phosphoramidon and Seizures

1. The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure-associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the gamma-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg-1). 2. Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg-1), arterial O2 partial pressure (PaO2) significantly dropped from 17.49 +/- 1.20 kPa to 7.51 +/- 2.21 kPa (P < 0.01) and arterial CO2 partial pressure (PaCO2) significantly increased from 4.64 +/- 0.56 kPa to 8.15 +/- 0.99 kPa (P < 0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end-inspiratory airway pressure (Paw) rapidly increased. 3. Concomitantly there was a time-dependent increase of big ET-1 and ET-1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicuculline injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not contain detectable amounts of ET. 4. Pretreatment with the endothelin-converting enzyme inhibitor, phosphoramidon (5.4 mg kg-1, i.v.) for 5 min significantly (P < 0.001) reduced peak ET-1 levels in BAL fluid by 65.4 +/- 9.9% at 8 min after bicuculline injection. Simultaneously it afforded protection from hypoxia. PaCO2 did not increase and PaO2 decreased only slightly from 14.63 +/- 1.00 kPa to 12.97 +/- 0.61 kPa (P > 0.05) after phosphoramidon pretreatment. In contrast, vehicle-treated animals that received bicuculline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in Paw by 76.7 +/- 12.4% (P <0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.5. Pretreatment with the ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.), for 5 min did not affect the levels of ET-1 in the BAL fluid at 8 min after bicuculline injection but did ameliorate the development of hypoxia. No hypercapnia developed and Pa02 decreased only moderately from 16.65 +/-0.25 kPa to 14.19 +/-2.15 kPa (P>0.05) in BQ-123-treated animals. In contrast, vehicle-treated animals that received bicuculline exhibited significant hypercapnia as well as profound hypoxia. BQ-

Topics: Acidosis; Animals; Aspartic Acid Endopeptidases; Bicuculline; Blood Gas Analysis; Blood Pressure; Bronchoalveolar Lavage Fluid; Convulsants; Electroencephalography; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors; Pulmonary Edema; Rats; Rats, Wistar; Seizures

After the intracisternal injection of three protease inhibitors which prevent the degradation of methionine enkephalin (amastatin, Des-Pro2-bradykinin, and phosphoramidon) and a mixture of these protease inhibitors, we investigated the effect on convulsive seizures in the seizure-susceptible El mouse. We also measured the cerebral methionine enkephalin content by high-performance liquid chromatography coupled with radioimmunoassay. Protease inhibitors significantly decreased both the incidence of seizures and the seizure score in El mice in a dose-dependent manner. This anticonvulsant effect was reversed by naloxone (2 mg/kg, sc). The cerebral methionine enkephalin content increased significantly after the administration of protease inhibitors in comparison with saline injection. These findings suggest that it was not protease inhibitors but instead increase of endogenous methionine enkephalin that reduced the incidence of seizures and the seizure score in El mice. Together with our previous data, the present findings support our hypothesis that a deficit in anticonvulsant endogenous methionine enkephalin is involved in the pathogenesis of seizures in the El mouse.

Topics: Animals; Anti-Bacterial Agents; Bradykinin; Brain; Chromatography, High Pressure Liquid; Enkephalin, Methionine; Glycopeptides; Mice; Mice, Mutant Strains; Naloxone; Peptides; Protease Inhibitors; Radioimmunoassay; Seizures

In order to elucidate the relationship between REM sleep and the enkephalinergic system, the effects of REM sleep deprivation (REMSD), stress and the enkephalinase inhibitor phosphoramidon on handling-induced convulsions were studied in mice. REMSD, stress and phosphoramidon (25-500 micrograms icv) increased the frequency of handling-induced convulsions (HIC) in normal mice. However, only in the last two groups were HIC antagonized by naloxone (1 mg/kg IP). In REMSD mice, phosphoramidon decreased the frequency of HIC, this effect being abolished by naloxone. The increase of neuronal excitability during REMSD is suggested to be associated with an insufficiency of the enkephalinergic system.

Topics: Animals; Disease Susceptibility; Glycopeptides; Handling, Psychological; Humans; Male; Mice; Mice, Inbred Strains; Naloxone; Neprilysin; Protease Inhibitors; Seizures; Sleep Deprivation; Sleep, REM; Stress, Psychological