Role of Different Beta-Receptor Subtypes in Control of Contractile Activity in Rat Jejunal Circular Muscle
Brigitte Goetz*1,2, Bernhard Stoklas1,2, Petra Benhaqi1,2, Mario H. Mueller1,2, Martin E. Kreis1,2, Michael S. Kasparek1,2
1Department of Surgery, Ludwig-Maximilians-University Munich, Munich, Germany; 2Walter Brendel Centre of Experimental Medicine, LMU Munich, Munich, Germany
Background
Beta-receptors participate in control of gastrointestinal contractile activity and might be involved in pathophysiology of motility disorders such as postoperative ileus. Our aim was to determine the mechanisms of action of three beta-receptor subtypes in rat jejunal circular muscle.
Methods
Muscle strips (n=8 per rat) were obtained from 6 naïve, male Sprague Dawley rats and studied in organ chambers. Dose-responses to exogenous beta-1- (β1a; xamoterol; 10-8-3x10-6M), beta-2- (β2a; fenoterol; 3x10-9-10-6M), and beta-3-agonists (β3a; BRL37344; 10-10-3x10-8M) were studied without and with precontraction with bethanechol (3x10-6M), tetrodotoxin (TTX; blocking enteric nervous system; 10-6M), or propranolol (non-selective β-antagonist; 5x10-6M). Responses to bethanechol (3x10-6M) were studied without and with β1a (10-6M), β2a (3x10-6M), β3a (10-8M), TTX, or propranolol. Electrical field stimulation (EFS; 30Hz) was applied to release neurotransmitters from enteric nerves. Dominant inhibitory effects of endogenously released nitric oxide were blocked with l-nitro-l-arginine (L-NNA; 10-4M) and the effect of β-agonists on EFS responses were studied without and with propranolol or atropine (10-7M). Data is mean±SEM change of baseline contractile activity [%] (negative value: inhibition).
Results
Beta-agonists caused a dose-dependent inhibition of spontaneous and stimulated contractile activity (all p<0.01; ANOVA) independent of precontraction and blockade of the enteric nervous system by TTX (NS; ANOVA). Propranolol prevented this inhibition in large part (responses at maximum concentration of β-agonist: β1a: -60±2 vs. -23±5% (with propranolol); β2a: -97±1% vs. -27±12%; β3a: -80±5 vs. -13±14%; all p<0.05; ANOVA). β1a increased bethanechol-induced excitation more than 3-fold (1073±891 vs. 3919±891%; p<0.05; ANOVA) while β2a, β3a, TTX, and propranolol had no effect on bethanechol-induced excitation (NS; ANOVA). EFS with L-NNA caused excitation (263±124%; p<0.02; ANOVA) that was increased in presence of β2a (705±241%; 10-7M; p<0.05; ANOVA). This effect of β2a was prevented by propranolol and atropine (293±156% and 65±29%, respectively; both p<0.05 vs. with β2a). β1a and β3a had no effect on EFS responses.
Conclusion
In jejunal circular muscle of naïve rats spontaneous and stimulated contractile activity can be inhibited via beta-1, 2, and 3-adrenergic mechanisms. This inhibition is mediated by effects on receptors located on the smooth muscle and not on the enteric nervous system. Activation of beta-1 receptors increases the response to exogenous bethanechol while the endogenous release of acetylcholine can be increased by beta-2-adrenergic mechanisms. These potentially pro-contractile effects might be mediated by presynaptic beta-1 and 2 receptors on the enteric nervous system and need further investigations. DFG KA 2329/5-1
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