Modulation of norepinephrine release from sympathetic neurons of the rabbit aorta by prejunctional prostanoid receptors.

The pharmacological properties and subtypes of prostanoid receptors involved in the prejunctional modulation of [(3)H]norepinephrine release from sympathetic neurons were studied using isolated rabbit aorta. Rings preincubated with [(3)H]norepinephrine were washed with physiological salt solution that contained cocaine plus corticosterone, uptake(1) and uptake(2) inhibitors, respectively, and rauwolscine to block prejunctional alpha(2)-adrenoceptors. Electrical field stimulation was used to evoke (3)H overflow. Prostaglandin (PG)E(2) (10(-9) to 3 x 10(-7) M) reduced the stimulation-evoked (3)H overflow; the pEC(50) value was 8.3, and E(max) value was 98%. This effect was also seen with PGE(1), PGD(2), PGF(2alpha), the EP(1)/EP(3) receptor agonist sulprostone, the EP(2)/EP(3) receptor agonist misoprostol, and the EP(1)/IP receptor agonist iloprost; the rank order (pEC(50)) was sulprostone (8.4) > PGE(2) (8.3) > misoprostol (8.1) > PGE(1) (7.9) > PGF(2alpha) (6.0) > PGD(2) (<5.0). This rank order suggests that these agents act on prejunctional prostaglandin receptors of the EP(3) subtype. The stable thromboxane A(2) analog U46619 (9,11-dideoxy-11alpha, 9alpha-epoxymethano-PGF(2alpha)) slightly reduced the stimulation-evoked (3)H overflow. The FP receptor agonist fluprostenol and the EP(2) receptor agonist butaprost had no effect. The EP receptor antagonist AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) did not alter the inhibitory effect of PGE(2) and sulprostone. AH6809 did not modulate the stimulation-evoked (3)H overflow. This suggests that prejunctional EP(1) receptors are not involved. The IP receptor agonist cicaprost reduced the (3)H overflow only at concentrations higher than 3 x 10(-5) M. We conclude that the postganglionic sympathetic neurons in rabbit aorta are endowed with prejunctional inhibitory EP(3) receptors. FP and IP receptors are not present, and the possible presence of inhibitory DP receptors requires further study.