Zinc modulation of basal and β-adrenergically stimulated L-type Ca2+ current in rat ventricular cardiomyocytes: consequences in cardiac diseases

Zinc exists in biological systems as bound and histochemically reactive free Zn2+ in the nanomolar range. Zinc is required as either structural or catalytic component for a large number of enzymes. It also modulates current passage through many ion channels. Here, we reinvestigated the effects of extracellular and intracellular Zn2+ on the L-type Ca2+ current (I (CaL)) and its modulation by beta-adrenergic stimulation in rat ventricular cardiomyocytes. In the absence of Ca2+ ions, Zn2+ could permeate through the L-type channel at much lower concentrations and at a more positive voltage range, but with a lower permeability than Ca2+. In the presence of Ca2+, extracellular Zn2+ demonstrated strong bimodal inhibitory effects on the I (CaL), with half-inhibition occurring around 30 nM, i.e., in the range of concentrations found in the plasma. Intracellular Zn2+ also significantly inhibited the I (CaL) with a half-inhibitory effect at 12.7 nM. Moreover, beta-adrenergic stimulation was markedly reduced by intracellular Zn2+ at even lower concentrations (< 1 nM) as a consequence of Zn2+-induced inhibition of the adenylyl cyclase. All these effects appeared independent of redox variations and were not affected by dithiothreitol. Thus, both basal intracellular and extracellular Zn2+ modulate transmembrane Ca2+ movements and their regulation by beta-adrenergic stimulation. Considering that, in many pathological situations, including diabetes, the extracellular Zn2+ concentration is reduced and the intracellular one is increased, our results help to explain both Ca2+ overload and marked reduction in the beta-adrenergic stimulation in these diseases.