Characterization of Neuromedin U Effects in Canine Smooth Muscle

Abstract

Two endogenous receptors for the potent smooth musclestimulating peptide neuromedin U (NmU) have recently been identified and cloned. Pharmacological, binding, and expression studies were conducted in an attempt to determine the receptor(s) involved in the smooth muscle-stimulating effects of NmU. The NmU peptides caused a concentration-dependent contraction of canine isolated urinary bladder. NmU did not have this same effect in the urinary bladder from rat, guinea pig, rabbit, mouse, or ferret. Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon. As well as causing contraction of canine bladder in vitro, NmU administered systemically resulted in a significant increase in urinary bladder pressure in vivo. High-affinity binding sites for NmU were identified in canine bladder. The four NmU peptides porcine NmU-8, rat NmU-23, human NmU-25, and porcine NmU-25 displaced 125 I-NmU-25 binding with similar K i values (0.08 -0.24 nM). A different binding profile was revealed in human embryonic kidney-293 cells transiently expressed with the canine NmU-2 receptor where porcine NmU-8 (K i ϭ 147.06 nM) was much less potent than the other NmU peptides. Using TaqMan, expression of NmU-1 was detected in human urinary bladder, small intestine, colon, and uterus. Expression of NmU-2 was much lower or absent in these human tissues and undetectable in canine bladder and stomach. The results of this study reveal significant species differences in the activity of NmU. The contractile activity in human and canine smooth muscle seems to be mediated by the recently cloned NmU-1 receptor.

Effects of neuromedin-U on immature rat adrenocortical cells: In vitro and in vivo studies

“…Our present RT-PCR and ICC studies clearly demonstrate the expression of NMUR1 as mRNA and protein in the cortex of immature rat adrenals, thereby confirming earlier findings obtained in adult animals (9,(27)(28)(29)33,34). Moreover, the detection of NMUR1 mRNA in dispersed zona glomerulosa and zona fasciculata-reticularis cells rules out the possibility that the expression was due to the presence in the specimens assayed of the non-parenchymal components of the gland (connective tissue and capillaries).…”

“…NPY, cholecystokinin, galanin, leptin, orexins, beacon and NPW) (11)(12)(13)(14)(15)(16)(17), also NMU appears to regulate the hypothalamic-pituitary-adrenal (HPA) axis. The expression of NMU and NMUR 2 was found in the hypothalamus and anterior pituitary (10,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33), while in the adrenal glands only the expression of NMUR1 was detected (9,(27)(28)(29)33,34). NMU has been shown to enhance c-fos expression in the hypothalamic paraventricular nucleus (1,2,30,35), to increase CRH and vasopressin output from rat hypothalamic explants, and to stimulate ACTH and corticosterone secretion in the rat (2,4,5,(36)(37)(38).…”

Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice

“…We observed no difference in the intestinal transit of a charcoal-based marker between wild-type and NmU Tg mice. Although NmU stimulates ileal smooth muscle contraction in dogs and humans in vitro (Maggi et al 1990, Westfall et al 2002, it failed to stimulate porcine jejunum, guinea pig ileal smooth muscle, and rat small and large intestinal longitudinal smooth muscle in vitro (Minamino et al 1985a, Brown & Quito 1988, Benito-Orfila et al 1991. The absence of a difference between wild-type and NmU Tg mice in this regard is therefore not entirely surprising, and indicates that changes in intestinal motility are probably not involved in the phenotype observed.…”

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…Most studies agree that NMUR1 is preferentially expressed in the periphery, particularly in the gastrointestinal tract, while NMUR2 is predominantly expressed in the central nervous system (41 ). Human NMUR1 mRNA has been detected at the highest concentrations in stomach and small intestine, while it is also present in pancreas, adrenal cortex, heart, lung, trachea, mammary gland, bone marrow, peripheral lymphocytes, genitourinary system, placenta, mammary gland, spleen, and adipose tissue (14,29,36,38,42 ). Some studies have also detected low concentrations of NMUR1 expression in human brain, but this finding has not been consistent.…”