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General pharmacological effects of [Ethyl p-(6-guanidinohexanoyloxy)benzoate] methanesulfonate (FOY), a new antiproteolytic agent, were studied and the following results were obtained. Acute administration of large doses of FOY in conscious dogs and rabbits caused a decrease in spontaneous motility, ataxia, cyanosis, collapse, mydriasis, and respiratory paralysis. The agent had no effect on the central nervous system and exhibited hypotensive effects in dogs in doses of more than 1 mg/kg. Hypotensive responses were not inhibited by treatment with atropine or hexamethonium. FOY had no effects on ECG in the rabbit at doses of less than 30 mg/kg and at doses from 10(-6) to 10(-4)g/ml, distinctly reduced the amplitude of the spontaneous and rhythmic contractions of the isolated rabbit ileum, guinea-pig ileum and rat uterus preparation. The contractile response to nerve stimulation, noradrenaline and barium was suppressed in isolated guinea-pig vas deferens. FOY had no effects on the twitch response of gastrocnemius muscle to sciatic nerve stimulation in rats. The drug caused local irritant effects in rabbits and rats.

To clarify the mode of action of loperamide, the interaction with various agonists was investigated in guinea pig intestines. The following results were obtained. Prostaglandin E1 (0.1 microgram) or acetylcholine (1 approximately 3 microgram) injection into the mesenteric artery at 10 min intervals caused a constant rise of intraluminal pressure of the intestinal loop in situ. Loperamide (0.01 approximately 0.1 mg/kg i.v.) markedly suppressed the response induced by prostaglandin E1. Morphine (0.1 approximately 1.0 mg/kg i.v.) and atropine (0.01 mg/kg i.v.) also suppressed the response. The intestinal response induced by acetylcholine was inhibited markedly by atropine and slightly by loperamide (0.1 mg/kg i.v.) but not by morphine. Contractions of the isolated ileum induced by coaxial stimulation, BaCl2, nicotine and serotonin were suppressed by loperamide (10(-9) approximately 2 X 10(-7) g/ml). Morphine, methadone and codeine showed the same effect as loperamide but the activity was weaker than that of loperamide. Contractions of isolated ileum induced by acetylcholine, histamine and bradykinin, and Ca-contraction in the depolarized taenia coli were inhibited by relatively high concentrations of loperamide (2 X 10(-7) g/ml or above). These results suggest that loperamide suppresses the function of cholinergic neurons in the intestines.

As the extract of cattle prostate (PE) is clinically effective in treating prostatic hypertrophy, a study was carried out on urinary bladders of rat, guinea pig, rabbit and dog as well as on guinea pig ileum. Muscle strip of rat and/or dog bladder contracted with PE with increasing spontaneous movement, and was unaffected by atropine. The isolated ileum of guinea pig also contracted with PE, and the contraction was inhibited by papaverine, but not by atropine. A rise in intravesical pressure was observed with increasing spontaneous movement in guinea pig bladder treated with PE, as well as in rabbit bladder in vitro or in situ. The sphincter vesica of guinea pig was dilated by PE as well as by ACh and methacholine.

Dibenamine (DB) produced contraction due to influx and release of Ca in normal medium, whereas it produced relaxation of the K-induced contraction due to depression of the activity of the muscle cell membrane. DB inhibited active influx, passive influx and release of Ca induced by ACh in this order as the concentrations were increased and also inhibited the contraction by histamine selectively as compared with the contractions by ACh, K and Ba, the inhibition of the ACh-, K- and Ba-contractions being almost to the same degree. In addition, DB inhibited to much the same degree the phasic contraction(PC) and tonic contraction(TC) by histamine, whereas it inhibited TC in preference to PC induced by ACh, K and Ba. Irreversible inhibition by DB of ACh-, K- and Ba-induced contractions were protected by Ca, whereas those of histamine-induced contraction were selectively protected by histamine and antihistamine, but not by Ca. These results indicate that the antagonism of DB and its irreversibility against histamine may be due to blockade of the histaminergic receptor, whereas those against ACh, K and Ba may be due to inhibition of the Ca-site. Evidence has been obtained suggesting that the irreversible parallel shift to the right of the log concentration-action curve of histamine after washout of DB may be due to spare receptors, whereas that of ACh, K or Ba may be due to inhibition of the Ca-site.

Effects of perimetazine on the motility of the isolated smooth muscle of guinea pig (ileum, taenia coli, uterus, vas deferens and trachea) and the ileum of rabbit were studied. The results obtained are as follows: Perimetazine showed a specific antihistamine, antiadrenaline and antiserotonin action. Moreover, antiacetylcholine and anti-BaC12 actions were observed with high doses of perimetazine as well as chlorpromazine and such actions were attributed to the nonspecific direct action on the smooth muscle. Both the spontaneous movement and the tonus of guinea pig taenia coli were also inhibited by a high concentration of perimetazine. The spontaneous membrane action potentials of the taenia coli recorded by the use of the sucrose-gap method were inhibited by a high concentration of perimetazine both in frequency and in amplitude with relaxation of the tonus. The action potentials were abolished however and change in the resting membrane level was not clearly observed.

The action mechanism of the bronchodilator activity of BB-1502 was studied in comparison with aminophylline. Orally administered BB-1502 did not inhibit passive cutaneous anaphylaxis in rats, an immediate allergic reaction of Type I, but strongly protected the same antigen-mediated anaphylactic asthma by the intraduodenal route, the activity being approximately 13 times more potent than that of aminophylline. BB-1502 also inhibited IgG-mediated anaphylactic asthma in guinea pigs by the oral route. Both IgE- and IgG-mediated histamine releases from rat lung were similarly inhibited by BB-1502, the potency being 2--3 times that of aminophylline. Disodium cromoglycate showed specific inhibition of the IgE-mediated reaction. BB-1502 and aminophylline showed nonspecific inhibition of the spasms of guinea pig ileum elicited by histamine, acetylcholine and BaCl2. Both compounds inhibited cyclic AMP and cyclic GMP phosphodiesterases (PDEs) derived from guinea pig organs. BB-1502 specifically inhibited the cyclic AMP PDE of lung and brain origins, while aminophylline showed no such specificity. The results of the present study suggested that the bronchodilator and anti-asthmatic actions of BB-1502 might, at least in part, be due to the regulation of cyclic nucleotide PDEs.