Increased smooth muscle contractility of intestine in the genetic null of the endothelin ETB receptor: a rat model for long segment Hirschsprung's disease.
OBJECTIVE
The endothelin ETB receptor null rat (ETB(-/-)R) has an intestinal segment without ganglia, and this rat is characterised by intestinal obstruction similar to that observed in human Hirschsprung's disease. In the present study, we have examined the myogenic mechanism responsible for obstruction in the ETB(-/-)R.


RESULTS
The ETB(-/-)R had an enlarged belly and the average lifespan was 18.1 days. The bowel from the rectum to the lower part of the small ileum was constricted whereas the upper region was dilated with faecal stasis and thus presented as megaileum. The constricted muscle segments without ganglia had a greater increase in absolute force when stimulated by carbachol, high K+, and endothelin-1 compared with that of normal siblings. In contrast, in the dilated part with ganglia, the absolute contractile force due to these stimulants in the ETB(-/-)R was not different from that in the ETB(+/+)R. Such a functional hypertrophy of the musculature was observed in parts of the colon, caecum, and distal ileum without ganglia but not in the part of the proximal ileum and jejunum with ganglia. Morphological study demonstrated that the thickness of the circular and longitudinal muscle layers was greater in the constricted part of the intestine in the ETB(-/-)R, and these changes were associated with an increase in the number of smooth muscle cells.


CONCLUSIONS
Our findings suggest that both increased contractility of smooth muscle and increased thickness of the intestinal muscular wall may contribute to the intestinal obstruction in the ETB(-/-)R.
Won
K-J
KJ
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Yayoi 1-1-1, Tokyo 113-8657, Japan.
Torihashi
S
S
Mitsui-Saito
M
M
Hori
M
M
Sato
K
K
Suzuki
T
T
Ozaki
H
H
Karaki
H
H
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007422:Intestines / Q000473:pathology / Q000503:physiopathology*; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009130:Muscle, Smooth / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011922:Rats, Mutant Strains; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics* / Q000502:physiology
D018679:Cholinergic Agonists; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D002217:Carbachol