻¹·day⁻¹), or vehicle intraperitoneally. Glomerular number and volume, damage indexes (glomerular, vascular, and interstitial), and glomerular (podocytes, mesangial, and endothelial) cell number and volume were assessed in perfused kidneys after a 12-wk treatment period. Lower numbers of podocytes per glomerulus were observed in the UNX + vehicle group compared with the sham group, and this was prevented in the UNX + R-568 group but not in the UNX + calcitriol group. In parallel, albuminuria was higher in the untreated UNX group compared with the sham group, and the increase was prevented in the UNX + R-568 group. Interstitial fibrosis was more prevalent in the vehicle-treated UNX group compared with the sham group, and this was prevented in the UNX group treated with R-568 and less effectively with calcitriol treatment. In all UNX groups, the weight of the residual kidney was significantly higher compared with all sham groups. No differences were observed in serum ionized calcium and systolic blood pressure between the groups. The calcimimetic R-568 prevented interstial fibrosis and podocyte loss after uninephrectomy in ApoE-/- mice. Minor renal dysfunction, lack of secondary hyperparathyroidism, and hypertension in this model support the hypothesis of direct effects of this compound on glomerular cells.

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Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats

Cited by 16 publications

References 16 publications

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The calcimimetic R-568 prevents podocyte loss in uninephrectomized ApoE^−/−mice

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Acute cardiovascular effects of the calcimimetic R-568 and its enantiomer S-568 in rats

Cited by 16 publications

References 16 publications

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

Calcimimetic R-568 and Its Enantiomer S-568 Increase Nitric Oxide Release in Human Endothelial Cells

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure

The calcimimetic R-568 prevents podocyte loss in uninephrectomized ApoE−/−mice

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The vascular Ca²⁺-sensing receptor regulates blood vessel tone and blood pressure

The calcimimetic R-568 prevents podocyte loss in uninephrectomized ApoE^−/−mice