Submitted on October 11, 2006
Accepted on May 2, 2007
Roles of muscarinic receptor subtypes in small intestinal motor dysfunction in acute radiation enteritis
Claudine L Frisby1, Robert J Fraser2, Murray B Schirmer3, Eric K Yeoh3, and L. Ashley Blackshaw4*
1 Nerve Gut Reserach Laboratory, Royal Adelaide Hospital, Adelaide, South Australia, Australia
2 Gastroenterology, Repatriation General Hospital, Adelaide, South Australia, Australia
3 Department of RAdiation Oncology, Royal Adelaide Hopsital, Adelaide, South Australia, Australia
4 NerveGut Research Laboratory, Royal Adelaide Hospital, Level 1 Hanson Centre, Adelaide SA 5000, Australia; Nerve Gut Research Laboratory, Royal Adelaide Hospital, Adelaide SA 5000, Australia
* To whom correspondence should be addressed. E-mail: ablacksh{at}mail.rah.sa.gov.au.
Administration of abdominal radiotherapy results in small intestinal motor dysfunction. We have developed a rat radiation enteritis model which, after exposure in vivo, shows high amplitude, long duration pressure waves (HALDs) in ex vivo ileal segments. These resemble in vivo dysmotility where giant contractions migrate both antegradely and retrogradely. Mediation of these motor patterns is unclear although enteric neural components are implicated. After induction of acute radiation enteritis in vivo, ileal segments were isolated and arterially perfused. Tetrodotoxin, hexamethonium, atropine or the selective muscarinic antagonists pirenzepine (M1), methoctramine (M2) and 4-DAMP (M3) were added to the perfusate. The baseline mean rate/minute/channel (/min/ch) of HALDs was 0.35±0.047. This was significantly reduced by TTX (83.3%, p<0.01), hexamethonium (90.3%, p<0.03) and atropine (98.4%, p<0.01). HALD rate/min/ch was significantly reduced by pirenzepine (81.1%, p<0.03), methoctramine (96.8%, p<0.001) and 4-DAMP (93.1%, p<0.03) when compared to pre-drug baseline data. As an indicator of normal motility patterns, the frequency of low amplitude, short duration (LASD) pressure waves was also assessed. The mean rate of 5.15±0.98/min/ch was significantly increased by TTX (19%, p<0.05) but significantly reduced by pirenzepine (35.1%, p<0.02) and methoctramine (75%, p<0.0003). However, the rate of small amplitude pressure waves was not affected by hexamethonium, atropine or the M3 antagonist 4-DAMP. The data indicate a role for neuronal mechanisms and the specific involvement of cholinergic receptors in generating dysmotility in acute radiation enteritis. The effect of selective M3 receptor antagonism suggests that M3 receptors may provide specific therapeutic targets in acute radiation enteritis.
