Studies on mechanisms for beta-adrenoceptor mediated inhibition of colon motility.

Radioligand binding studies show that both beta 1- and beta 2-adrenoceptors were present in the colon wall, but with a considerably higher concentration of the beta 2-subtype than of the beta 1-subtype. The effect of selective beta-adrenoceptor agonists on isometric force recordings of spontaneous contractile activity and electrically integrated activity were determined in isolated proximal cat and rat colon strips. The use of selective beta-adrenoceptor blocking agents revealed both beta 1- and beta 2-adrenoceptor inhibitory interaction by the beta-agonists employed. Comparison of qualitative effects of the selective beta-adrenoceptor agonists led to the hypothesis that the beta 1- and beta 2-adrenoceptors were separated on two functional levels within the colon organ. This hypothesis was confirmed by the reduced maximal inhibitory response of the partial beta-adrenoceptor agonist, prenalterol, induced by tetrodotoxin. Further confirmation was found in the decrease in affinity after tetrodotoxin treatment of the beta-adrenoceptor antagonist, metoprolol. Pretreatment with 6-hydroxy-dopamine induced an upregulation of the beta 1-adrenoceptor density but a decrease in the total efficacy of prenalterol. This may additionally indicate a beta 1-adrenoceptor-mediated effect of endogenously released noradrenaline and the requirement of sympathetic nerves for part of the beta-adrenoceptor mediated effect. Atropine and physostigmine influenced the basal contractile activity in a way suggesting that endogenous cholinergic tone existed in the isolated colon preparation. Furthermore, atropine shifted the concentration-effect curves for isoprenaline and terbutaline in a way suggesting that this tonus exerts functional antagonism for the beta-adrenoceptor stimulation. The efficacy of prenalterol was increased by atropine and was markedly reduced by extremely low concentrations of carbachol and bethanechol. This reveals that functional antagonism may be exerted at more than one effector level in the colon wall. Furthermore, it indicates that the nerves responsible for the propagation of the inhibitory effect to beta-adrenoceptor stimulation in the nervous plexa are not of the cholinergic type. It is concluded that the beta 1-adrenoceptor mediates the inhibitory sympathetic effect mainly in nervous plexa of the colon, whereas the beta 2-adrenoceptor mediates this effect at the smooth muscle cells.