Hiroyuki Mizuno

Effect of fudosteine, a new cysteine derivative, on mucociliary transport

We examined the effect of fudosteine ((—)‐(R)‐2‐amino‐3‐(3‐hydroxypropylthio)propionic acid) on the mucociliary transport (MCT) rate in quails. The MCT rate was estimated by ash transport velocity on the tracheal mucosa of quails. Fudosteine (500 mg kg−1, p.o.) did not affect the normal MCT rate. However, topical application of fudosteine to the tracheal mucosa dose‐dependently protected the impairment of the MCT rate caused by exposure to cigarette smoke. The results suggest that fudosteine may participate in the defence mechanism in the respiratory tract against irritant gases.

Effects of SS320A, a new cysteine derivative, on the change in the number of goblet cells induced by bacterial endotoxin in rat tracheal epithelium.

We examined the effects of SS320A, a new cysteine derivative, on the change in the number of goblet cells induced by bacterial endotoxin in rat tracheal epithelium. Four types of goblet cell were characterized in tracheal epithelium according to their size and staining affinity with Alcian blue (AB)/periodic acid Schiff (PAS). Each rat was intratracheally given a single instillation of lipopolysaccharide (LPS) (2 mg/ml). The results showed that treatment with LPS increased the number of AB/PAS-positive cells that were recognizable as goblet cells in tracheal epithelium. On the other hand, LPS evoked acute lung inflammation related to neutrophil accumulation in the lung before the increase in goblet cells. SS320A (10-100 mg/kg, p.o.) and dexamethasone (10 mg/kg, p.o.) each significantly inhibited the increase in the number of goblet cells induced by LPS. On the other hand, ambroxol, bromhexine, l-cysteine ethyl ester and S-carboxymethylcysteine, which are used as expectorants, had no inhibitory effects on the LPS-induced change in the number of goblet cells. SS320A slightly inhibited the lung injury based on a histological examination. These data suggest that SS320A may have a beneficial effect against mucus hypersecretion in respiratory disease.

Effect of fudosteine, a cysteine derivative, on blood flow of tracheal microvasculature increased by airway inflammation.

We examined the effect of fudosteine, a cysteine derivative, on blood flow of tracheal microvasculature increased by airway inflammation. Airway inflammation was elicited by sulfur dioxide (SO(2)) exposure for 2 weeks in rabbits. Each drug (500 mg/kg, p.o.) or 0.5% carboxymethylcellulose-Na (control group) was daily administered just before SO(2) exposure. After final SO(2) exposure was finished, blood flow of tracheal microvasculature was measured by blood perfusion monitor. Fudosteine or S-carboxymethylcysteine (S-CMC) significantly suppressed blood flow of tracheal microvasculature increased by SO(2) exposure. However, no effect of fudosteine was observed on the pharmacological microvascular response in trachea of SO(2)-exposed rabbits. On the other hand, fudosteine or S-CMC scavenged superoxide anion generated from rat neutrophils, and enzymatically generated from xanthine oxidase-acetaldehyde reaction. The results suggest that suppressive action in increased tracheal blood flow of fudosteine is due to anti-inflammatory activity, at least in part, via scavenging of superoxide anion.

Neural reflex-mediated tracheal response during bronchoconstriction induced by ovalbumin antigen in guinea pigs

1. The biphasic reflex tracheal response (constriction followed by dilatation) occurred during bronchoconstriction induced by inhalation of ovalbumin antigen (OA) in sensitized guinea pigs. 2. The reflex tracheal constriction was largely reduced by atropine, and the dilatation was inhibited by propranolol and N omega-nitro-L-arginine methyl ester (L-NAME). The noradrenaline, adrenaline, cyclic AMP, and cyclic GMP contents in the tracheal segment were significantly higher during reflex tracheal dilatation. 3. These findings suggest that cholinergic nerves may mediate reflex tracheal constriction and that adrenergic and NOergic nerves may mediate the ensuing reflex tracheal dilatation.

アセチルコリン誘発気道収縮における新規抗喘息薬 Flutropium bromide と Salbutamol，Aminophylline および Disodium cromoglycate の併用効果

Effects of flutropium bromide, a new bronchodilator with an anticholinergic action, alone or in combination with other antiasthma drugs were investigated in guinea pigs by using an index of inhibition of the acetylcholine (ACh)-induced bronchoconstriction. Single inhalation of flutropium bromide (0.0003%) into the airways of guinea pigs inhibited the ACh (i.v.)-induced bronchoconstriction without changing the fall in blood pressure induced by ACh. When salbutamol (3 micrograms/kg, i.v.), aminophylline (5 mg/kg, i.v.) or disodium cromoglycate (10 mg/kg, i.v.) was administered in combination with flutropium bromide (0.0003%), bronchodilation was enhanced as compared with single administration of the respective antiasthma drugs. From the above results, it is indicated that inhalation of flutropium bromide provides a more efficient bronchodilation in combination with other antiasthma drugs that possess different mechanisms of antiasthma effects.

[Effects of flutropium bromide, a new antiasthma drug, with repeated administration on bronchomotor response and hepatic drug metabolizing enzymes].

Effects of flutropium bromide, a new antiasthma drug possessing the quarternary ammonium structure of atropine derivatives, were investigated on the bronchodilatory activity with repeated inhalations in guinea pigs and on the hepatic drug metabolizing enzyme activities with repeated i.v. administration in rats. Single inhalation of flutropium bromide (0.03%) inhibited the ACh-induced bronchoconstriction without changing the fall in blood pressure induced by ACh. Flutropium bromide (0.03%) was inhaled for 5 min a day by placing the animal in an inhalation box, successively during periods of 14 and 28 days. The bronchodilatory effect of flutropium bromide after 14- or 28-day repeated inhalations was almost the same potency as that after single inhalation. Twenty-eight-day repeated inhalations did not change the body weight curve in guinea pigs; and in addition, 14-day repeated i.v. administration did not change the hepatic drug metabolizing enzyme activities in rats. From the above results, it is indicated that flutropium bromide causes neither reduction in response nor cumulative effect after repeated inhalations, and that the agent maintains the bronchodilatory effect without change in the hepatic drug metabolizing enzyme activities.