Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Abstract

AIMTo investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.METHODSFor in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [ZnPPIX, 50 μg/kg/intraperitoneal (ip)] and hemin (50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation (EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine (ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron (3 μmol/L, 15 min), ZnPPIX (10 μmol/L, 60 min) or CO-releasing molecule-3 (CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment with or without atropine (3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine (L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTSAdministration of granisetron (50, 75 μg/kg) in vivo significantly increased the time to first defecation (P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of ZnPPIX or hemin alone had no effect on this gastrointestinal motility parameter, ZnPPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone (3 μmol/L) did not significantly modify the colon’s contractile response to either EFS or ACh. Incubation with ZnPPIX alone (10 μmol/L) significantly reduced the colon’s contractile response to EFS (P = 0.016) but had no effect on contractile response to ACh. Co-administration of ZnPPIX and atropine (3 μmol/L) abolished the ZnPPIX-mediated decrease in contractile response to EFS. Conversely, incubation with CORM-3 (400 μmol/L) alone increased both the contractile response to EFS at 10 Hz (10 Hz: 71.02 ± 19.16 vs 116.25 ± 53.70, P = 0.01) and the contractile response to ACh (100 μmol/L) (P = 0.012). Co-administration of atropine abolished the CORM-3-mediated effects on the EFS-mediated response. When granisetron was co-incubated in vitro with ZnPPIX, the ZnPPIX-mediated decrease in colon contractile response to EFS was lost. On the other hand, co-incubation of granisetron and CORM-3 (400 μmol/L) further increased the colon’s contractile response to EFS (at 5 Hz: P = 0.007; at 10 Hz: P = 0.001) and to ACh (ACh 10 μmol/L: P = 0.001; ACh 100 μmol/L: P = 0.001) elicited by CORM-3 alone. L-NNA co-administered with granisetron and CORM-3 abolished the potentiating effect of CORM-3 on granisetron on both the EFS-induced and ACh-induced contractile response.CONCLUSIONTaken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.

Effect of fecal microbiota transplantation in patients with slow transit constipation and the relative mechanisms based on the protein digestion and absorption pathway

“…It has been elaborated that nitric oxide(NO) plays an important role in relaxation of the smooth muscle in the gastrointestinal tract and the reduced production of NO may be an important contributing factor to gastrointestinal motility dysfunction [40]. L-Arginine and nitric oxide synthases (NOS) can synthesize NO to relieve symptoms of constipation [41][42][43]. L-Threonine is involved in the metabolism of vitamin B6, which is involved in the formation of the neurotransmitter serotonin (5-HT) [39].…”

Preclinical Studies to Evaluate the Gut Stimulatory Activity of Aloe Musabbar

“…e preparation was allowed to equilibrate for 45 minutes under 1 g tension. e concentration-dependent responses of A. musabbar extract as well as acetylcholine was recorded in the absence and presence of atropine sulphate (1 ng/ml) using a 4-channel polyriter (Recorders and Medicare systems (P) Ltd. Ambala) [15]. e dose-response curve (DRC) of acetylcholine (Ach) was tested at concentrations 1 μg/ml to 1 mg/mL.…”

Gut Stimulatory Effect of Terminalia chebula in Experimental Animal Models

“…After sacrificing the animals by cervical dislocation under light ether anaesthesia, the abdomen was open and the colon was removed and mounted in the organ bath perfused under modified Ringerʼs solution. The concentration-dependent responses of Terminalia extract, as well as acetylcholine, were recorded in the absence and presence of Atropine sulphate (1 ng mLG 1 ) using 4 channels Polyrite (Recorders and Medicare systems (P) Ltd. Ambala) 14 .…”