Adrenoceptors and regulation of intestinal tone in the isolated colon of the mouse.

ABSTRACT

Adrenaline, noradrenaline, phenylephrine, dopamine, clonidine and apomorphine at low concentrations (from 10(-9) M to 10(-6) M) contracted the longitudinal muscle of the isolated distal colon of the mouse. Phentolamine, tetrodotoxin and indomethacin antagonized these contractile responses. Yohimbine antagonized them at lower concentrations than prazosin. Dopamine and clonidine had the same contractile activity on preparations from mice pretreated with 6-hydroxydopamine (6-OHDA). Isoprenaline (10(-9) to 3 X 10(-7) M) induced relaxations of the colon which were antagonized by propranolol. At higher concentrations, adrenaline and noradrenaline (from 3 X 10(-7) M), dopamine (from 3 X 10(-5) M), phenylephrine (from 3 X 10(-6) M) and apomorphine (from 10(-4) M) relaxed the colon. Clonidine (10(-6) to 3 X 10(-5) M) inhibited the spontaneous activity of the colon but never induced relaxations. At 10(-4) and 10(-3) M clonidine elicited contractions. Prazosin antagonized the inhibitory effect of phenylephrine and clonidine, a mixture of propranolol and prazosin antagonized the relaxations to adrenaline, noradrenaline and dopamine and unmasked contractions that were sensitive to yohimbine and tetrodotoxin. The relaxations induced by apomorphine and the contractions induced by clonidine (greater than 10(-6) M) were resistant to all these antagonists. Electrical field stimulation (1 ms, 2 Hz, 2-20 V) of the mouse colon induced contractile responses which increased with the frequency of the stimulus. After cessation of stimulation at 4 Hz a rebound contraction was generally observed, followed by a progressive decline in tone. In the presence of atropine, the contractile response to field stimulation was abolished and transformed into a rapid and sustained relaxation. A rebound contraction was always observed after cessation of stimulation. The responses to electrical stimulation (in the presence or absence of atropine) were abolished by tetrodotoxin. The rebound contractions were abolished by indomethacin. The relaxations induced in the presence of atropine were not modified by phentolamine, propranolol, guanethidine, methysergide, mepyramine, cimetidine or naloxone. Tetrodotoxin (from 3 X 10(-8) M) caused a sustained contraction of the colon with increased spontaneous activity. This contraction was not modified by atropine, phentolamine, propranolol, guanethidine, methysergide, mepyramine, cimetidine, naloxone, but was abolished by preincubation of the preparation with indomethacin. These results indicate that, at low concentrations, various sympathomimetics contracted the mouse distal colon by stimulating alpha 2 presynaptic adrenoceptors. The responses appeared provided intramural prostaglandin synthesis was unaffected. Higher concentrations of sympathomimetics induced relaxations by stimulation of postjunctional alpha 1- and beta-adrenoceptors. Electrical field stimulation of the mouse colon produced cholinergically mediated contractions or, in the presence of atropine, non-adrenergic non-cholinergic (NANC) relaxations followed by rebound contractions, provided prostaglandin synthesis was unaffected. 6 These data suggest that in the mouse isolated colon, muscle tone and contractility are regulated by 2 opposing mechanisms (1) a neurogenic cholinergic activity and a local prostaglandin synthesis leading to an increase in muscle tone; (2) a neurogenic NANC inhibitory control the nature of which remains to be elucidated. alpha 2-Presynaptic receptors, when activated inhibit the neurogenic inhibitory control and liberate the mechanism by which muscle tone is increased, causing a contraction.