Metal-induced inhibition of Na+/K+-ATPase and SERCA in the rainbow trout (Oncorhynchus mykiss) heart: Implications for cardiac ion regulation.

Metal ions are known to inhibit sarcolemmal ion currents and induce cardiac arrhythmias in fish, but their actions are not fully explained by ion channel blockade. To further clarify the effects of di- and trivalent cations on fish heart function, we examined the impact of eight metals on the activities of Na+/K+-ATPase and Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA) in vitro in ventricular homogenates of rainbow trout (Oncorhynchus mykiss). Unfractionated ventricular homogenates were exposed in vitro to eight metals (Al3+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+ or Hg2+) at concentrations of 0.1-30 μM. Na+/K+-ATPase activity was strongly inhibited by Hg2+ and Cu2+ in a concentration-dependent manner, with IC50 values of 1.4 ± 0.13 μM and 3.2 ± 1.0 μM, respectively, and Na+/K+-was less sensitive to Zn2+ (IC50 10.6 ± 2.9 μM). Other metals had little or no effect. SERCA activity was inhibited only by Hg2+ (IC50 value of 2.6 ± 0.7 μM). The inhibition of Na+/K+-ATPase and SERCA by Hg2+ occurred at concentrations comparable to those previously associated with cardiac arrhythmias in rainbow trout. These findings suggest that the arrhythmogenic effects of Hg2+ arise not only from voltage-gated channel blockade but also from inhibition of active ion transport across the sarcolemma and reduced Ca2+ uptake by the sarcoplasmic reticulum. Our findings support the hypothesis that inhibition of Na+/K+-ATPase by Hg2+ and Cu2+, and of SERCA by Hg2+, may contribute to cytosolic Ca2+ overload, triggering early and delayed afterdepolarizations and ultimately arrhythmic activity in the fish heart.