Evaluation of the muscle relaxant properties of a novel beta-carboline, ZK 93423 in rats and cats.
The muscle relaxant action of ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate ethyl ester), a novel beta-carboline with agonistic properties at the benzodiazepine receptor, was examined by assessing its effect on the tonic electromyogram (EMG) activity of the gastrocnemiussoleus (GS) muscle of genetically spastic rats and on ventral root reflexes, presynaptic inhibition and fusimotor activity in the spinal cord of decerebrate cats. ZK 93423 (0.1-10.0 mg kg-1) depressed the tonic EMG activity in mutant rats in a dose-dependent manner. This effect was reversed by the benzodiazepine antagonist Ro 15-1788 (5.0 mg kg-1). Both ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) enhanced the presynaptic inhibition of the GS muscle and associated dorsal root potentials in decerebrate cats in an almost identical manner. The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) depressed the activity of both static and dynamic fusimotor neurones, as deduced from changes in the afferent responses of muscle spindle primary endings to low frequency (1 s-1) sinusoidal stretching. The depressant action of diazepam (0.3 mg kg-1) was weaker than that of ZK 93423 (0.5 mg kg-1). The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) failed to alter the magnitude of monosynaptic ventral root reflexes evoked by electrical stimulation of a flexor and an extensor nerve, whereas diazepam (0.3 mg kg-1) had a depressant effect on both types of monosynaptic reflexes, which was antagonized by Ro 15-1788 (5.0 mg kg-1). Neither ZK 93423 (0.5 mg kg-1) nor diazepam (0.3 mg kg-1) depressed polysynaptic ventral root reflexes evoked by electrical stimulation of a flexor and a cutaneous nerve. The present results demonstrate that ZK 93423 exerts a potent muscle relaxant action due to a specific interaction with benzodiazepine receptors. However, its profile of actions on spinal motor mechanisms is not identical to that of diazepam.
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology*; D002415:Cats; D003655:Decerebrate State; D003975:Diazepam / Q000494:pharmacology; D004576:Electromyography; D005071:Evoked Potentials / Q000187:drug effects; D005260:Female; D005442:Flumazenil; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects; D051381:Rats; D011922:Rats, Mutant Strains; D012018:Reflex / Q000187:drug effects; D013045:Species Specificity; D013997:Time Factors
D001570:Benzodiazepinones; D002243:Carbolines; D009125:Muscle Relaxants, Central; D005442:Flumazenil; C042569:ZK 93423; D003975:Diazepam