Effects of KW-5617 (Zaldaride Maleate), a Potent and Selective Calmodulin Inhibitor, on Secretory Diarrhea and on Gastrointestinal Propulsion in Rats

Aikawa, Nobuo; Karasawa, Akira

doi:10.1254/jjp.76.199

Cited by 17 publications

(4 citation statements)

References 20 publications

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“…Loperamide inhibited diarrhea caused by various agents and also the stool output stimulated by WRS in the present study, as previously reported (24,25). In our study, effective doses of loperamide were very variable with a 100 times difference between the different diarrhea models.…”

Section: Discussionsupporting

confidence: 90%

Laxative and Anti-diarrheal Activity of Polycarbophil in Mice and Rats

Saito

Mizutani

Iwanaga

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the laxative and anti-diarrheal activity of polycarbophil, an insoluble hydrophilic polymer, in comparison with other agents used for treating functional bowel disorder (FBD). In naive rats, polycarbophil (500 mg /kg) increased fecal weight and water contents without producing diarrhea. Carboxymethylcellulose (CMC) did not produce evident changes in bowel movement. Picosulfate markedly produced diarrhea. Loperamide, trimebutine and granisetron decreased stool output dose-dependently. Constipation, indicated by decrease in fecal weight, was produced by loperamide and clonidine in rats. Polycarbophil (500 mg /kg) and CMC increased fecal weight without diarrhea. Conversely trimebutine further decreased fecal weight in constipated rats. Polycarbophil (500 mg /kg) suppressed diarrhea induced by castor oil, and at 250 -500 mg /kg, it produced shaped stools in animals with stools loosened by prostaglandin E2, serotonin or carbachol in mice. Polycarbophil (500 mg /kg) also reduced stools in rats with stool output increased by wrap restraint stress (WRS). CMC had no effect in the diarrhea models, except for carbachol-induced diarrhea, and WRS-induced evacuation. Loperamide, trimebutine and granisetron inhibited diarrhea production and WRS-induced evacuation, except for carbachol-induced diarrhea. The results show that polycarbophil prevents constipation and diarrhea without inducing diarrhea or constipation, which is different from the other agents. Hydrophilic polymers such as polycarbophil will be promising agents for the treatment of FBD.

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Section: Discussionsupporting

confidence: 90%

Laxative and Anti-diarrheal Activity of Polycarbophil in Mice and Rats

Saito

Mizutani

Iwanaga

et al. 2002

Japanese Journal of Pharmacology

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“…While intestinal or hepatic lipid accumulation has not been explored in cholera, host MsrA and its interaction with luminal MetO may play a role in the osmotic diarrhea of this disease. Calmodulin is a well-established facilitator of secretory diarrhea, and calmodulin antagonists have been developed as anti-diarrheal treatments [43, 44]. This is true, in particular, for cholera, whose secretory diarrhea depends on the CFTR chloride and SK potassium channels, both of which are calmodulin-dependent [45, 46].…”

Section: Discussionmentioning

confidence: 99%

Vibrio cholerae ensures function of host proteins required for virulence through consumption of luminal methionine sulfoxide

et al. 2017

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Vibrio cholerae is a diarrheal pathogen that induces accumulation of lipid droplets in enterocytes, leading to lethal infection of the model host Drosophila melanogaster. Through untargeted lipidomics, we provide evidence that this process is the product of a host phospholipid degradation cascade that induces lipid droplet coalescence in enterocytes. This infection-induced cascade is inhibited by mutation of the V. cholerae glycine cleavage system due to intestinal accumulation of methionine sulfoxide (MetO), and both dietary supplementation with MetO and enterocyte knock-down of host methionine sulfoxide reductase A (MsrA) yield increased resistance to infection. MsrA converts both free and protein-associated MetO to methionine. These findings support a model in which dietary MetO competitively inhibits repair of host proteins by MsrA. Bacterial virulence strategies depend on functional host proteins. We propose a novel virulence paradigm in which an intestinal pathogen ensures the repair of host proteins essential for pathogenesis through consumption of dietary MetO.

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“…Indeed, NOS1-deficient mice have been shown to have reduced gastric emptying (31). In contrast, the major action of loperamide is to reduce intestinal transit, rather than gastric emptying (32,33). Nevertheless, although loperamide is primarily an agonist of -opioid receptors, it can also block Ca 2ϩ channels and inhibit calmodulin-mediated effects in neurons (28).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

Zhou

Singer

2006

The Journal of Immunology

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NO produced by inducible NO synthase (NOS2) is important for the control of numerous infections. In vitro, NO inhibits replication and differentiation of the intestinal protozoan parasite Giardia lamblia. However, the role of NO against this parasite has not been tested in vivo. IL-6-deficient mice fail to control Giardia infections, and these mice have reduced levels of NOS2 mRNA in the small intestine after infection compared with wild-type mice. However, NOS2 gene-targeted mice and wild-type mice treated with the NOS2 inhibitor N-iminoethyl-l-lysine eliminated parasites as well as control mice. In contrast, neuronal NOS (NOS1)-deficient mice and wild-type mice treated with the nonspecific NOS inhibitor NG-nitro-l-arginine methyl ester and the NOS1-specific inhibitor 7-nitroindazole all had delayed parasite clearance. Finally, Giardia infection increased gastrointestinal motility in wild-type mice, but not in SCID mice. Furthermore, treatment of wild-type mice with NG-nitro-l-arginine methyl ester or loperamide prevented both the increased motility and the elimination of parasites. Together, these data show that NOS1, but not NOS2, is necessary for clearance of Giardia infection. They also suggest that increased gastrointestinal motility contributes to elimination of the parasite and may also contribute to parasite-induced diarrhea. Importantly, this is the first example of NOS1 being involved in the elimination of an infection.

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Effects of KW-5617 (Zaldaride Maleate), a Potent and Selective Calmodulin Inhibitor, on Secretory Diarrhea and on Gastrointestinal Propulsion in Rats

Cited by 17 publications

References 20 publications

Laxative and Anti-diarrheal Activity of Polycarbophil in Mice and Rats

Laxative and Anti-diarrheal Activity of Polycarbophil in Mice and Rats

Vibrio cholerae ensures function of host proteins required for virulence through consumption of luminal methionine sulfoxide

Neuronal Nitric Oxide Synthase Is Necessary for Elimination of Giardia lamblia Infections in Mice

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