Effects of 4-Methyl-2-aminopyridine on [ 3H]-Noradrenaline Overflow and Contractility of Isolated Rabbit Arteries

Abstract

1. The effects of 4-methyl-2-aminopyridine (4M2AP) and 4-aminopyridine (4AP) on spontaneous and evoked [ 3H]-noradrenaline overflow were compared in rabbit ear artery strips. The effects of 4M2AP on smooth muscle contractility were also investigated in isolated perfused ear arteries. 2. Both 4M2AP and 4AP enhanced spontaneous [ 3H] overflow from arterial strips in a concentration-dependent manner (10–1000 μM). A bell-shaped dose-response relation was obtained for evoked [ 3H] overflow over the same concentration range, with maximum effects occurring at 10 μM for 4M2AP (163±31% increase) and 100 μM for 4AP (154±16% increase). 3. 4M2AP did not significantly affect evoked tension in the 1- to 100-μM range but clearly depressed it at 1,000 μM (by 65±11%). In contrast, 4AP enhanced evoked tension in the 10- to 100- μM range (by 30–50%). 4. 4M2AP (10–100 μM) enhanced vasoconstrictor responses to exogenous noradrenaline injections in isolated perfused rabbit ear arteries, whereas higher concentrations (1,000 μM) caused significant depression. 5. 4M2AP (1,000 μM) markedly potentiated vasoconstrictor responses induced by perfusion with a high extracellular K + solution. When 4M2AP was present during the reloading of noradrenaline-sensitive Ca 2+ stores, it enhanced the subsequent vasoconstrictor responses to noradrenaline obtained in a Ca 2+-free medium. 6. The results show that 4M2AP, like 4AP, enhances [ 3H] overflow from sympathetic nerve terminals and has complex effects on vascular smooth muscle contractility, indicating the ability of these compounds to affect the Ca 2+ permeability of both extracellular and intracellular membrane systems.