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

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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Objectives: Blockade of the T-type calcium channel (TCC), which is expressed in the renal efferent arterioles of the juxtamedullary nephron and vasa recta, has been shown to protect against renal injury. Studies were designed to determine the effects of a specific TCC blocker, R(-) efonidipine [R(-)EFO], on the regulation of renal circulation. Methods and Results: Renal medullary blood flux (MBF) and cortical blood flux (CBF) were simultaneously monitored using laser-Doppler flowmetry in Sprague-Dawley rats. Responses were also determined in rats with angiotensin II (AngII) induced renal ischemia. Intravenous (i.v.) or renal interstitial (r.i.) infusion of R(-)EFO (0.25mg/h, i.v. or r.i.) significantly increased MBF by 24.0±7.0 and 21.0±4.4%, respectively, but without changing CBF or mean arterial pressure. The nitric oxide (NO) synthase inhibitor NG-nitro-L- argininemethylester (L-NAME, 1μg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50ng/kg per min, i.v.) reduction of MBF (28.4±1.7%), which was associated with increased urinary NO2+NO3 excretion and decreased urinary hydrogen peroxide (H2O2) excretion. Intracellular H2O2 fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1μmol/L, 235±52 units), which was significantly inhibited by pre and coincubation with R(-)EFO. R(-)EFO stimulation also increased the intracellular NO concentration in the epithelial cells of mTAL (220±62 units). Conclusion: 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.

Original languageEnglish
Pages (from-to)1620-1631
Number of pages12
JournalJournal of hypertension
Volume30
Issue number8
DOIs
Publication statusPublished - 2012 Aug

Keywords

  • R(-) efonidipine
  • angiotensin II
  • hydrogen peroxide
  • laser-Doppler flowmetry
  • nitric oxide
  • renal medullary blood flux

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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