Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation

Abstract

. Regional gastric contractility alterations in a diabetic gastroparesis mouse model: effects of cholinergic and serotoninergic stimulation. Am J Physiol Gastrointest Liver Physiol 287: G612-G619, 2004. First published April 23, 2004 10.1152/ ajpgi.00431.2003.-The C57BLKS/J db/db mouse develops hyperglycemia and has delayed gastric emptying that is improved with tegaserod, a partial 5-HT4 agonist. Our aims here were to determine regional gastric contractility alterations in C57BLKS/J db/db mice and to determine the effects of serotonin and tegaserod. The contractile effects of bethanechol, serotonin, and tegaserod in fundic, antral, and pyloric circular muscle were compared in C57BLKS/J db/db mice and normal littermates. The effects of tetrodotoxin, atropine, and 5-HT receptor antagonists were studied. Contractions in response to bethanechol were decreased in the fundus, similar in the antrum, but increased in the pylorus in diabetic mice compared with controls. Serotonin and, to a lesser extent, tegaserod caused contractions that were more pronounced in the fundus than in the antrum and pylorus in both diabetic and normal mice. Serotonin-induced contractions were partially inhibited by atropine, the 5-HT4 antagonist GR113808, and the 5-HT2 antagonist cinanseron but not tetrodotoxin. Regional gastric contractility alterations are present in this diabetic gastroparesis mouse model. Fundic contractility was decreased, but pyloric contractility was increased in the pylorus to cholinergic stimulation in diabetic mice. Serotonin's contractile effect is mediated, in part, through muscarinic, 5-HT2, and 5-HT4 receptors. This study suggests that fundic hypomotility and pyloric hypercontractility, rather than antral hypomotility, play important roles for the gastric dysmotility that occurs in diabetes.serotonin; tegaserod GASTROPARESIS (delayed gastric emptying) is frequent in diabetic patients. It is a well-recognized complication of longstanding diabetes. Although classically, gastroparesis occurs in insulin-dependent diabetic patients, it also develops in type 2 (T2DM) or non-insulin-dependent diabetes mellitus (15). Gastroparesis is associated with antral hypomotility and perhaps pyloric dysfunction (2, 23).Treatment of gastroparesis is with prokinetic agents, which accelerate gastric emptying. Tegaserod, an aminoguanidine indole compound, is a recently developed 5-HT 4 partial agonist (1). Activation of 5-HT 4 receptors triggers the release of neurotransmitters from the enteric nerves resulting in increased contractility and stimulation of the peristaltic reflex (10). Tegaserod has been shown to accelerate gastric emptying in some (6) but not all studies (28).Strains of rats and mice with spontaneously developing hyperglycemia have been recognized as useful models to study the effects of diabetes. The Jackson Laboratory C57BLKS/J db/db mouse spontaneously develops hyperglycemia (12) and is a model for non-insulin-dependent diabetes mellitus (24). Prior studies in this mouse strain (22) have shown delayed gastric em...

Obesity and non-insulin-dependent diabetes mellitus in Swiss-Webster mice associated with late-onset hepatocellular carcinoma

“…Similar gross lesions have been observed in diabetic rats (Karakida & Homma 1989, Liu et al 1990, proposed as a model of gastrointestinal autonomic neuropathy -a complication commonly seen in humans with type 1 diabetes (insulin dependent) mellitus. Signs of digestive dysfunction and delayed gastric emptying (gastroparesis) have also been described in human diabetics and mouse models of T2D (Asakawa et al 2003, James et al 2004. Gastroparesis without overt diabetes has also been noted by us in SW female mice (Garcia et al 2001).…”

Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice

“…Domperidone (Barone, 1999;Drolet et al, 2000) and tegaserod are both used therapeutically as prokinetic agents, although domperidone is often thought to be more effective on the proximal gut (Longo and Vernava, 1993;Jost, 1997) and so has been used to relieve the symptoms of dyspepsia and gastroparesis (Horowitz and Fraser, 1995;Tonini et al, 2004), whereas tegaserod is used to treat chronic constipation and constipation-predominant irritable bowel syndrome (Prather et al, 2000;Muller-Lissner et al, 2001;Johanson, 2004;Galligan and Vanner, 2005). Domperidone and DA, however, have both been shown to exert effects on the colon and rectum as well as on the upper bowel (Wiley and Owyang, 1987), whereas tegaserod accelerates gastric emptying (Degen et al, 2001;James et al, 2004;Crowell et al, 2005) and has also been useful in treating dyspepsia and gastroparesis (Banh et al, 2005;Galligan and Vanner, 2005;Zuberi et al, 2005). The acceleration by D 2 knock-out of total gastrointestinal and colonic motility suggests that D 2 receptors are important at all levels of the gut and are not restricted in their function to the proximal † † …”

Diabetes induces sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum

“…Abnormal gastrointestinal motility in diabetes mellitus is likely multifactorial in origin, reflecting disturbances in enteric and vagal neural activity as well as interstitial cells of Cajal and smooth muscle function (20,28,33,38). Of these, enteric neuropathy may be particularly important (5,6,48).…”