Relaxin Depresses Small Bowel Motility Through a Nitric Oxide-Mediated Mechanism. Studies in Mice1

Abstract

Gastrointestinal motility is reduced and the incidence of functional gastrointestinal disorders is increased in pregnancy, possibly due to hormonal influences. This study aims to clarify whether the hormone relaxin, which attains high circulating levels during pregnancy and has a nitric oxide-mediated relaxant action on vascular and uterine smooth muscle, also reduces bowel motility and, if it does, whether nitric oxide is involved. Female mice in proestrous or estrous were treated for 18 h with relaxin (1 microg s.c.) or vehicle (controls). Isolated ileal preparations from both groups were used to record contractile activity, either basal or after acute administration of relaxin (5 x 10(-8) M). Drugs inhibiting nitric oxide biosynthesis or neurotransmission were used in combination with relaxin. Expression of nitric oxide synthase isoforms by the ileum was assessed by immunocytochemistry and Western blot analysis. Relaxin caused a clear-cut decay of muscle tension and a reduction in amplitude of spontaneous contractions upon either chronic administration to mice or acute addition to isolated ileal preparations. These effects were significantly blunted by N(G)-nitro-L-arginine, but not by the neural blockers we used. Moreover, relaxin increased the expression of nitric oxide synthases II and III, but not synthase I. Relaxin markedly inhibits ileal motility in mice by exerting a direct action on smooth muscle through the activation of intrinsic nitric oxide biosynthesis.

Relaxin exerts two opposite effects on mechanical activity and nitric oxide synthase expression in the mouse colon

“…Drug concentrations were in the range of those previously used in murine gastrointestinal preparations and proved to be effective (4,8,40). Particularly, because no studies are present in literature on the effects of relaxin on mouse colonic preparations, the efficacy of relaxin was evaluated in a concentration ranging from 1 ϫ 10 Ϫ9 to 1 ϫ 10 Ϫ7 M. The effects of relaxin were fully manifested from 1 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ7 M. Thus, an intermediate concentration (5 ϫ 10 Ϫ8 M) was employed.…”

“…Interestingly, the depression of muscle contractility reported in the mouse stomach and ileum was mediated by different NOS isoforms. While in the stomach relaxin induced an increase in both the constitutive NOS isoforms, i.e., neuronal (n) NOS and endothelial (e) NOS (3,40), in the ileum it increased the expression of eNOS and of inducible (i) NOS isoforms (8,4). In summary, relaxin is able to act on different NOS isoforms depending on the gut region considered.…”

“…The latter effects can be direct on the smooth muscle cells (SMC) or mediated by the endothelial cells (2,12,17,30,36). In the gastrointestinal tract, relaxin has been shown to cause depression of muscle contractility by modulating the activity and expression of the different nitric oxide synthase (NOS) isoforms (8,3,4,40). Interestingly, the depression of muscle contractility reported in the mouse stomach and ileum was mediated by different NOS isoforms.…”

17β-Estradiol Inhibites Nitric Oxide-cGMP-Dependent Pathway but may Activate Independent Pathway in Small Intestinum of Ovariectomized Rat

“…Importantly, 17β-estradiol did not alter the amplitude of spontaneous contractile tension of jejunum. Moreover, it has been reported in many studies that NO pathway directly affecting smooth muscles causes significant decrease in gastro intestinal motility [22,23] . In our study, it is possible to indicate that decreasing spontaneous contractility might be associated the interaction of estrogen with NO.…”

The effect of dietary L-arginine intake on the level of antibody titer, the relative organ weight and colon motility in broilers

“…Nitric oxide released from non-adrenergic non-cholinergic (NANC) nerves in intestines decreases intestinal motility in rat (Lie and Rand 1990), mice (Bani et al 2002) and dog (Bult et al 1990), in vitro. Similarly, the diet supplemented with sodium nitroprusside (SNP), an exogenous NO donor increases the nNOS expression in jejunum of broilers, while N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, decreases the nNOS expression (Bulbul et al 2013).…”