Ionic currents involved in vasodilating actions of E4080, a newly synthesized bradycardia-inducing agent, in dispersed smooth muscle cells of the rabbit portal vein

M. Kamouchi, Z. Xiong, N. Teramoto, S. Kajioka, K. Okabe, K. Kitamura

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The effects of E4080 {(E)-N-[3-((N'-(2-(3,5-dimethoxyphenyl) ethyl)-N'-methyl)amino)propyl]-4-(4-(1H-imidazol-1-yl) phenyl)-3-butenamide dihydrochloride dihydrate} on ionic currents recorded from the rabbit portal vein were investigated by using the patch-clamp technique. A depolarization of the membrane produced an inward Ca current (I(Ca)), a transient outward current (I(TO)), a sustained outward current (I(SO)) and an oscillatory outward current (I(OO)), whereas a hyperpolarization of the membrane produced a hyperpolarization-activated current (I(h)). When I(Ca) was evoked by a depolarizing pulse to 0 mV from the holding potential of -80 mV, 1 μM E4080 increased and higher concentrations (10 μM) inhibited I(Ca), whereas, at the holding potential of -60 mV, E4080 (>1 μM) consistently inhibited I(Ca)), in a concentration-dependent manner. E4080 inhibited I(TO), I(SO) (≥1 μM) and I(h) (≥ 0.1 μM) concentration dependently. Inasmuch as 1 μM E4080 did not inhibit I(Ca) at the holding potential of -80 mV, the inhibition of I(TO) induced by 1 μM E4080 was not related to the inhibition of I(Ca). When a continuous depolarization (0 mV) was applied to the cell, E4080 (1 μM) produced a maintained outward current (14.0 ± 15.3 pA), which was inhibited by glibenclamide. I(OO) was inhibited by E4080 (≥0.1 μM) and application of 1 μM glibenclamide partly restored I(OO). With single channel recording using the outside-out membrane patch, E4080 (≤1 μM) did not modify the activities of the large-conductance Ca-dependent K channels. These results indicate that E4080 has multiple actions on various ionic currents in the rabbit portal vein. The main factor contributing to the vasodilating action of E4080 in smooth muscle cells of rabbit portal vein is postulated from the electrical events to be closely related to reduction in cytosolic Ca.

Original languageEnglish
Pages (from-to)1396-1403
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - Dec 1 1991


All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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