Cellular mechanism for mibefradil-induced vasodilation of renal microcirculation: studies in the isolated perfused hydronephrotic kidney.
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 micromol/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.
Hayashi
Koichi
K
Department of Internal Medicine, School of Medicine, Keio University, Shinanomachi, Tokyo, Japan. khayashi@sc.itc.keio.ac.jp
Ozawa
Yuri
Y
Wakino
Shu
S
Kanda
Takeshi
T
Homma
Koichiro
K
Takamatsu
Ichiro
I
Tatematsu
Satoru
S
Saruta
Takao
T
D000704:Analysis of Variance; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D006869:Hydronephrosis / Q000188:drug therapy*; D008297:Male; D020748:Mibefradil / Q000627:therapeutic use*; D051381:Rats; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D002121:Calcium Channel Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D020748:Mibefradil