Influence of Relaxin on the Neurally Induced Relaxant Responses of the Mouse Gastric Fundus1

Abstract

The peptide hormone relaxin has been reported to depress the amplitude of contractile responses in the mouse gastric fundus by upregulating nitric oxide (NO) biosynthesis at the neural level. In the present study, we investigated whether relaxin also influenced nonadrenergic, noncholinergic (NANC) gastric relaxant responses in mice. Female mice in proestrus or estrus were treated for 18 h with relaxin (1 microg s.c.) or vehicle (controls). Mechanical responses of gastric fundal strips were recorded via force-displacement transducers. In carbachol precontracted strips from control mice and in the presence of guanethidine, electrical field stimulation (EFS) elicited fast relaxant responses that may be followed by a sustained relaxation. All relaxant responses were abolished by tetrodotoxin. Relaxin increased the amplitude of the EFS-induced fast relaxation without affecting either the sustained one or the direct smooth muscle response to papaverine. In the presence of the NO synthesis inhibitor L-N(G)-nitro arginine (L-NNA), that abolished the EFS-induced fast relaxation without influencing the sustained one, relaxin was ineffective. In strips from relaxin-pretreated mice, EFS-induced fast relaxations were enhanced in amplitude with respect to the controls, while sustained ones as well as direct smooth muscle responses to papaverine were not changed. Further addition of relaxin to the bath medium did not influence neurally induced fast relaxant responses, whereas L-NNA did. In conclusion, in the mouse gastric fundus, relaxin enhances the neurally induced nitrergic relaxant responses acting at the neural level.

Relaxin counteracts the altered gastric motility of dystrophic (mdx) mice: functional and immunohistochemical evidence for the involvement of nitric oxide

“…This latter possibility is strongly supported by the observation that the NO synthesis inhibitor L-NNA increased to a lesser extent the amplitude of the EFS-induced contractile responses in strips from mdx mice compared with the WT ones, suggesting the removal of a weaker nitrergic inhibitory influence in the former ones, in keeping with previous findings (7,29). In mdx mice, the reduced amplitude of the EFS-induced fast relaxant responses and their abolition by L-NNA, which confirms their nitrergic nature (3,7), also support this view. In keeping with these functional data, the morphological findings show a significant decrease in nNOS-IR in the myenteric neurons of mdx mice compared with the WT.…”

“…The identification of specific relaxin-binding sites in the smooth muscle cells of the gastrointestinal tract of pregnant pigs (42) suggests that this hormone also influences gut func- tions, in keeping with early reports that a relaxin preparation extracted from the ovary reduced the strength and the frequency of contractions in the rat ileum (26) and that relaxin had disruptive effects on the migrating myoelectric complex in the rat small intestine (25). Our more recent studies have also provided evidence that relaxin influences gastrointestinal motility in mice and that its effects likely occur through a NO-mediated mechanism (3,5,10).…”

“…Mice of the second group (6 WT and 6 mdx animals), referred to as relaxin-pretreated WT or mdx mice, received a single subcutaneous injection of 2 g of highly purified porcine relaxin (2,500 -3,000 U/mg) prepared according to the method of Sherwood and O'Byrne (57) and generously donated by Dr. O. D. Sherwood, University of Illinois (Urbana, IL). The hormone was dissolved in 0.2 ml of 1% benzopurpurin (Fluka, Buchs, Switzerland) in PBS, a repository vehicle that allows a slow release of the hormone over 24 h. The chosen dose, vehicle, and route of administration were in the range of those previously used in mice and proved effective to upregulate NOS expression (3,5,6,9,10). The mice of the third group (6 WT and 6 mdx animals) received the vehicle alone and are referred to as vehicle-pretreated WT or mdx mice.…”

“…Particularly, in the gastrointestinal tract of healthy female mice, relaxin has been shown to influence the motor responses by modulating the expression of the different NOS (3,5,10).…”

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

“…Depending on the cell type under investigation, relaxin may activate endothelial nitric oxide synthase (eNOS) (Baccari et al, 2007;Dschietzig et al, 2012) and neuronal NOS (nNOS) (Baccari et al, 2004;Mookerjee et al, 2009) or stimulate the expression of inducible NOS (iNOS) (Bani et al, 1998a;Alexiou et al, 2013) (Fig. 4).…”