In addition to the previously studied Zn2+, low concentrations (about 0.5 mM) of Be2+, Ba2+, Cd2+, Ni2+, Cu2+, Pt4+ and, outstandingly, 0.5 µM of UO22+, potentiate the twitch of frog sartorius and toe muscles by prolonging the active state of contraction. The degree of potentiation is a roughly S-shaped function of p(metal2+), suggesting that each metal binds to a ligand of the muscle fiber, representative apparent affinity constants being: UO22+, 5 x 106; Zn2+, 2.8 x 105; and Cd2+, 2 x 104. UO22+ potentiation effects are rapidly reversed by PO4, and Zn2+ and Cd2+ effects by EDTA, PO4, and cysteine. The rapidity of these reversals by the nonpenetrating EDTA and PO4, and the fact that heavy metal ions evidently potentiate by prolonging the action potential, indicate that the metal potentiators exert their primary action at readily accessible (i.e. plasma and T tubular) membrane sites. The relatively slow kinetics of development of potentiation, and the even slower reversal of it in pure Ringer's solution, indicate that the metal ions are bound to connective tissue, as well as to muscle fibers. The binding effects at the readily accessible membrane sites evidently impairs delayed rectification and thus modifies the action potential and excitation-contraction coupling so as to cause potentiation. SH is excluded, and PO4 and imidazole are possibilities, as the membrane ligand binding the potentiating metal ions.

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