1. Sensory nerves supplying the mammalian uterus have been shown to contain substance P (SP) and neurokinin (NK)A. This review presents some of the advances that have led to a greater understanding of the effects of tachykinins on uterine smooth muscle. 2. The cell-surface peptidase neprilysin (EC.3 24.11, endopeptidase 24.11, enkephalinase, CALLA, CD10) has been shown to play a major role in regulating the actions of tachykinins on both rat and human myometrium. Because this peptidase is known to be regulated by steroids and pregnancy, its effects may be of physiological relevance. 3. Tachykinins produce contractions of isolated myometrial preparations from non-pregnant rats and mice. The NK2 receptor mediates these effects in rat uterus, while the NK1 receptor may mediate these effects in the mouse uterus. 4. The effects of tachykinins have been examined on myometrial preparations obtained at Caesarean section from near-term pregnant women. In the presence of the peptidase inhibitors (thiorphan, captopril and bestatin), the mammalian tachykinins SP, NKA and NKB produced concentration-dependent uterine contractions. 5. The order of agonist potency NKA > SP = NKB suggested that NK2 receptors mediate uterine contractions in the human. This was confirmed using the stable analogues [Sar9,Met(O2)11]SP, [Lys5MeLeu9Nle10]NKA(4-10) and [N-MePhe7]NKB, which are NK1, NK2 and NK3 receptor selective, respectively. Only [Lys5MeLeu9Nle10]NKA(4-10) produced concentration-related contractions of human uterine smooth muscle. 6. The experimental findings described in the present review, taken together with results published previously in the literature, indicate that tachykinin peptides may play a physiological or pathophysiological role in regulating uterine smooth muscle activity. However, more extensive research will be required to confirm such a role for these peptides.

Noradrenaline (10-50 nM) and tyramine (0.05-1 mM) enhanced contractile force elicited by field stimulation of strips of myometrium from non-pregnant and pregnant women. In higher concentrations, noradrenaline produced sustained contractions. The EC50 values for noradrenaline were 0.4 microM in tissues from pregnant women and 3.1 microM in tissues from non-pregnant women; maximum responses were greater in the former tissues. In addition, the effects of noradrenaline on myometrium from pregnant women were more marked on the inner layer than on the outer layer, antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.1 and 1.0 microM), and unaffected by the inhibitor of neuronal uptake, nisoxetine (0.1 microM). Taken together, these observations confirm that supersensitivity to noradrenaline develops during pregnancy and is present near term. The supersensitivity to noradrenaline at term can be attributed only in part to a decrease in its removal by the sympathetic innervation, which declines towards term, because responses to tyramine were also enhanced in tissues from pregnant women. It is possible that gap junction formation may also contribute to this supersensitivity.

The hypothesis that inhibitory effects of isoprenaline on myometrial contractility may be constrained by activation of putative intracellular beta-adrenoceptors negatively-coupled to adenylate cyclase was examined. Field-stimulated preparations of guinea-pig and human myometrium were used to examine the influence of the catecholamine extraneuronal uptake2 inhibitors, corticosterone and beta-oestradiol, on the inhibitory effects of the beta-adrenoceptor agonist, isoprenaline, on uterine contraction. Longitudinal and circular myometrial layers were obtained from guinea-pigs in dioestrus, primed with oestrogen before progesterone, or pregnant (Days 62-65). In the guinea-pig myometrium, corticosterone (30 microM) did not affect responses to isoprenaline. beta-oestradiol (10 microM) induced a small potentiation of the effects of isoprenaline on longitudinal myometrium from dioestrus guinea-pigs. Myometrial preparations were obtained from pregnant women (36-40 weeks gestation) undergoing caesarean section. Isoprenaline inhibited stimulation-evoked contractions in 7 of 10 preparations of the inner myometrial layer and in 5 of 8 preparations of outer myometrial layer. Corticosterone (30 microM) reduced the effects of isoprenaline on the inner layer and did not affect the outer layer. These results do not support the existence of mechanism involving isoprenaline-sensitive intracellular receptors which constrain responses to beta-adrenoceptor agonists.