No / The pharmacology of bimatoprost, a synthetic prostaglandin-amide, was examined in prostaglandin F2¿ (PGF2¿)-sensitive preparations. Bimatoprost potently contracted the rabbit isolated uterus (pEC50=7.92±0.16). In contrast, bimatoprost exhibited weak excitatory activity in human myometrium from pregnant and nonpregnant donors, mouse uterus, rat uterus, and endothelium-intact rabbit jugular veins, and did not stimulate DNA synthesis in mouse fibroblasts. The possibility that the effects of bimatoprost may reflect partial agonism at prostanoid FP receptors was examined and the contractile effects of full agonists, 17-phenyl PGF2¿ (FP) and U-46619 (TP, a control), were determined in the absence and presence of 1 ¿M bimatoprost on the mouse uterus. Analyses of the agonist¿agonist functional studies showed no antagonism, indicating that bimatoprost is not a partial agonist. Bioassay metabolism studies of bimatoprost and latanoprost (FP receptor agonist prodrug) in the rabbit uterus were conducted using recipient mouse uterus. Results indicated that the potent responses to bimatoprost in the rabbit uterus are produced by the intact molecule and not by its putative free acid metabolite, 17-phenyl PGF2¿. Some hydrolysis of latanoprost to latanoprost free acid appears to have occurred in the rabbit uterus, according to biological detection. The pharmacology of bimatoprost could not be explained by its interaction with known prostanoid FP receptors and was independent of species-, tissue-, or preparation-related factors. The potent contractile effects of bimatoprost in the rabbit uterus provide further pharmacological evidence for the presence of a novel receptor population that preferentially recognises bimatoprost.

No / Human saphenous vein endothelial cells (HSVECs) derived from primary cultures of adult human veins constitute an excellent in vitro model for studying human endothelial metabolism. In this study we report the14C-labelled prostanoid profile of HSVECs under resting and stimulated conditions and the effect of the n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid on them. Results indicate that HSVECs while under resting conditions produce mainly prostaglandin F2 ¿(PGF2 ¿). After stimulation with calcium ionophore A23187, the cells were found to synthesise PGI2, PGE2and PGF2¿as major products and thromboxane B2and PGD2as minor products. Production of14C-labelled hydroxyeicosatetraenoic acids was not detected. Eicosapentaenoic acid was found to inhibit basal and stimulated prostanoid production whereas docosahexaenoic acid inhibited basal but strongly increased stimulated prostanoid production. These results may offer the basis for further studies aiming to investigate targets for pharmacological intervention in inflammatory conditions.