E4080 has a dual action, as a K+ channel opener and a Ca2+ channel blocker, in canine coronary artery smooth muscle.

To clarify the vasodilating mechanism of action of E4080, which possesses vasodilating and bradycardic effects, we investigated its effects on intracellular Ca2+ concentrations ([Ca2+]i), as measured with fura-2, and force of contraction in canine coronary artery. E4080 reduced the increase in [Ca2+]i and force of contraction induced by 30 and 90 mM KCl physiological salt solution (PSS) in a concentration-dependent manner. The effects of E4080 in 30 mM KCl-PSS were inhibited by 10(-5) M glibenclamide. In 30 mM KCl-PSS, the slope of the [Ca2+]i-force relationship in the presence of E4080 was steeper than that of control, suggesting that E4080 decreased the sensitivity of contractile elements to Ca2+, as an effect which was also inhibited by glibenclamide. However, the [Ca2+]i-force curve was not changed by E4080 in 90 mM KCl-PSS. These results suggest that E4080 is a vasodilator in canine coronary artery, having K+ channel opening and Ca2+ channel blocking actions. The membrane hyperpolarization induced by E4080 may reduce the sensitivity of contractile elements to Ca2+.