Effects of K⁺ Channel Modulators on the Relationship Between Action Potential Duration and Ca²⁺ Transients in Single Ventricular Myocytes of the Guinea Pig

Abstract

Effects of K⁺ channel modulators, cromakalim and E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine], on the relationship between the action potential duration (APD) and Ca²⁺ transients were examined in single myocytes isolated from guinea pig cardiac left ventricle. Application of cromakalim decreased APD at 90% repolarization (APD₉₀) and Ca²⁺ transient elicited at 0.5 Hz (IC₅₀s=0.6 and 3 μM, respectively). Application of 0.3 μM E4031 increased these parameters by 110% and 45%, respectively. Under voltage-clamp, the relation between the duration of depolarization to 0 mV and Ca²⁺ transients could be described by the sum of two exponential components; the time constants were approximately 5 and 280 msec, respectively. The first component was abolished by 10 μM ryanodine, suggesting the involvement of Ca²⁺-induced Ca²⁺ release (CICR). Neither cromakalim nor E4031 directly affected Ca²⁺ current and Ca²⁺ transients under voltage clamp. When APD was changed by K⁺ channel modulators, the relation between APD₉₀ and Ca²⁺-transients was almost similar to that obtained by changing the depolarization duration under voltage-clamp. CICR was changed significantly only when APD₉₀ was markedly shortened by cromakalim. The extensively prolonged AP and Ca²⁺ transient in the presence of E4031 were reduced by an addition of cromakalim. It is concluded that these two K⁺ channel modulators can significantly alter the AP-induced Ca²⁺ transient mainly by changing APD, which regulates both Ca²⁺ influx and extrusion.