Adenosine A2A agonist and A2B antagonist mediate an inhibition of inflammation-induced contractile disturbance of a rat gastrointestinal preparation

Abstract

Adenosine can show anti-inflammatory as well as pro-inflammatory activities. The contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. In this study, we examined the effect of the adenosine A 2A receptor agonist CGS 21680 and the A 2B R antagonist PSB-1115 on acute inflammation induced experimentally by 2,4,6-trinitrobenzenesulfonic acid (TNBS) on rat ileum/jejunum preparations. Preincubation of the ileum/jejunum segments with TNBS for 30 min resulted in a concentration-dependent inhibition of acetylcholine (ACh)-induced contractions. Pharmacological activation of the A 2A R with CGS 21680 (0.1-10 µM) preincubated simultaneously with TNBS (10 mM) prevented concentration-dependently the TNBS-induced inhibition of the ACh contractions. Stimulation of A 2B R with the selective agonist BAY 60-6583 (10 µM) did neither result in an increase nor in a further decrease of ACh-induced contractions compared to the TNBS-induced inhibition. The simultaneous pre-incubation of the ileum/jejunum segments with TNBS (10 mM) and the selective A 2B R antagonist PSB-1115 (100 µM) inhibited the contractiondecreasing effect of TNBS. The effects of the A 2A R agonist and the A 2B R antagonist were in the same range as the effect induced by 1 µM methotrexate. The combination of the A 2A R agonist CGS 21680 and the A 2B R antagonist PSB-1115 at subthreshold concentrations of both agents found a significant amelioration of the TNBS-diminished contractility. Our results demonstrate that the activation of A 2A receptors or the blockade of the A 2B receptors can prevent the inflammation-induced disturbance of the AChinduced contraction in TNBS pre-treated small intestinal preparations. The combination of both may be useful for the treatment of inflammatory bowel diseases.

Adenosine Receptors: New Targets to Protect Against Tissue Damage in Inflammatory Bowel Symptoms

“…As shown previously T N B S ( 1 m M -1 M ) r e s u l t e d i n a concentration-dependent inhibition of ACh-induced contractions (damage) with an IC 50 value of 63 mM. 100 mM TNBS reduced the ACh-induced contraction to approximately 35 % in comparison to intact preparation of the same animal (Michael et al, 2010). The combined preincubation of the ileum/jejunum preparation with TNBS (0.01 M, 30 min) and STW 5 (64-512 µg/ml) or STW 6 in equivalent concentrations (3-24.1 µg/ml) diminished concentration-dependently the TNBS-induced damage of the AChcontraction.…”

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

“…The inhibition of adenosine kinase by GP515 has been explored as a potential target for the treatment of colitis [621]. In a review about purinergic receptors in gastrointestinal inflammation [403], it was concluded that P1 (A 2A and A 2B ) and P2Y receptor-based therapy is highly promising for the treatment of inflammatory conditions of the gut, as well as for fibrotic liver diseases (see [477]). Serum adenosine deaminase activity has been claimed to be a predictor of disease severity in ulcerative colitis [55].…”

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

“…Preclinical studies indicated a potential of A 2B agonists for the treatment of atherosclerosis and hyperlipidemia [30]. A 2B antagonists may be useful for the treatment of asthma, diabetes, pain, and inflammatory diseases in general, although the A 2B AR has been reported to promote pro-as well as antiinflammatory effects [6,[31][32][33]. Furthermore, A 2B antagonists were proposed for the treatment of cancer and the prevention of metastasis [34,35].…”