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In pithed rats, we studied the effects of prostaglandin E2 and of subtype-selective prostaglandin E receptor (EP receptor) ligands on the rise in blood pressure induced by electrical stimulation of the preganglionic sympathetic nerves. Prostaglandin E2, the EP1/EP3 receptor agonist sulprostone and the EP2/EP3 receptor agonist misoprostol inhibited the electrically induced increase in diastolic blood pressure (rank order of potencies sulprostoneor = misoprostolor = prostaglandin E2); the rise in blood pressure induced by exogenously added noradrenaline was not affected by these compounds. The inhibitory effect of sulprostone on the electrically induced vasopressor response was not significantly changed by indomethacin. Iloprost (an agonist at EP1 and prostacyclin receptors (IP receptors)) failed to affect the electrically evoked increase in blood pressure. The present study suggests that prostaglandin E2 inhibits the release of catecholamines in pithed rats via prostanoid receptors of the EP3 subtype, probably located presynaptically on the postganglionic sympathetic nerve fibres.

The dose-response curve for the vasopressor effect of alpha, beta-methylene ATP in pithed rats was influenced by four suramin-related drugs (each at 100 mumol/kg). The curve was shifted to the right by a factor of 8 by 'compound 3' and by a factor of 2 by two other derivatives, but was not affected by the fourth analogue. Compound 3 had no effect on the vasopressor response to noradrenaline or neuropeptide Y. In conclusion, compound 3 is a purine P2X receptor antagonist which is approximately as potent as suramin, and which, like suramin, does not exhibit antagonistic properties at alpha-adrenoceptors and neuropeptide y receptors.

A novel compound, SB-236057 (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo]2,3-f]indole-3,4'-piperidine]) has been shown to have high affinity for human 5-hydroxytryptamine 1B (5-HT 1B ) receptors (pK i = 8.2) and displays over 75 or more-fold selectivity for the human 5-HT 1B receptor over other 5-HT receptors, including the human 5-HT 1D receptor, and a range of other receptors, ion channels and enzymes. In functional studies using [ 35 S]GTPγS binding, SB-236057 displayed negative intrinsic activity (pEC 50 = 8.0) at human 5-HT 1B receptors stably expressed in Chinese Hamster Ovary (CHO) cells and caused a rightward shift of agonist concentration response curves consistent with competitive antagonism (pA 2 = 8.9). SB-236057 potentiated [ 3 H]5-HT release from electrically stimulated guinea pig or human cortical slices. SB-236057 also abolished the inhibitory effect of exogenously superfused 5-HT on electrically-stimulated release from slices of the guinea pig cortex. These studies using SB-236057 confirm that, in both the guinea pig and human cerebral cortex, the terminal 5-HT autoreceptor is of the 5-HT 1B subtype.

In pithed rats, we studied the effects of prostaglandin E2 and of subtype-selective prostaglandin E receptor (EP receptor) ligands on the rise in blood pressure induced by electrical stimulation of the preganglionic sympathetic nerves. Prostaglandin E2, the EP1/EP3 receptor agonist sulprostone and the EP2/EP3 receptor agonist misoprostol inhibited the electrically induced increase in diastolic blood pressure (rank order of potencies sulprostone ≥ misoprostol ≥ prostaglandin E2); the rise in blood pressure induced by exogenously added noradrenaline was not affected by these compounds. The inhibitory effect of sulprostone on the electrically induced vasopressor response was not significantly changed by indomethacin. Iloprost (an agonist at EP1 and prostacyclin receptors (IP receptors)) failed to affect the electrically evoked increase in blood pressure. The present study suggests that prostaglandin E2 inhibits the release of catecholamines in pithed rats via prostanoid receptors of the EP3 subtype, probably located presynaptically on the postganglionic sympathetic nerve fibres.

Strips of human saphenous veins were incubated with [3H]noradrenaline and subsequently superfused with physiological salt solution containing cocaine, corticosterone and propranolol. The electrically (6 Hz) evoked overflow of tritium (78% of which was accounted for by unmetabolized [3H]noradrenaline) was abolished by tetrodotoxin or omission of Ca2+ from the superfusion fluid. Unlabelled noradrenaline, alpha-methylnoradrenaline, B-HT 920 and clonidine inhibited the evoked overflow (maximum effect of clonidine lower than that of the other compounds) whereas methoxamine was ineffective. The alpha 2-adrenoceptor antagonists, BDF 6143 and rauwolscine, facilitated the evoked overflow but no effect was obtained with prazosin. Rauwolscine produced a shift to the right of the concentration-response curve of B-HT 920 for its inhibitory effect on evoked outflow and BDF 6143 caused a shift to the right of the corresponding curve of clonidine. It is concluded that the stimulation-evoked release of noradrenaline from the sympathetic nerve fibres of the human saphenous vein is modulated via presynaptic alpha 2-adrenoceptors.