Effects of Phenytoin on Rocuronium-induced Neuromuscular Blockade Using a Rat Phrenic Nerve-diaphragm Preparation

Abstract

Background: Chronic anticonvulsant therapy with phenytoin antagonizes the action of nondepolarizing muscle relaxants. Rocuronium is a new non depolarizing muscle relaxant of rapid onset and intermediate duration. This study was designed to investigate the effects of phenytoin on rocuronium-induced neuromuscular blockade using a rat phrenic nerve-diaphragm preparation. Methods: Male Sprague-Dawley rats (200 g, n = 70) were randomly allocated into a control group (C, n = 10), three phenytoin-pretreated groups (PP, n = 30) and three phenytoin-non-pretreated groups (PNP, n = 30). In phenytoin-pretreated groups, phenytoin 50 mg/kg/day was administered intraperitoneally once a day for one day (PP), seven days (PP) or twenty eight days (PP). Animals were anesthetized with 40 mg/kg of thiopental sodium intraperitoneally and the diaphragm with the phrenic nerve were dissected, and the phrenic nerve-diaphragm preparation was suspended in 100 ml of Krebs solution in an organ bath. The bath was aerated with 95% O-5% CO at 32, and the phrenic nerve was stimulated with supramaximal intensity using a stimulator. Twitch responses were measured using a precalibrated force displacement transducer and recorded. The cumulative dose-response relationships of rocuronium and phenytoin were determined. After one hour's stabilization, rocuronium 100g was added to the bath, and when a stable 3 - 5 twitch was obtained, incremental 50llg doses of rocuronium were added to obtain more than 95% neuromuscular twitch inhibition at 0.1 Hz. In the phenytoin-non-pretreated group, phenytoin was administered simultaneously with the initial dose of rocuronium to a phenytoin concentration of lg/ml (PNP1), l0g/ml (PNPlO), or 100g/ml (PNP) in Krebs solution. Data were analyzed by probit and logistic models. In the PP group, the plasma concentration of phenytoin was analyzed by high performance liquid chromatography. Results: The dose-response curve of rocuronium was significantly shifted to the left in the PNP group (P group (P