Kinetic mechanisms by which nickel alters the calcium (Ca2+) transport in intact rat liver

Abstract

In the present work, the multiple-indicator dilution (MID) technique was used to investigate the kinetic mechanisms by which nickel (Ni²⁺) affects the calcium (Ca²⁺) transport in intact rat liver. ⁴⁵Ca²⁺ and extra- and intracellular space indicators were injected in livers perfused with 1 mM Ni²⁺, and the outflow profiles were analyzed by a mathematical model. For comparative purposes, the effects of norepinephrine were measured. The influence of Ni²⁺ on the cytosolic Ca²⁺ concentration ([Ca²⁺]_c) in human hepatoma Huh7 cells and on liver glycogen catabolism, a biological response sensitive to cellular Ca²⁺, was also evaluated. The estimated transfer coefficients of ⁴⁵Ca²⁺ transport indicated two mechanisms by which Ni²⁺ increases the [Ca²⁺]_c in liver under steady-state conditions: (1) an increase in the net efflux of Ca²⁺ from intracellular Ca²⁺ stores due to a stimulus of Ca²⁺ efflux to the cytosolic space along with a diminution of Ca²⁺ re-entry into the cellular Ca²⁺ stores; (2) a decrease in Ca²⁺ efflux from the cytosolic space to vascular space, minimizing Ca²⁺ loss. Glycogen catabolism activated by Ni²⁺ was transient contrasting with the sustained activation induced by norepinephrine. Ni²⁺ caused a partial reduction in the norepinephrine-induced stimulation in the [Ca²⁺]_c in Huh7 cells. Our data revealed that the kinetic parameters of Ca²⁺ transport modified by Ni²⁺ in intact liver are similar to those modified by norepinephrine in its first minutes of action, but the membrane receptors or Ca²⁺ transporters affected by Ni²⁺ seem to be distinct from those known to be modulated by norepinephrine.

Keywords: Ca2+-sensing receptor; Enzyme kinetics; Heavy metal; Liver hemodynamic; Toxicity.