Proinflammatory role of vasopressin through V1b receptors in hapten-induced experimental colitis in rodents: implication in IBD.
Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1b⁻(/)⁻ mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3-30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1b⁻(/)⁻ mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1b⁻(/)⁻ mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1b⁻(/)⁻ mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.
Ferrier
Laurent
L
INRA, UMR Neuro-Gastroentérologie et Nutrition, Toulouse, France.
Serradeil-Le Gal
Claudine
C
Schulte
Anke M
AM
Vasina
Valentina
V
Gaultier
Eric
E
Schroedel
Silke
S
Ursino
Maria Grazia
MG
Chaumaz
Gilles
G
Pascal
Marc
M
De Ponti
Fabrizio
F
Bueno
Lionel
L
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006241:Haptens; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017483:Receptors, Vasopressin / Q000235:genetics / Q000378:metabolism*; D013892:Thioxanthenes / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014667:Vasopressins / Q000378:metabolism / Q000494:pharmacology*; D014868:Water Deprivation; D015430:Weight Gain; D044004:Xanthones / Q000494:pharmacology
C456029:1-(5-chloro-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide; D065092:Antidiuretic Hormone Receptor Antagonists; D006241:Haptens; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D011759:Pyrrolidines; D017483:Receptors, Vasopressin; D013892:Thioxanthenes; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; D014667:Vasopressins; D014302:Trinitrobenzenesulfonic Acid; C010134:doxantrazole