Heavy metals: effects on synaptic transmission.

The acute effects of Pb++, Cd++ and Hg++ on synaptic transmission were studied on the in vitro sciatic nerve-sartorius muscle preparation of the frog, using electrophysiological techniques. Biochemical procedures were used to examine the effects of Pb++ and Cd++ on in vitro preparations of synaptosomes. In the electrophysiological studies Pb++ was shown to be a powerful competitive inhibitor of action potential-evoked release of acetylcholine (ACh) as judged by its depressant effects on the amplitude of endplate potentials (EPPs). The dissociation constant between Pb++ and the presynaptic Ca++ receptor is about 1 microM. Pb++ also increases spontaneous transmitter release as determined by the frequency of miniature endplate potentials (MEPPs). The increase in MEPP frequency is assumed to be due to an intracellular action of Pb++ to reduce the ability of nerve terminal organelles to buffer Ca++ and thereby, increases the intracellular concentration of Ca++. Cd++ also blocks evoked ACh release by a competitive inhibitory mechanism which appears similar to that for Pb++. The dissociation constant for Cd++ is about 2.8 microM. In contrast to Pb++, Cd++, does not increase resting MEPP frequency. Hg++ is unique in that it first causes an increase in evoked ACh release and then a sudden and complete blockade; the MEPP frequency follows a similar time course. The mechanism underlying these effects of Hg++ is uncertain. In rat brain synaptosomes, Pb++ and Cd++ competitively inhibit the K+-stimulated influx of 45Ca++. The dissociation constants for the interaction of Pb++ and Cd++ with Ca++ channels is 1.1 microM and 2.2 microM respectively. These data strongly support the idea that the electrophysiological effects of Pb++ and Cd++ on the EPP are due to a reduction of voltage-gated Ca++ entry into presynaptic nerve terminals.