Selective drug action on two Ca2+ uptake processes in normal and hyperexcitable presynaptic membrane

Synaptic transmission in the bullfrog sympathetic ganglion in vitro reflects Ca2+-dependent presynaptic and Na+-dependent postsynaptic membrane excitabilities. Aminopyridines (e.g., 3-AP, 4-AP,3,4-DAP) produce Ca2+-dependent presynaptic membrane hyperexcitability (increased transmitter release), evident as synchronized, stimulus-bound repetitive postsynaptic spike responses (SBR) to each single preganglionic stimulus (0.1 Hz). The SBR induced by 3,4-DAP is selectively eliminated as the normal [Ca2+]0 of 1.8 mM is reduced to 0.6 mM, whereas failure of the primary spike response begins only at 0.33 mM [Ca2+]0 and is complete at 0.07 mM. These differences in Ca2+ dependence suggest that two separate presynaptic Ca2+ uptake processes are involved in transmission (the primary spike) and in SBR. The authors' present work with Ca2+-channel blockers (CCBs) reinforces the preceding evidence for quantitatively separate presynaptic Ca2+ uptake processes. Thus, aminopyridine-induced SBR is also selectively abolished by verapamil (V) or diltiazem (D). From threshold to complete abolition of SBR the effective CCB ranges are: V,0.04-0.15 mM; D,0.01-0.08 mM. Higher concentrations are required to block synaptic transmission (the primary spike), the effective CCB ranges being: V,0.25-0.75 mM; D,0.1-0.4 mM. The CCBs thus display considerable concentration selectivity in stabilizing the hyperexcitable presynaptic membrane and in depressing its normal excitability. This is fully analogous to the authors' earlier work, in which SBR induced by physostigmine or 3,4-DAP was selectively abolished by d-tubocurarine or lidocaine concentrations below transmission-blocking levels.(ABSTRACT TRUNCATED AT 250 WORDS)