| dc.description.abstract | The endocrine renin-angiotensin system (RAS) is important in the regulation of extracellular fluid volume and systemic blood pressure in strenuous conditions such as hypovolemia. Also present locally in peripheral tissues, all components of RAS are expressed and have been shown to modulate development, cell growth and inflammation. Since the two main receptor subtypes to angiotensin II (AngII) commonly exert counteracting influences their relative expression determines RAS function. The present thesis focuses on AngII influences on mucosal and smooth-muscle function in the small intestine and in particular the angiotensin II type 2 receptor (AT2R) and its postulated post-receptor mediators bradykinin and nitric oxide (NO).To confirm AT1R and AT2R gene transcript and protein expressions, PCR and Western blot were used respectively. Mucosal function in vivo was represented by duodenal mucosal alkaline secretion in adult Sprague-Dawley rats assessed by pH-stat titration, and by mucosal nitric oxide release in jejunum of young landrace pigs assessed by tonometry and chemiluminescense. Smooth-muscle contractility (isometric tension in an organ bath system) was studied in longitudinal preparations of rat and human small-intestine tissue.The receptor-expression analyses demonstrated presence of AT1R and AT2R along the small intestine in rats, pigs and humans. AT2R was not detected in human smooth-muscle preparations. The selective AT2R-agonist CGP42112A at the dose 0.1 microg kg-1 min-1 i.v. stimulated rat duodenal alkaline secretion, a response which was sensitive to the selective bradykinin type 2 receptor antagonist HOE140, indicating mediation by bradykinin receptor type 2 (BK2). Immunohistochemisrtry showed that BK2 receptors were located to duodenal crypt epithelium. The level of AT2R expression varied together with duodenal alkaline secretory responses to CGP42112A. The AT2R-agonist also stimulated NO release from porcine jejunal mucosa, an action which was sensitive to the selective AT2R-antagonist PD123319. In small-intestine smooth-muscle preparations contractile action by AngII was mediated by AT1R in rats and humans. In rat ileum blockade of AT2R, using PD123319, ameliorated AngII-induced contractions indicating a AT2R-mediated relaxatory action. This was not observed in human preparations which also lacked AT2R expression.To summarise, the results demonstate that AT2R influences mucosal and smooth-muscle function in normal small-intestine. The functional significance on an integrated level remains to be elucidated in further detail. It is known that AT1R induces depression of mucosaprotective functions in strenouos circulatory conditions. A function of the AT2R-induced increase in mucosal buffering capacity could be to counteract risk of autodigestive injury. NO contributes to maintenance of mucosal barrier functions. The AT2R-stimulated NO release could be a previously unknown link between RAS and barrier properties of the gastrointestinal mucosa. The emerging view on AT2R-upregulation as 'tissue-preserving' gives new opportunities for treatment in pathological conditions such as inflammation, tumorogenesis and ischemia/reperfusion. | en |
