PROSTANOID RECEPTORS OF THE EP(3) SUBTYPE MEDIATE THE INHIBITORY EFFECT OF PROSTAGLANDIN E(2) ON NORADRENALINE RELEASE IN THE MOUSE-BRAIN CORTEX

Mouse or rat brain cortex slices were preincubated with H-3-noradrenal ine and superfused with physiological salt solution containing desipra mine. We studied the effects of prostaglandin E(2) (PGE(2)), prostagla ndin D-2 (PGD(2)) and related drugs on the electrically evoked (50 mA, 2 ms, 0.3 Hz) tritium overflow.PGE(2) inhibited the electrically evok ed tritium overflow from mouse brain cortex slices; the maximum effect of PGE(2) (79%) was attenuated by the az-adrenoceptor agonist talipex ole (to 52%) and enhanced by the alpha(2)-adrenoceptor antagonist rauw olscine (to 92%). Rauwolscine was added to the superfusion medium in a ll subsequent experiments. The effect of PGE(2) was readily reversible upon withdrawal from the medium and remained constant upon prolonged exposure of the tissue to the prostanoid. Studies with EP receptor ago nists, mimicking the inhibitory effect of PGE(2), showed the following potencies (pIC(50)): sulprostone (8.22); misoprostol (8.00); PGE(2) ( 7.74); PGE(1) (7.61); iloprost (5.86). The concentration-response curv e of PGE(2) was marginally shifted to the right by the EP(1) receptor antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid; appa rent pA(2) 3.97) and by the TP receptor antagonist vapiprost (4.50). A H 6809, by itself, did not affect the evoked overflow whereas vapipros t increased it. PGD(2) inhibited the evoked overflow at high concentra tions (pIC(50) 4.90); this effect was not altered by the DP receptor a ntagonist BW A868C l)-1-(2-cyclohexyl-2-hydroxyethylamino)hydantoin), which, by itself, did not affect the evoked overflow. Indometacin slig htly increased the evoked overflow and tended to increase the inhibito ry effect of PGE(2). PGE(2) inhibited the electrically evoked tritium overflow also in mt brain cortex slices. The maximum effect (obtained in the presence of rauwolscine) was 61%; the pIC(30) value was 7.67. T he present study suggests that PGE(2) inhibits noradrenaline release f rom mouse brain cortex via EP(3) receptors and that its maximum effect is more marked in the mouse than in the rat. The inhibitory effect of PGD(2) (in the mouse brain) does not involve DP receptors and may als o be related to EP(3) receptors. The EP(3) receptors interact with alp ha(2)-adrenoceptors and may be activated by endogenous prostanoids.