Divalent cations modulate the transient outward current in rat ventricular myocytes

Abstract

The modulation of the transient outward K+ current (Ito) by divalent cations was studied in enzymatically isolated rat ventricular myocytes with the whole cell patch-clamp technique. At holding potentials negative to -70 mV, 1 mM Cd2+ suppressed Ito, whereas, at potentials positive to -50 mV, the current was augmented. These effects were caused by shifts in the voltage dependence of both activation and inactivation of Ito toward more positive potentials. Cd2+ also slowed the activation kinetics of Ito by shifting the voltage dependence of its rate of activation, but the rate of inactivation was unaffected. Other divalent cations produced similar shifts but at markedly different concentrations. Thus, in the millimolar range, a rightward shift of approximately 20 mV was produced by 3 Co2+, 5 Ni2+, and 10 Ca2+, whereas 10 microM concentrations of Cu2+ and Zn2+ produced equivalent shifts. Similar effects were seen in hippocampal neurons with micromolar concentrations of Zn2+. Thus divalent cations have marked and specific effects on the kinetics and voltage dependence of Ito and may serve as a regulatory mechanism in its activation, particularly in cells with resting potentials positive to -60 mV.

Suppression of neuronal potassium A‐current by arachidonic acid

“…This protocol causes an underestimation of the size of IA. Inactivation removal was measured at -40 mV as the peak current evoked after 1 s prepulses to the different potentials, and after subtracting the current evoked by a 1 s pre-pulse to -60 mV, to reduce the contribution of Zr+ cardiac A-currents [27,28]. All the experiments presented below were performed in manganese extracellular solution.…”

“…The first group includes the action of divalent cations in neuronal [271, and this paper and cardiac ceils [28], and the modulation by muscarinic [I 5,171 and by GABA, agonists [18] in brain neurons. The second group includes the reduction induced by al-adrenergic agonists in dorsal raphe neurons [14], atria1 [22] and ventricular [19], but see [20] myocytes, and the effect of arachidonic acid presented in this paper.…”

Modulation of transient outward current by extracellular protons and Cd2+ in rat and human ventricular myocytes

“…Protons and divalent cations induce a shift of voltagedependent channel gating which is usually explained by a screening of membrane surface charge which changes the potential sensed by the voltage sensor of the channels (see Hille, 1984). However, this theory cannot easily explain the different sensitivity of various channels to divalent ions (Mayer & Sugiyama, 1988;Talukder & Harrison, 1995) nor the wide range of potency of various divalents (Mayer & Sugiyama, 1988;Agus et al 1991;Talukder & Harrison, 1995). Hence the existence of divalent-specific binding sites adjacent to the voltage sensor of the channel has been proposed.…”

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

“…Whole-cell currents and membrane potentials were low pass-filtered at 1 kHz, sampled at 5 kHz and analysed using the Pulse-fit software (v. 8 . At this rather low concentration, Cd 2+ inhibits I Ca,L but only marginally affects other currents such as I to and I NCX [1,20]. Moreover, more specific inhibitors of I Ca,L , such as dihydropyridines or D600, are potent inhibitors of I to and would thus interfere with the estimation of Q Ca .…”