Role of specific T-type calcium channel blocker R(−) efonidipine in the regulation of renal medullary circulation

Hu, Chunyan; Mori, Takefumi; Lu, Yi‐Chun; Guo, Qi; Sun, Ying; Yoneki, Yoshimi; Ohsaki, Yusuke; Nakamichi, Takashi; Oba, Ikuko; Sato, Emiko; Ogawa, Susumu; Dickinson, Bryan C.; Chang, Christopher J.; Miyata, Toshio; Satô, Hiroshi; Ito, Sadayoshi

doi:10.1097/hjh.0b013e3283550e9f

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…Animal experiments were performed after at least 3 days of acclimation. Sample size was chosen based on previously published experiments performed under similar conditions 48 – 50 .…”

Section: Methodsmentioning

confidence: 99%

“…The CBF and MBF were continuously measured while clamped, and for 30 min after clamp removal. At the end of experiment, Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) (6.0 mg/kg bw/h) was infused for 30 min intravenously as a positive control; L-NAME does not affect CBF but decreases MBF 40 , 48 . The data without L-NAME response were excluded from the analysis.…”

Section: Methodsmentioning

confidence: 99%

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Pathophysiological and molecular mechanisms involved in renal congestion in a novel rat model

Shimada

Hirose

Takahashi

et al. 2018

Sci Rep

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Increased central venous pressure in congestive heart failure causes renal dysfunction; however, the underlying mechanisms are unclear. We created a rat renal congestion model and investigated the effect of renal congestion on hemodynamics and molecular mechanisms. The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion in the left kidney only. Left kidney congestion reduced renal blood flow, glomerular filtration rate, and increased renal interstitial hydrostatic pressure. Tubulointerstitial and glomerular injury and medullary thick ascending limb hypoxia were observed only in the congestive kidneys. Molecules related to extracellular matrix expansion, tubular injury, and focal adhesion were upregulated in microarray analysis. Renal decapsulation ameliorated the tubulointerstitial injury. Electron microscopy captured pericyte detachment in the congestive kidneys. Transgelin and platelet-derived growth factor receptors, as indicators of pericyte-myofibroblast transition, were upregulated in the pericytes and the adjacent interstitium. With the compression of the peritubular capillaries and tubules, hypoxia and physical stress induce pericyte detachment, which could result in extracellular matrix expansion and tubular injury in renal congestion.

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“…Animal experiments were performed after at least 3 days of acclimation. Sample size was chosen based on previously published experiments performed under similar conditions 48 – 50 .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pathophysiological and molecular mechanisms involved in renal congestion in a novel rat model

Shimada

Hirose

Takahashi

et al. 2018

Sci Rep

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“…In a recent study by Hu and coworkers, efonidipine increased the renal medullary blood flux, with no effect on the cortical blood flow or the blood pressure (Hu et al . ). In summary, in vivo animal studies have established an important role for T‐type channels, especially as the only voltage‐gated calcium channels in the cortical efferent arteriole.…”

Section: Renal In Vivo Effect Of T‐type Channelsmentioning

confidence: 97%

“…In spontaneously hypertensive rats, a T-type blockade increases the renal plasma flow more than the GFR, resulting in a decreased filtration fraction (Yokoyama et al 1992). In a recent study by Hu and coworkers, efonidipine increased the renal medullary blood flux, with no effect on the cortical blood flow or the blood pressure (Hu et al 2012). In summary, in vivo animal studies have established an important role for T-type channels, especially as the only voltage-gated calcium channels in the cortical efferent arteriole.…”

Section: Renal In Vivo Effect Of T-type Channelsmentioning

confidence: 99%

Functional and pharmacological consequences of the distribution of voltage‐gated calcium channels inthe renal blood vessels

Hansen¹

2013

Acta Physiologica

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Calcium channel blockers are widely used to treat hypertension because they inhibit voltage-gated calcium channels that mediate transmembrane calcium influx in, for example, vascular smooth muscle and cardiomyocytes. The calcium channel family consists of several subfamilies, of which the L-type is usually associated with vascular contractility. However, the L-, T- and P-/Q-types of calcium channels are present in the renal vasculature and are differentially involved in controlling vascular contractility, thereby contributing to regulation of kidney function and blood pressure. In the preglomerular vascular bed, all the three channel families are present. However, the T-type channel is the only channel in cortical efferent arterioles which is in contrast to the juxtamedullary efferent arteriole, and that leads to diverse functional effects of L- and T-type channel inhibition. Furthermore, by different mechanisms, T-type channels may contribute to both constriction and dilation of the arterioles. Finally, P-/Q-type channels are involved in the regulation of human intrarenal arterial contractility. The calcium blockers used in the clinic affect not only L-type but also P-/Q- and T-type channels. Therefore, the distinct effect obtained by inhibiting a given subtype or set of channels under experimental settings should be considered when choosing a calcium blocker for treatment. T-type channels seem to be crucial for regulating the GFR and the filtration fraction. Use of blockers is expected to lead to preferential efferent vasodilation, reduction of glomerular pressure and proteinuria. Therefore, renovascular T-type channels might provide novel therapeutic targets, and may have superior renoprotective effects compared to conventional calcium blockers.

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“…1c) due to a chiral center in 1, 4-dihydropyridine. R-enantiomer and S-enantiomer exhibits completely different biological activities [4,5] and have been used in different fields which is the case for most chiral drugs. Asymmetric synthesis of S-efonidipine isomer and its crystal structure has been reported by R. Sakoda [6] in 1992.…”

Section: Introductionmentioning

confidence: 99%

Crystallization of the Racemic Conglomerate and Racemic Compound of Efonidipine

Zhu¹,

Li²,

Yu³

et al. 2017

Proceedings of the 2016 International Conference on Biological Engineering and Pharmacy (BEP 2016)

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Abstract-Efonidipine is a dual blocker of T-type and L-type calcium channels with 1, 4-dihydropyridine structure attached to a phosphonate skeleton. As a chiral compound, it has a special property that can exist as a racemic conglomerate or a racemic compound based on the different crystallization conditions. One racemic conglomerate and one racemic compound were disclosed and characterized in this research. Efonidipine conglomerate could obtain from its racemic solution when ethanol, methanol, tetrahydrofuran, ethyl acetate and acetonitrile were chosen as the crystallized solvent. While, racemic compound which existed as an acetone solvate could be prepared by crystallization from acetone only and the crystallization process must be keep stood without agitating. In order to confirm this conclusion, three single crystals of R-efonidipine, S-efonidipine and R/S-efonidipine acetone solvate have been prepared and determined.

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Role of specific T-type calcium channel blocker R(−) efonidipine in the regulation of renal medullary circulation

Abstract: These results suggest that TCC blockade with R(-)EFO selectively increases MBF, an effect that appears to be mediated by changes in renal NO and oxidative stress balance, which may protect against ischemic renal injury in the renal medullary region.

Cited by 6 publications

References 38 publications

Pathophysiological and molecular mechanisms involved in renal congestion in a novel rat model

Pathophysiological and molecular mechanisms involved in renal congestion in a novel rat model

Functional and pharmacological consequences of the distribution of voltage‐gated calcium channels inthe renal blood vessels

Crystallization of the Racemic Conglomerate and Racemic Compound of Efonidipine

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