ABSTRACT
To investigate the effects of nikethamide on the generation and modulation of rhythmic respiration of neonatal rats and the role of 5-HT(2A) receptor in this course, experiments were performed on the transverse medullary slices of neonatal rats (both sexes, 1-3 d) in vitro. The slices containing the medial region of the nucleus retrofacialis (mNRF) with the hypoglossal nerve rootlets were prepared in which the respiratory-related rhythmic discharge activity (RRDA) was recorded from the hypoglossal nerve rootlets by suction electrode. The possible role of nikethamide on RRDA was investigated by administration of an agonist of 5-HT(2A) receptor, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and an antagonist of 5-HT(2A) receptor, ketanserine, dissolved in modified Krebos solution (MKS). Thirty slices were randomly divided into five groups: Group 1: the slices were perfused with different concentrations of nikethamide (0.5, 1, 3, 5, 7, 10 μg/mL), and the most effective concentration was selected; Group 2: the slices were perfused with DOI (40 μmol/L); Group 3: the slices were perfused with ketanserine (40 μmol/L); Group 4: the slices were perfused with ketanserine + DOI; Group 5: the slices were perfused with nikethamide, then perfused with nikethamide + ketanserine after washout of nikethamide. Nikethamide increased RRDA in transverse medullary slices at 0.5-7 μg/mL, and 5 μg/mL was the most effective concentration. DOI increased RRDA with prolonged inspiratory time (TI), increased integral amplitude (IA), and shortened respiratory cycle (RC). Ketanserine decreased RRDA with shortened TI, decreased IA and prolonged RC. Ketanserine + DOI had no significant effects on RRDA. The effects of nikethamide on RC and IA were totally and partially reversed by additional application of ketanserine, but the effect of nikethamide on TI was not influenced by ketanserine. It is proposed that nikethamide increases RRDA partly via 5-HT(2A) receptors.
Subject(s)
Animals , Female , Male , Rats , Animals, Newborn , In Vitro Techniques , Medulla Oblongata , Physiology , Nikethamide , Pharmacology , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A , Metabolism , Respiration , Respiratory Center , Physiology , SerotoninABSTRACT
<p><b>OBJECTIVE</b>To investigate the role of GABA A receptor in nikethamide-induced respiratory enhancement in the medullary slices of neonatal rats.</p><p><b>METHODS</b>Ex vivo medullary slices of neonatal rats (1 to 3 days old) containing the medial region of the nucleus retrofacialis with the hypoglossal nerve rootlets were prepared and perfused with modified Kreb's solution to record respiration-related rhythmic discharge activity (RRDA) from the hypoglossal nerve rootlets using suction electrodes. Thirty RRDA-positive slices were randomized into 5 equal groups and perfused with nikethamide (at concentrations of 0.5, 1, 3, 5, 7, and 10 microg/ml with the optimal nikethamide concentration determined), GABA (at 10, 20, 40, and 60 micromol/ to determine the optimal concentration), 10 micromol/ bicuculline, 10 micromol/ bicuculline plus 40 micromol/L GABA, and 5 microg/ml nikethamide followed by 5 microg/ml nikethamide plus 10 micromol/ bicuculline after wash out, respectively.</p><p><b>RESULTS</b>Nikethamide increased RRDA at the concentrations of 0.5-7 microg/ml, and 5 microg/ml nikethamide showed the most distinct effect on the inspiratory time (TI), integral amplitude (IA), and respiratory cycle (RC). GABA at 40 micromol/ showed the most effective inhibition of RRDA in terms of TI, IA, and RC. Bicuculline at 10 micromol/ could increase the IA, TI and RC, but the combination of 10 micromol/ bicuculline and 40 micromol/ GABA had no significant effects on RRDA. Compared with nikethamide used alone, nikethamide plus bicuculline significantly increased TI and IA without affecting RC.</p><p><b>CONCLUSION</b>Nikethamide can enhance RRDA of the hypoglossal nerve rootlets in the medullary slices of neonatal rats, and the effect can be partially mediated by the GABA A receptor.</p>
Subject(s)
Animals , Female , Male , Rats , Animals, Newborn , Central Nervous System Stimulants , Pharmacology , In Vitro Techniques , Medulla Oblongata , Physiology , Nikethamide , Pharmacology , Random Allocation , Rats, Sprague-Dawley , Receptors, GABA-A , Physiology , Respiration , Respiratory Center , PhysiologyABSTRACT
Em funcao da controversia na literatura sobre a utilidade da administracao de niquetamida na intoxicacao alcoolica, foi realizado um trabalho experimental onde camundongos pre-tratados com 3,0/kg de etanol receberam niquetamida. Os resultados mostraram que o tempo de sono (perda do reflexo postural) sob a acao do etanol nao foi modificado pelo analeptico. Portanto, atraves do parametro utilizado, nao foi observada alteracoes da intoxicacao alcoolica pela niquetamida. Nos grupos que receberam as doses mais altas de niquetamida foram observadas convulsoes e mortes
Subject(s)
Animals , Alcoholic Intoxication , NikethamideABSTRACT
LD50 determinations showed that both Doxapram HCl and Nikethamide fall in the category of moderate toxicity; but Doxapram HCl was the less toxic. Assessment of the arousal capacity of Doxapram HCl against sleeping doses of pentobarbitone sodium in mice demonstrated that the drug has a high therapeutic index. Assessment of the restorative activity of Doxapram HCl and of Nikethamide against toxic doses of pentobarbitone sodium as percentage survival in mice, demonstrated the higher potency of Doxapram HCl
Subject(s)
Animals, Laboratory , Doxapram/pharmacology , Nikethamide/toxicity , Respiratory System Agents/adverse effects , Central Nervous System Stimulants/toxicity , Mice , Comparative StudyABSTRACT
Experiments in pentobarbitone-sodium anesthetized dogs revealed that Doxapram HCl was a more potent respirogenic agent than Nikethamide; but at higher doses tachyphylaxis develops. Further assessments of its respirogenic activity in halothane-anesthetized dogs, by calculation of the minutevolume demonstrated a significant increase in ventilatic. These respirogenic effects were accompanied by transientrise in blood pressure at lower doses, and by bradycardia at higher doses. Nikethamide lowered the blood pressure at all dose levels, while it produced no ECG changes. Both drugs produced a dose-related direct myocardial depression of the isolated heart. The site of the respirogenic and cardiovascular effects of Doxapram HCl, was investigated after vagotomy, by intravertebral injection and in the spinal dog. The results demonstrated that the drug acts by central and peripheral mechnisms; and that its action may be partly through sympathetic influence
Subject(s)
Animals , Doxapram/pharmacology , Nikethamide/pharmacology , Respiratory System Agents/pharmacology , Comparative Study , Dogs , Cardiovascular System/drug effectsABSTRACT
The level of y-aminobutyric acid (GABA) was determined in the brain of rats 1 hr. after i.p. injection of chlorpromazine, prochlorperazine, diazepam, trimipramine, methamphetamine and nikethamide. Diazepam increased, and, trimipramine and amphetamine decreased the brain GABA level over wide dose ranges. Low doses of chlorpromazine and prochlorperazine increased but high doses of the drugs reduced the GABA level. Low doses of nikethamide reduced whereas high doses increased the level of GABA. The effects of the drugs have been discussed in relation to the brain GABA level.