5‐HT₄ receptor agonists enhance both cholinergic and nitrergic activities in human isolated colon circular muscle

Abstract

Previous studies have demonstrated mixed inhibitory and facilitatory effects of 5-hydroxytryptamine-4 (5-HT(4)) receptor agonists on electrical field stimulation (EFS)-induced responses in human isolated colon. Here we report three types of responses to EFS in human isolated colon circular muscle: monophasic cholinergic contraction during EFS, biphasic response (nitrergic relaxation during EFS followed by cholinergic contraction after termination of EFS) and triphasic response (cholinergic contraction followed by nitrergic relaxation during EFS and a tachykininergic contraction after EFS). The effects of two 5-HT(4) receptor agonists, prucalopride and tegaserod were then investigated on monophasic responses only. Each compound inhibited contractions during EFS in a concentration-dependent manner. In the presence of N(omega)-nitro-l-arginine methyl ester (l-NAME) however, prucalopride and tegaserod enhanced the contractions in a concentration-dependent manner. In strips where the tone was elevated with substance-P and treated with scopolamine, EFS-induced relaxations were enhanced by the two agonists. The above observed effects by the two agonists were abolished by 5-HT(4) receptor antagonist SB-204070. The two agonists did not alter the tone raised by substance-P in the presence of scopolamine and l-NAME and did not affect carbachol-induced contractions in the presence of tetrodotoxin. These results suggest that in the circular muscle of human colon, 5-HT(4) receptor agonists simultaneously facilitate the activity of neurones which release the inhibitory and excitatory neurotransmitters, nitric oxide and acetylcholine respectively.

Different stimulatory effects of methylisogermabullone on the spontaneous contractility of rat gastrointestinal segments

“…Interestingly, MIGB significantly stimulated the giant contraction (frequency and amplitude) of distal colon longitudinal and circular muscles. These findings may be meaningful in the respects of pharmacological and therapeutical property of MIGB to treat and/or prevent the functional disorder of GI motility including constipation-dominant irritable bowel syndrome, because the circular muscle of human colons is generally though of as providing the major mechanical force behind intestinal propulsion (Cellek et al, 2006), and the main physiological function of distal colons is the propulsion of luminal contents distally (Bassotti et al, 1999).…”

Cholinergic interactions between donepezil and prucalopride in human colon: potential to treat severe intestinal dysmotility

“…In the most common -chronic constipation, laxatives remain the mainstay of pharmacological intervention, although new drugs have recently been introduced. These include prucalopride, a selective 5-HT4 receptor agonist, which facilitates enteric cholinergic and nitrergic activities to promote intestinal motility (Cellek et al, 2006), and lubiprostone and linaclotide, which, respectively, activate chloride type-2 channels and guanylate cyclase type-C receptors to promote defecation primarily by increasing fluid secretion into the lumen (Lembo et al, 2011;Chey et al, 2012). Such breakthroughs have renewed interest in how best to treat other conditions associated with hypomotility and also with acute or chronic small and/or large intestinal dilation.…”

Hexane extract of Poncirus trifoliata (L.) Raf. stimulates the motility of rat distal colon

“…Among seven different types of serotoninergic receptors, the 5-HT 3 and 5-HT 4 receptors are the most thoroughly understood subtypes with the regards to physiological function and histological distribution in GI tract (Chetty et al, 2006;Cellek et al, 2006). The 5-HT 3 receptor induces a rapid depolarization of the myenteric neuron through enhancing ACh release (Kim and Camilleri, 2000;Talley, 2001), and 5-HT 4 receptor expressed in the nerve terminal facilitates the releases of neurotransmitters including ACh, substance P and vasoactive intestinal peptides (Jin et al, 1999;Talley, 2001).…”

“…doi:10.1016/j. jep.2009.11.032 propulsive GI motility for defecation in vivo, because colonic contractility is generally though of as providing the major mechanical force behind intestinal propulsion (Cellek et al, 2006;Gonzalez and Sarna, 2001). In view of functional importance of colonic motility for migrating GI contents into rectum and therapeutic use of PT to improve the defecation disorders in Korean traditional medicine, we have hypothesized that PT possibly increases the contractility of colonic smooth muscles, results in facilitating the physiological function of defecation.…”