Actions of prostaglandin E₂ on rat supraoptic neurones

Prostaglandins (PGs) have been implicated in the regulation of vasopressin (VP) and oxytocin (OT) release in response to various stimuli. To examine the site and mechanism of actions of PGs, we studied effects of PGE₂ and PG-receptor agonists on supraoptic nucleus (SON) neurones of rat hypothalamic slice preparations using extracellular recording and whole-cell patch-clamp techniques. PGE₂ modulated the electrical activity of more than 80% of the neurones studied. The effects of PGE₂ on both phasic and non-phasic neurones were mostly excitatory, and dose-dependent. The effects of PGE₂ were mimicked by PGF(2α) or the FP agonist, fluprostenol, whereas PGD₂ or the selective EP₁ IP or TP agonist was less effective or had no effect. The effects of PGE₂ were unaffected by the EP₁ antagonist, SC-51322, but reduced to 80% of control by the EP₁/FP/TP antagonist, ONO-NT-012, which reduced the effects of fluprostenol to 32% of control. Moreover, some neurones responsive to PGE₂ did not respond to fluprostenol. Patch-clamp analysis in SON slice preparations revealed that PGE₂ at 10^-6 M depolarized the membrane potential by 3.9 ± 0.3 mV from the resting membrane potential of -58.4 ± 2.2 mV in the current-clamp mode. In the voltage-clamp mode, PGE₂ induced inward currents at a holding potential of -70 or -80 mV, while it did not affect spontaneous excitatory postsynaptic currents. PGE₂ induced currents also in dissociated SON neurones and the reversal potential of the currents was -35.5 ± 0.9 mV, which was similar to that of currents induced by fluprostenol. These results suggest that SON neurones possess at least two types of PG receptors, FP receptors and EP receptors of a subclass different from EP₁, EP₂, or EP₃, and that activation of these receptors leads to the opening of nonselective cation channels, membrane depolarization and increase of the action potential discharge.