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+.
Okada
Y
Y
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Taira
N
N
D000704:Analysis of Variance; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002396:Catechols / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D005905:Glyburide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D015220:Calcium Channels; D002396:Catechols; D007093:Imidazoles; D015221:Potassium Channels; D014665:Vasodilator Agents; C072129:E 4080; D005905:Glyburide