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Background and Purpose: β(3) -Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β(3) -adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats.Experimental Approach: PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl(4) -treated cirrhotic rats before and during infusion of the selective β(3) -adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed.Key Results: At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β(3) -adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β(3) -adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats.Conclusions and Implications: β(3) -Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target. [ABSTRACT FROM AUTHOR]

β3-Adrenoceptor agonists protect against experimental gastric ulcers. We investigated the effects of the β3-adrenoceptor agonist SR58611A on 2,4-dinitrobenzene sulphonic acid-induced colitis in rats and analysed the expression of β3-adrenoceptors in the colonic wall. SR58611A was administered orally (1–10 mg kg−1) for 7 days, starting the day before induction of colitis. Colitis was assessed by macroscopic and histological scores, tissue myeloperoxidase activity, interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) levels. Reverse transcription-polymerase chain reaction and immunohistochemical analysis were used to examine the expression of β3-adrenoceptors. SR58611A significantly reduced the severity of colitis as well as the tissue levels of TNF-α, IL-1β and IL-6. Colitis was associated with a decreased expression of β3-adrenoceptor mRNA in the mucosal/submucosal layer of distal colon and this reduction was not affected by SR58611A. Immunohistochemical analysis revealed β3-adrenoceptors within the muscularis externa, in myenteric neurons and nerve fibres and in the submucosa. β3-Adrenoceptor immunoreactivity was decreased in inflamed tissues compared to controls, particularly in the myenteric plexus; this reduction was counteracted by SR58611A. Amelioration of experimental colitis by the selective β3-adrenoceptor agonist SR58611A suggests that β3-adrenoceptors may represent a therapeutic target in gut inflammation. [ABSTRACT FROM AUTHOR]

Background Mediators released in the mucosal milieu have been suggested to be involved in visceral hypersensitivity and abdominal pain in patients with irritable bowel syndrome (IBS). However, their impact on myenteric neurons remains unsettled. Methods Mucosal biopsies were obtained from the descending colon of patients with IBS and controls. Mucosal mast cells were identified immunohistochemically. The impact of spontaneously released mucosal mediators on guinea pig electrically stimulated longitudinal muscle myenteric plexus (LMMP) preparations was assessed in vitro by means of selective receptor antagonists and inhibitors. Key Results Patients with IBS showed an increased mast cell count compared with controls. Application of mucosal mediators of IBS to LMMPs potentiated cholinergic twitch contractions, an effect directly correlated with mast cell counts. Enhanced contractions were inhibited by 50.3% with the prostaglandin D2 antagonist BW A868C, by 31.3% and 39% with the TRPV1 antagonists capsazepine and HC-030031, respectively, and by 60.5% with purinergic P2X antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid. Conversely, the serotonin1-4, histamine1-3, tachykinin1-3 receptor blockade, and serine protease inhibition had no significant effect. Conclusions & Inferences Colonic mucosal mediators from patients with IBS excite myenteric cholinergic motor neurons. These effects were correlated with mast cell counts and mediated by activation of prostanoid receptors, TRPV1, and P2X receptors. These results support the role of mucosal inflammatory mediators and mast cell activation in altered motor function of IBS. [ABSTRACT FROM AUTHOR]

Acute colonic pseudo-obstruction (Ogilvie’s syndrome) can be defined as a clinical condition with symptoms, signs and radiological appearance of acute large bowel obstruction unrelated to any mechanical cause. Recent reports of the efficacy of cholinesterase inhibitors in relieving acute colonic pseudo-obstruction have fuelled interest in the pharmacological treatment of this condition. The aim of the present review is to outline current perspectives in the pharmacological treatment of patients with acute colonic pseudo-obstruction. The best documented pharmacological treatment of Ogilvie’s syndrome is intravenous neostigmine (2–2.5 mg), which leads to quick decompression in a significant proportion of patients after a single infusion. However, the search for new colokinetic agents for the treatment of lower gut motor disorders has made available a number of drugs that may also be therapeutic options for Ogilvie’s syndrome. Among these agents, the potential of 5-hydroxytryptamine-4 receptor agonists and motilin receptor agonists is discussed. [ABSTRACT FROM AUTHOR]