Cellular Mechanism for Mibefradil-Induced Vasodilation of Renal Microcirculation: Studies in the Isolated Perfused Hydronephrotic Kidney

Koichi Hayashi, Yuri Ozawa, Shu Wakino, Takeshi Kanda, Koichiro Homma, Ichiro Takamatsu, Satoru Tatematsu, Takao Saruta

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Although nifedipine and other conventional calcium antagonists elicit preferential vasodilation of renal afferent arterioles, we demonstrate that mibefradil and nickel, T-type calcium channel blockers, reverse the angiotensin II-induced constriction of both afferent and efferent arterioles. Since the angiotensin II-induced vasoconstriction involves inositol trisphosphate (IP3)-induced calcium release from the sarcoplasmic reticulum in the afferent arteriole, and both IP3- and protein kinase C (PKC)-mediated pathways in the efferent arteriole, we investigated the cellular mechanism for the mibefradil-induced dilation of angiotensin II-constricted renal arterioles, using the isolated perfused hydronephrotic rat kidney. Mibefradil caused a dose-dependent dilation of angiotensin II-constricted afferent and efferent arterioles, with 88 ± 9% and 74 ± 10% reversal observed at 1 μmol/L, respectively. The blockade of PKC by staurosporine did not alter the mibefradil-induced vasodilator responses of either arterioles (P > 0.5). In contrast, the pretreatment with thapsigargin, which predominantly blocked the IP3-mediated intracellular calcium release, prevented the afferent arteriolar constrictor response to angiotensin II, but caused a significant constriction of efferent arterioles. The subsequent addition of mibefradil had no effect on the efferent arteriolar diameter. Furthermore, the efferent arteriolar constriction induced by direct PKC activation by phorbol myristate acetate was refractory to mibefradil, but completely reversed by LOE908, a nonselective cation channel blocker. In summary, mibefradil markedly dilates the angiotensin II-induced renal arteriolar constriction; the action of mibefradil is most likely mediated by the inhibition of the IP3-mediated pathway, but the inhibitory action on the PKC pathway appears modest.

Original languageEnglish
Pages (from-to)697-702
Number of pages6
JournalJournal of Cardiovascular Pharmacology
Volume42
Issue number6
DOIs
Publication statusPublished - 2003 Dec 1

Keywords

  • Afferent arteriole
  • Calcium antagonists
  • Efferent arteriole
  • Inositol trisphosphate
  • Mibefradil
  • T-type calcium channel

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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