Abstract
Distension of the small intestine can play a role in the pathogenesis of various functional intestinal disorders. This study determined the role of vasoactive intestinal polypeptide (VIP) in the adaptative response of intestinal smooth muscle to acute and chronic distension of the ileum in vivo. Several in vitroexperiments were performed to identify the mechanism of receptor regulation. Distension was applied by a balloon inflated with air in the ileum either during a single episode in anesthetized or repeatedly in conscious guinea pigs. Then, muscle cells were isolated by enzymatic digestion from the distended and nondistended adjacent ileal segments. In addition, in vitro experiments were performed on freshly dispersed cells for determination of mechanisms. Control cells maximally relaxed (Cmax) at 1 μM VIP (EC50 = 50 pM) and 100 μM isoproterenol (EC50 = 7 nM). Both acute and chronic distensions triggered a right-ward shift of the concentration-response curves for VIP (Cmax = 100 μM, EC50 = 10 nM). A desensitization of the relaxing effect of VIP receptors was also observed when cells were preincubated for 30 minin vitro with VIP. By contrast, the relaxing effect of isoproterenol was affected neither by in vivo distension nor by in vitro incubation with isoproterenol. Desensitization of VIP receptors was prevented by in vitro incubation of cells with VIP plus a VIP antagonist [(d-P-Cl-Phe6,Leu17)VIP] and by intraluminal perfusion of the VIP antagonist during acute distentionin vivo. Moreover, desensitization of VIP receptors did not occur after 30 min preincubation with either forskolin or 8-Bromo-cyclic AMP. These results indicate that mechanical distension of the ileum induces a homologous desensitization of VIP receptors on circular smooth muscle cells, which requires the occupation of its receptors by VIP.
Footnotes
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Send reprint requests to: Dr. M. Delvaux, Department of Pharmacology, INRA, BP 3, F-31931 TOULOUSE Cedex, France.
- Abbreviations:
- cAMP
- adenosine 3′,5′-cyclic monophosphate
- cGMP
- guanosine 3′,5′-cyclic monophosphate
- CCK
- cholecystokinin
- CCK8
- sulfated C-terminal octapeptide of CCK
- Cmax
- concentration of agonist inducing a maximal effect, EC50, effective concentration inducing a half-maximal effect
- IBS
- irritable bowel syndrome
- NANC
- nonadrenergic noncholinergic
- PAF
- platelet-activating factor
- VIP
- vasoactive intestinal polypeptide
- Received October 20, 1997.
- Accepted June 15, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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