In 1939 Harvey studied the effect of quinine on skeletal muscle and found that. it had an action both on the neuromuscular junction and directly on the muscle fibre. He concluded that the direct action of the drug was to cause a longer persistence of the contraction wave. Since then, Hill (1949) has introduced the concept of the active state of muscle, the process underlying the contraction, and it has become possible to account for the mechanical effects of several drugs on the contractions of skeletal muscle by an action on this process (Goffart & Ritchie, 1952; Hill & Macpherson, 1954; Ritchie, 1954b). In the present experiments the action of quinine on the muscle fibre was investigated to see how far the effects of this drug could be explained in terms of this concept.It was found that quinine prolonged the time course of the active state of frog's muscle, and the same effect was obtained with its optical isomer, quinidine.
METHODSExperiments were done on the tibialis anterior and soleus muscles of cats in situ, and on the isolated frog's sartorius muscle.Experiments on cats. The cats were usually anaesthetized with chloralose (80 mg/kg), but in some experiments they were decerebrated or spinalized under preliminary ether anaesthesia. Twitch and tetanic contractions were elicited either directly, or indirectly via the tied sciatic nerve, by means of rectangular electrical shocks. The duration of the shocks for indirect stimuation was 30-100 ,usec, if not otherwise stated, and their strength five times threshold value: for direct stimulation the duration was 1 msec and the strength such that the twitch contractions were equal to those evoked with maximal indiract stimulation. Tetanic contractions of JA sec duration were evoked, using frequencies of stimulation ranging from 16 to 500 shocks/sec. In the experiments with direct stimulation, the animals were fully curarized by an intravenous injection of tubocurarine chloride; the curarization was regularly checked by indirect stimulation of the muscle. For direct stimulation, a silver wire was wound round the tendon to form one electrode; the drill fixing the femur served as the other. * W.H.O. Fellow.
Cetiedil, a new vasodilating drug with anticholinergic properties, was shown to be metabolised very rapidly in man after intravenous and oral administration of the 14C-compound. Higher concentrations of labelled compound after oral than after intravenous administration at the same sampling time, and proportional differences in urinary excretion, suggest that metabolic handling of the drug differs depending on the route of administration. Experiments in which inhibition of saliva secretion was measured indicated that (an) active metabolite(s) probably was (were) responsible for the action of the drug. As an anticholinergic drug, cetiedil is at least 400 times weaker than atropine.
In the rat d-tubocurarine is taken up by the liver and excreted in bile. A fraction of the drug is taken up very rapidly by lysosomes. This lysosomal localization of the drug was demonstrated by purification of Triton WR 1339 loaded lysosomes ('tritosomes') on a sucrose density gradient by flotation; 3H-labeled d-tubocurarine was accumulated in the same fractions as acid phosphatase activity. Lysosome-bound d-tubocurarine is not available for biliary excretion and remains in the lysosomes even when the cytosolic concentration decreases to very low levels. The biliary excretion rate was linearly related to the amount of d-tubocurarine present in the cytosol. Lysosomal uptake of d-tubocurarine was decreased or prevented by the basic drug quinacrine in vivo. The lysosomal storage of d-tubocurarine is discussed in relation to its relevance for the clinical use of this and related drugs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.