Satish Rattan

The internal anal sphincter IAS plays a key role in continence anddefecation. Its disorders underlie many clinical abnormalities, such asfecal incontinence and constipation. Disorders of the IAS may also beinvolved in a number of anal diseases such as hemorrhoids and analfissures. Also, since disorders of the IAS occur more frequently in theelderly, studies on IAS function are of particular importance in this agegroup. The objectives of the present research proposal are toinvestigate: 1 the nature of inhibitory neurotransmitters and mediatorsresponsible for IAS relaxation in response to the rectoanal inhibitoryreflex; 2 the neural pathways in the rectoanal inhibitory reflex androle of regulatory peptides and other neurohumoral substances on IASfunction; and 3 the cellular bases underlying myogenic tone in the IAS. Studies are planned in vivo and in vitro in which the activity of the IASwill be isolated from that of the external anal sphincter EAS bysimultaneous electrical and mechanical recordings. Studies will beperformed to examine the structure-activity-relationship, receptorbinding, second messengers, immunocytochemical localization ofphysiologically relevant neuropeptides, radioimmunoassay RIA ofneuropeptides, the direct release of mediators, membrane potentialchanges using intracellular electrical recordings, changes in the freeintracellular Ca2, PI turnover and protein kinase C While these studieswill yield a diverse spectrum of information, they will be specificallyaimed at elucidating various aspects of the objectives mentioned above: inhibitory neurotransmitters, neurohumoral factors and neural pathways, and the cellular bases of myogenic tone. These studies will be performed in opossums, but other animal specieswill also be used to determine species differences in the control of thesphincter. Some studies are planned in awake animals to understand thenormal physiology of the IAS. It is envisaged that the proposed studiesprovide important information on the physiology and pharmacology of theIASleading to a better understanding of the pathophysiology and in turnthe treatment, of anorectal disorders.