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

AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide(HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous(sc)], zinc protoporphyrin IX [Zn PPIX, 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), Zn PPIX(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 withor without atropine(3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine(L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTS Administration 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 Zn PPIX or hemin alone had no effect on this gastrointestinal motility parameter, Zn PPIX 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 Zn PPIX 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 Zn PPIX and atropine(3 μmol/L) abolished the Zn PPIX-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 ZnP PIX, the ZnP PIX-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 EFSinduced and ACh-induced contractile response.CONCLUSION Taken together, findings from in vivo and in vitro studies suggest that the HO/CO pathway is involved in the constipating effects of granisetron.

A Mathematical Model of Renal Blood Distribution Coupling TGF,MR and Tubular System

Objective：To investigate the relationship between renal blood distribution and the physiological activities of the kidney. Methods：A mathematical model is developed based on response （MR） Hagan-Poiseuille law and mass transport, coupling mechanics of myogenic tubuloglomerular feedback （TGF） and the tubular system in the renal medulla. The model parameters, including the permeability coefficients, the vascular lumen radius and the solute concentration at the inlet of the tubes, are derived from the experimental results. Simulations of the blood and water flow in the loop of Henel, the collecting duct and vas rectum, are carried out by the model of the tubular system in the renal medulla, based on conservations of water and solutes for transmural transport. Then the tubular model is coupled with MR and TGF mechanics. Results：The results predict the dynamics of renal autoregulation on its blood pressure and flow, and the distributions are 88.5% in the cortex, 10.3% in the medulla, and 1.2% at papilla,respectively. The fluid flow and solute concentrations along the tubules and vasa recta are obtained. Conclusion ：The present model could assess renal functions qualitatively and quantitatively and provide a methodological approach for clinical research.