ABSTRACT
Ethosuximide is a drug used for the treatment of absence seizures. Its prolonged application leads to gastrointestinal (GI) disturbances. The purpose of the present study was to determine the severity and nature of the disturbances, as well as the influence exerted upon them by neostigmine methylsulfate and metoclopramide. The drug-induced alterations, occurring in the rat GI tract, were registered by X-ray contrast examination. In vitro experiments were carried out on isolated GI smooth muscle (SM) preparations. The latter revealed that the drug hyperpolarized the SM tissues and inhibited their contractile activity. X-rays of ethosuximide-treated rats showed GI hypotonia, disturbed peristalsis and decreased evacuation activity. The inhibition of the GI functions was associated with hyperpolarization of SM and a reduction in Ca(2+) influx, ensuring spontaneous contractile activity. The application of neostigmine methylsulfate significantly removed ethosuximide-induced functional GI disturbances in rats treated for 15 days with ethosuximide.
Subject(s)
Anticonvulsants , Cholinesterase Inhibitors/pharmacology , Ethosuximide , Gastrointestinal Tract/drug effects , Neostigmine/pharmacology , Animals , Anticonvulsants/antagonists & inhibitors , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Ethosuximide/antagonists & inhibitors , Gastrointestinal Motility/drug effects , Gastrointestinal Tract/diagnostic imaging , Gastrointestinal Tract/physiopathology , In Vitro Techniques , Intestines/diagnostic imaging , Intestines/drug effects , Male , Membrane Potentials/drug effects , Metoclopramide/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiopathology , Radiography , Rats , Rats, Wistar , Stomach/diagnostic imaging , Stomach/drug effects , Time FactorsABSTRACT
The development of epileptogenic activity has been proven to be closely related to changes in cerebral blood flow. This study was designed to examine the effects of ethosuximide, a widely used anticonvulsant drug, on cerebral hemodynamics. White Wistar rats were treated (p.o.) with 100 mg/kg b.w. ethosuximide. Three hours after administration, changes in cerebral blood flow due to vasodilation were recorded by means of angiography. Using the single sucrose gap method it was found that ethosuximide caused hyperpolarization of smooth muscle sample from rat internal carotid artery by 5.4 +/- 1.6 mV. The hyperpolarization was related to relaxation of smooth muscle tissue of vessels, which was recorded isometrically. Ethosuximide significantly depressed vascular reactions to the vasoconstrictive agents noradrenaline and serotonin. Ethosuximide-induced reaction was not significantly influenced by the Ca2+ antagonist verapamil, but was reduced by caffeine (10(-4) M) and apamine (5.10(-6) M), the latter being a blocker of Ca2+ -dependent K+ channels. The experimental data strongly suggest that changes in bioelectric and contractile activity of arterial smooth muscle samples are a result of Ca2+ -dependent K+ efflux, provoked by calcium which has been derived from intracellular Ca2+ store. These results show that ethosuximide-induced changes in cerebral blood flow are caused by reduced reactivity of smooth muscle tissue and vascular dilatation.
Subject(s)
Anticonvulsants/pharmacology , Cerebrovascular Circulation/drug effects , Ethosuximide/pharmacology , Hemodynamics/drug effects , Muscle, Smooth, Vascular/drug effects , Animals , Cerebral Angiography , Dose-Response Relationship, Drug , Drug Interactions , Electrophysiology , Ethosuximide/antagonists & inhibitors , In Vitro Techniques , Muscle Contraction/drug effects , Muscle Contraction/physiology , Muscle Relaxation/drug effects , Muscle Relaxation/physiology , Rats , Rats, Wistar , Vasodilation/drug effectsABSTRACT
Wistar rats from our laboratory spontaneously present frequent epileptic seizures whose clinical semeiology, EEG signs and pharmacological reactivity resemble absence seizures in humans. In these rats, GABAmimetics such as THIP enhance the duration of seizures in a dose-dependent fashion. In contrast to the action of these drugs, valproate sodium (VPA), which potentiates GABAergic transmission, abolishes the seizures. VPA injected in association with THIP completely loses its therapeutic effects; moreover, VPA potentiates the aggravating effects of THIP. Ethosuximide which does not interact with GABA, was still effective when given in association with THIP. These findings raise questions as to 1. the role of GABAergic neurotransmission in the occurrence of spontaneous petit-mal-like seizures in the rat, and 2. the mode of action of antiepileptics against these seizures.
