Effects of 4-aminopyridine on insulin secretion and plasma glucose levels in intact and adrenalectomized-chemically sympathectomized mice.

The effects of 4-aminopyridine (4-AP) on basal and glucose-induced insulin secretion and on plasma glucose concentrations were investigated in vivo in intact mice and in mice subjected to surgical adrenalectomy plus chemical sympathectomy induced by 6-hydroxydopamine. In normal intact mice, an i.v. injection of 4-AP, 26 micro mol/kg, induced an elevation of plasma glucose concentrations from 6.4 +/- 2 to 10.0 +/- 0.3 mmol/1 (P less than 0.001) seen after 30 min. Thereafter the plasma glucose concentration gradually returned to the normal level. Despite this marked elevation of plasma glucose levels, no change in plasma insulin concentrations was seen. In intact normal mice, the insulin secretion induced by a half-maximal dose of glucose was partially inhibited by 4-AP, 0.26 micro mol/kg. No further inhibition was observed after a larger dose, 26 micro mol/kg. In adrenalectomized-chemically sympathectomized mice, 4-AP, 26 micro mol/kg, did not affect plasma glucose concentrations or plasma levels of insulin. In these animals, 4-AP potentiated glucose-induced insulin secretion by approximately 65% at the two dose levels studied. This potentiation of glucose-induced insulin secretion was not affected by muscarinic receptor blockade. In summary, 4-AP increased plasma glucose levels in normal intact mice, but had no effect on plasma glucose levels in adrenalectomized-chemically sympathectomized mice. In addition, 4-AP inhibited glucose-induced insulin secretion in normal intact mice, but potentiated glucose-induced insulin secretion in adrenalectomized-chemically sympathectomized mice. It is concluded that the effect of 4-AP on insulin secretion and plasma glucose levels in normal mice is exerted indirectly, through stimulation of the sympatho-adrenal system. Further, from the results obtained in animals deprived of their sympatho-adrenal system it is suggested that the drug also has the capability to stimulate insulin secretion by acting directly on the insulin secreting cells.