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


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 (0.25 mg/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, 1 μg/kg per min, i.v. or r.i.) significantly attenuated R(-)EFO-induced increase in MBF. R(-)EFO inhibited the AngII-mediated (50 ng/kg per min, i.v.) reduction of MBF (28.4 ± 1.7%), which was associated with increased urinary NO(2) + NO(3) excretion and decreased urinary hydrogen peroxide (H(2)O(2)) excretion. Intracellular H(2)O(2) fluorescence (real-time fluorescence imaging) in the epithelial cells of isolated medullary thick ascending limb (mTAL) significantly increased following AngII stimulation (1 μmol/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).


CONCLUSIONS
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.
Division of Nephrology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Chunyan
C
Hu
Takefumi
T
Mori
Yi
Y
Lu
Qi
Q
Guo
Ying
Y
Sun
Yoshimi
Y
Yoneki
Yusuke
Y
Ohsaki
Takashi
T
Nakamichi
Ikuko
I
Oba
Emiko
E
Sato
Susumu
S
Ogawa
Bryan C
BC
Dickinson
Christopher J
CJ
Chang
Toshio
T
Miyata
Hiroshi
H
Sato
Sadayoshi
S
Ito
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001783:Blood Flow Velocity; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism; D004095:Dihydropyridines / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004336:Drug Antagonism; D007262:Infusions, Intravenous; D007511:Ischemia / Q000139:chemically induced / Q000378:metabolism*; D007679:Kidney Medulla / Q000098:blood supply / Q000187:drug effects*; D017078:Laser-Doppler Flowmetry; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009585:Nitrogen Dioxide / Q000652:urine; D009589:Nitrogen Oxides / Q000652:urine; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D009589:Nitrogen Oxides; D009596:Nitrophenols; D009943:Organophosphorus Compounds; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C031701:nitrogen trioxide; C066425:efonidipine; D009585:Nitrogen Dioxide; D019331:NG-Nitroarginine Methyl Ester