Actions of Chinoform and Oxine on the Isolated Phrenic Nerve-Diaphragm Preparation of the Rat: The Accumulation of Chinoform by Rat Diaphragm Strip

Abstract

Abstract-Theactions of chinoform and oxine on isolated phrenic nerve-diaphragm preparation of the rat and the uptake of chinoform by rat diaphragm strip were in vestigated. Chinoform and oxine decreased both twitch responses to indirect and, to a lesser extent, to direct stimuli in the rat phrenic nerve-diaphragm preparation. The depressant action of oxine was reversible whereas that of chinoform was irrever sible and always accompanied by a marked rise in muscle tone. The neuromuscular block caused by these drugs was enhanced rather than antagonized by eserine and KCl. The depressant action and the rise in muscle tone caused by chinoform dis appeared in vitro by lowering muscle temp., by suspending the drug in dog serum and also by conjugating it with glucuronic acid. When rat diaphragm strips were incubated aerobically in Krebs-bicarbonate solution containing chinoform for 1 to 5 hr at 37°C, the drug was accumulated against a concentration gradient until con centration ratio (muscle/medium) of up to 36: 1 had been attained. These findings indicate that rat diaphragm strips accumulate chinoform largely by intracellular bind ing and that the drug can act intracellularly as a metabolic poison.Some years ago the usefulness of the amebicidal property of chinoform (5-chloro 7-iodo-8-hydroxy-quinoline) in the treatment of amebic dysentery was widely established (1, 2). Tsubaki et al. (3) were, however, the first to denominate a group of neuropathic symptoms SMON (Subacute Myelo-Optico-Neuro-pathy) which was once suspected as an endemic in Japan. Pathological, epidemiological and virological investigations have since been done in an attempt to determine the pathogenesis of this disease.Despite multidisciplinary studies, the etiology is still unknown. Takasu et al. (4) and Igata et al. (5) observed that the coated tongues and feces of SMON patients usually assumed a green color. Subsequently, this green substance was isolated from the urine of SMON patients and was identified as chinoform Fe(III) complex by Tamura (6). More over, when the drug was given in large doses to dogs, a close resemblance to the pathog nomonic symptoms seen in SMON patients was observed (7) . Now the relationship between chinoform and SMON is almost certain. On March, 1972, at the investigation conference on SMON sponsored by the Japanese Ministry of Public Welfare it was concluded that the disease was an untoward side-reaction of chino 1 Iodochlorhydroxyquin (USP) ; Clioquinol (BP).