1 Electrophysiological effects of MS-551, a new class III antiarrhythmic drug, were examined and compared with those of (+)-sotalol in rabbit ventricular cells. 2 In rabbit ventricular muscles stimulated at 1.0 Hz, MS-551 (0.1-10 LM) and (+)-sotalol (3-100I1M) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization (V.,a). The class III effect of MS-551 was approximately 30 times more potent than that of (+)-sotalol. 3 Class III effects of MS-551 and (+)-sotalol showed reverse use-dependence, i.e., a greater prolongation of APD at a longer cycle length. 4 In rabbit isolated ventricular cells, 3 gM MS-551 and 100 JLM sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than -50 mV and saturated around + 20 mV. 5 MS-551 at a higher concentration of 10 JAM decreased the transient outward current (Ito) and the inward rectifier potassium current (IKI) although 100 tLM sotalol failed to inhibit these currents.6 MS-551 is a non-specific class III drug which can inhibit three voltage-gated K+ channels in rabbit ventricular cells.

The calcium sensitivity of the delayed rectifier K+ current (IK) was investigated in guinea pig single ventricular cells using the whole cell configuration of the patch-clamp technique with a cell dialysis method. The concentration-response curve of IK for intracellular Ca2+ indicated that IK started to increase at intracellular Ca2+ concentration [Ca2+]i of 10(-8) M (pCa 8) and it increased threefold at pCa 7. At lower [Ca2+]i than pCa 9, IK remained unchanged. A shift of the activation curve of IK by the elevation of [Ca2+]i was not observed. Although [Ca2+]i had little effect on time constants of the activation and deactivation of IK, it predominantly increased the amplitudes of the fast components in the activation process and the slow component in the deactivation process. In the ensemble noise analysis, the elevation of [Ca2+]i increased the number and open probability of functional IK channels but not the unit amplitude of IK channel. These results suggest that the elevation of [Ca2+]i enhances IK, probably by increasing the number and open probability of functional IK channels. Ca2(+)-sensitive IK in cardiac cells is a class of current different from Ca2(+)-activated K+ current in other tissue because the activation curve of Ca2(+)-sensitive IK was not shifted by the [Ca2+]i elevation, and the single channel conductance of IK was smaller than the one of Ca2(+)-activated K+ current.

The sarcoplasmic reticulum (SR) of rat ventricular myocytes already functions early in the fetal period. However, ignition of Ca(2+) sparks depends on postnatal t-tubule formation and resultant colocalization of DHPR and RyR.

Effects of protein kinase C (PKC) and intracellular calcium ion (Cai2+) on the delayed rectifier K+ current (IK) were investigated in the single ventricular cells of guinea pig by use of an internal-dialysis method and a whole cell voltage-clamp technique. 12-O-tetradecanoylphorbol-13-acetate (TPA, 10(-9) M), an activator of PKC, increased the amplitude of IK in the presence of Cai2+ higher than 10(-10) M. This effect of TPA was mimicked by a synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG), 50 micrograms/ml, 125 microM, and was blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (10 microM). The above findings suggest that IK channels were phosphorylated by PKC and thereby the amplitude of IK was increased. IK was also increased by elevating the concentration of Cai2+ in the absence of TPA. It is thus indicated that IK channels are modulated by Cai2+ not only through activation of PKC but also directly. Our observation may provide a possible mechanism by which Cai2+ mediates the link between the Ca2+ transients during contraction and the action potential duration.

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