The present study describes

These results indicate that human saphenous veins from both sexes express PR, as previously described for arterial blood vessels. This observation suggests that progesterone acts directly on these veins via a classic receptor-mediated pathway.

1 We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic in¯ammation in rat paw skin. We compared the eect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2 Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a ®ve-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) signi®cantly inhibited (40 to 60%) the development of neurogenic oedema, but did not aect cutaneous blood¯ow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating eect. 3 Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not aect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, signi®cantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4 COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5 A mast cell stabilizer, cromolyn, and a H 1 receptor antagonist, mepyramine, signi®cantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6 The co-injection of LOX inhibitors and compound 48/80 did not alter the eects of compound 48/80. Conversely, ethacrynic acid had a signi®cant potentiating eect. The pharmacological pro®le of the eect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7 The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not aect neurogenic or SPinduced oedema. 8 Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a signi®cant role in this process.

During pregnancy, the uterus undergoes major functional and structural remodelling. For the major part of pregnancy, the uterus gradually increases in size and the myometrium normally remains relatively quiescent. On the contrary, at the time of parturition, the myometrium has to generate co-ordinated and powerful contractions. Several extracellular signals including hormones, neurotransmitters and mechanical factors, as well as a change in During pregnancy, the uterus undergoes major functional and structural remodelling. It is well known that during the major part of pregnancy, the myometrium normally remains relatively quiescent but is able to generate powerful contractions at the time of parturition. However, the intracellular molecular events regulating myometrial contractility during pregnancy still remain poorly understood. We applied differential gene expression screening using cDNA array technology to probe myometrium samples from non-pregnant and mid-pregnant (15 days) rabbits. Among the differentially expressed genes, the farnesylated small G-protein of the Rho family, Rnd3, was found to be upregulated (3.6-fold) at mid-pregnancy. Upregulation of Rnd3 was confirmed at the protein level by a 3.4-fold increase in Rnd3 expression in mid-pregnant myometrium. Measurements of contractile properties of b-escin permeabilized smooth muscle strips revealed that the upregulation of Rnd3 correlated with an inhibition of RhoA-Rho kinase-mediated Ca 2+ sensitization at mid-pregnancy. Treatment of muscle strips from mid-pregnant myometrium with the farnesyl-transferase inhibitor manumycin A (10 mM) led to the recovery of RhoA-Rho kinasedependent Ca 2+ sensitization. At late pregnancy (31 days), upregulation of RhoA and Rho kinase expression was associated with an increase in Ca 2+ sensitivity of contractile proteins that was inhibited by the Rho kinase inhibitor Y-27632 (10 mM). These data thus demonstrate the timedependent regulation of the RhoA-Rho kinase-mediated Ca 2+ sensitization during the course of pregnancy. The depression of this mechanism at mid-pregnancy followed by its constitutive activation near term is associated with a co-ordinated modulation of Rnd3, RhoA and Rho kinase expression. The RhoA-Rho kinase signalling pathway and its regulators might thus represent potential targets for the development of new treatments for pre-term labour.