The effect of immunomodulator muramyl dipeptide on serotoninergic responses of isolated neuromuscular preparations.

The mode of action of muramyl dipeptide (MDP), a compound with immunopharmacological properties, was studied in isolated nerve smooth muscle preparations with different receptor systems. The amplitudes of contractions evoked directly by stimulants as well as neurogenic twitches or relaxations were registered. In the rat stomach strip EC50 of acetylcholine, serotonin (5-HT) and KCl was estimated. MDP (50 nmol/l) but not levamisole potentiated selectively the contractions evoked by 5-HT and significantly (p < 0.01) lowered the respective EC50. In the rat vas deferens MDP selectively potentiated the twitches enhanced by 5-HT but not those enhanced by noradrenaline. Such potentiation was blocked by 5-HT3 antagonists tropisetron and MDL 72,222 (1 alpha H,3 alpha,5 alpha-H-tropan-3-yl 3,5-dichlorobenzoate) but not by the 5-HT2 antagonist ketanserin. The antagonist methiothepin nonselectively abolished the potentiation by MDP as well as the enhancement of twitches by 5-HT and noradrenaline, whereas l-propranolol and isamoltan influenced neither the enhancement of twitches by 5-HT nor the potentiation by MDP. In the isolated longitudinal muscle of guinea pig proximal colon, 5-HT caused a biphasic response in the presence of atropine; the initial neurogenic relaxation was potentiated in the presence of MDP and was suppressed in the presence of tropisetron. Thus, the potentiating effect of MDP in the isolated organs studied was selective with respect to the serotoninergic system and might be mediated by 5-HT3 receptors.

Intracisternal administration of Mycobacterium tuberculosis potentiates the delayed type hypersensitivity in guinea-pigs.

The delayed type hypersensitivity (DTH) was studied in guinea-pigs using the skin test. The mycobacterium tuberculosis (M. tbc)--was applied by various routes. The control group received ovalbumin in Freund's incomplete adjuvant (FIA) into the footpad. The first experimental group received ovalbumin in Freund's complete adjuvant (FCA) into the footpad. The other experimental groups always received, in addition to ovalbumin plus FIA into the footpad, the M. tbc. 1. intracisternally, 2. intramuscularly, 3. intraperitoneally, 4. orally. On the day of administration of the sensibilizing substance, the body temperature was monitored. The skin test was measured after 14 and 21 days. It was established that, for the study of the DTH, the 21-day interval was more significant than the 14-day interval. A 100 times smaller dose of M. tbc. given intracisternally had the same immunostimulating effect as the injection of ovalbumin with M. tbc into the footpad (p less than 0.01). The size of the skin reaction was not only significantly influenced by the intramuscular and oral administration of M. tbc. On the other hand, the intraperitoneal administration inhibited the DTH (p less than 0.01). The increase of body temperature after the administration of M. tbc. correlated with the influence on the DTH except for the intraperitoneal administration. The route of the M. tbc. administration was crucial for the development of the DTH.

Smooth muscle stimulation by an immunomodulatory compound muramyl dipeptide: does it involve serotoninergic system?

Contractions evoked by muramyl dipeptide (MDP), a synthetic compound possessing immunostimulatory properties, were studied in several isolated nerve-smooth muscle preparations. The contractions by micromolar concentrations of MDP were evoked either by direct interaction with smooth muscle (rat stomach strip) or at least partly indirectly via neurogenic stimulation (guinea pig ileum); the effect was stereospecific since the MDP-D was not active. The insensitivity of the preparations to serotonin (5-HT), either inherent (vas deferens) or after 5-HT antagonists or after desensitization to 5-HT, prevented or markedly reduced the contractile activity by MDP. On the other hand, a nanomolar concentration of MDP enhanced the sensitivity of the rat stomach strip to 5-HT.