On the mechanism of alpha-receptor mediated modulation of ³H-noradrenaline release from slices of rat brain neocortex

Summary

Brain cortical slices were superfused with Krebs-Ringer media and the effects of oxymetazoline (an α-adrenoceptor agonist) and phentolamine (an α-antagonist) on depolarization-induced ³H-NA release were examined. Depolarization was effected by various K⁺-concentrations or by electrical pulses.

The effects of the α-receptor agents on stimulated ³H-NA overflow appeared to be dependent on the strength of the depolarizing stimulus. Thus, at low K⁺-concentrations (13 or 26 mM) oxymetazoline decreased and phentolamine increased the stimulated overflow, while at 56 mM K⁺ little or no modulation was found. The agents acting on α-receptors modulated ³H-NA release in a dose-dependent way (5 · 10⁻⁸–10⁻⁵ M).

The lack of modulation by oxymetazoline of ³H-NA release induced by 56 mM K⁺ seems not to be due to a high concentration of NA released into the synaptic cleft, since reduction of the endogenous NA level by pretreatment with α-methyl-para-tyrosine did not reveal such modulation.

However, oxymetazoline was found to decrease 56 mM K⁺-induced ³H-NA release effectively, if the Ca²⁺-concentration in the medium was lowered from 1.2 to 0.2 mM. This suggests that α-receptor mediated modulation of release may occur as a result of a change in Ca²⁺-availability to the depolarization-secretion process. In addition, hyperpolarization of nerve endings might be involved in the modulatory process, as concluded from calculations of the (theoretical) trans-membrane potential at various K⁺-concentrations.

Although the α-receptors modulating NA release seem to be localized presynaptically, their precise location remains uncertain. Experiments with tetrodotoxin suggested that the α-receptor mediated modulation does not operate via a local interneuronal loop.