Quantitative aspects in the assessment of liver injury. (1/924)

Liver function data are usually difficult to use in their original form when one wishes to compare the hepatotoxic properties of several chemical substances. However, procedures are available for the conversion of liver function data into quantal responses. These permit the elaboration of dose-response lines for the substances in question, the calculation of median effective doses and the statistical analysis of differences in liver-damaging potency. These same procedures can be utilized for estimating the relative hazard involved if one compares the liver-damaging potency to the median effective dose for some other pharmacologie parameter. Alterations in hepatic triglycerides, lipid peroxidation, and the activities of various hepatic enzymes can also be quantitiated in a dose-related manner. This permits the selection of equitoxic doses required for certain comparative studies and the selection of doses in chemical interaction studies. The quantitative problems involved in low-frequency adverse reactions and the difficulty these present in the detection of liver injury in laboratory animals are discussed.  (+info)

Effects of promazine, chlorpromazine, d-amphetamine, and pentobarbital on treadle pressing by pigeons under a signalled shock-postponement schedule. (2/924)

The effects of promazine on treadle pressing to postpone the presentation of electric shock were studied in three pigeons. The effects of chlorpromazine, d-amphetamine, and pentobarbital were studied in two of these pigeons. Each treadle press postponed electric shock for 20 sec and presentation of a preshock stimulus for 14 sec. Selected doses of both promazine and chlorpromazine increased the rates of treadle pressing in all birds. The response-rate increases produced by promazine and chlorpromazine were due to increased conditional probabilities of treadle pressing both before and during the preshock stimulus. d-Amphetamine (1 and 3 mg/kg) slightly increased responding in one of the birds, but not to the extent that promazine or chlorpromazine did. In the other bird, the 10 mg/kg dose of d-amphetamine increased shock rate but did not change response rate. Some doses of d-amphetamine increased the conditional probabilities of responding both in the absence of the preshock signal and during the preshock signal in both birds. Pentobarbital only decreased response rates and increased shock rates.  (+info)

Synaptic activation of GABAA receptors induces neuronal uptake of Ca2+ in adult rat hippocampal slices. (3/924)

Synaptically evoked transmembrane movements of Ca2+ in the adult CNS have almost exclusively been attributed to activation of glutamate receptor channels and the consequent triggering of voltage-gated calcium channels (VGCCs). Using microelectrodes for measuring free extracellular Ca2+ ([Ca2+]o) and extracellular space (ECS) volume, we show here for the first time that synaptic stimulation of gamma-aminobutyric acid-A (GABAA) receptors can result in a decrease in [Ca2+]o in adult rat hippocampal slices. High-frequency stimulation (100-200 Hz, 0.4-0.5 s) applied in stratum radiatum close (+info)

Effect of psychotropic drugs on caudate spindle in cats. (4/924)

To ascertain whether neuroleptics act on the caudate nucleus itself, the effects of these compounds as well as other centrally acting drugs were examined in relation to caudate spindle and EEG arousal responses (sciatic nerve stimulation) in gallamine-immobilized cats. Haloperidol and chlorpromazine enhanced the caudate spindle at a dose which had no effect on the EEG arousal response. On the other hand, clozapine and a higher dose of chlorpromazine enhanced the caudate spindle, but depressed the arousal response. High frequency stimulation of the sciatic nerve suppressed the caudate spindle. Pentobarbital, biperiden and diazepam, while depressing the arousal response, caused an enhancement of the caudate spindle. Imipramine at a low dose had no effect on either response, whereas at a high dose this drug enhanced the caudate spindle with concomitant depression of the arousal response. From these results, it may be concluded that the enhancing action on the caudate spindle induced by haloperidol and a low dose of chlorpromazine is due to an increase in susceptibility of the caudate nucleus itself. In addition, it is suggested that depression of the activating system is involved in an appearance of the caudate spindle.  (+info)

A single hydrophobic residue confers barbiturate sensitivity to gamma-aminobutyric acid type C receptor. (5/924)

Barbiturate sensitivity was imparted to the human rho1 homooligomeric gamma-aminobutyric acid (GABA) receptor channel by mutation of a tryptophan residue at position 328 (Trp328), which is located within the third transmembrane domain. Substitutions of Trp328 with a spectrum of amino acids revealed that nearly all hydrophobic residues produced receptor channels that were both directly activated and modulated by pentobarbital with similar sensitivities. Previous studies with ligand-gated ion channels (including GABA) have demonstrated that even conservative amino acid substitution within the agonist-dependent activation domain (N-terminal extracellular domain) can markedly impair agonist sensitivity. Thus, the lack of significant variation in pentobarbital sensitivity among the Trp328 mutants attests to an intrinsic difference between pentobarbital- and the GABA-dependent activation domain. Compared with the heterooligomeric alphabetagamma receptor channel, the mode of modulation for homooligomeric Trp328 mutants by pentobarbital was more dependent on the GABA concentration, yielding potentiation only at low concentrations of GABA (fractions of their respective EC50 values), yet causing inhibition at higher concentrations. Agonist-related studies have also demonstrated that residue 328 plays an important role in agonist-dependent activation, suggesting a functional interconnection between the GABA and pentobarbital activation domains.  (+info)

Acetazolamide and amiloride inhibit pentobarbital-induced facilitation of nocifensive reflexes. (6/924)

BACKGROUND: Neuronal excitation may result from stimulation of gamma-aminobutyric acid A (GABA(A)) receptors that prolong the channel opening, depolarizing the postsynaptic membrane. Drugs such as acetazolamide or amiloride can block GABA depolarization. Barbiturates facilitate nociceptive reflexes and also prolong the GABA(A) channel open-time. To evaluate the possible mechanism, the authors studied the impact of acetazolamide and amiloride on pentobarbital-induced nocifensive reflex facilitation. Because nitric oxide (NO) is a mediator of reflex facilitation, the authors evaluated the effects of NO synthase inhibition. METHODS: Nocifensive reflex thresholds were quantified with the hind paw withdrawal latency from radiant heat (HPW latency) in the rat. Nocifensive reflexes were facilitated with intraperitoneal injection of pentobarbital (30 mg/kg). The authors tested the roles of GABA-mediated depolarization and NO in reflex facilitation by pretreatment with acetazolamide and amiloride and inhibition of NO synthase with L-NAME and 7-NI, respectively. Sedative effects of pentobarbital were evaluated with the righting reflex, the response to vibrissal stimulation, and plasma drug concentrations. RESULTS: Pentobarbital decreased the hind paw withdrawal latency from 11.2+/-1 to 8.3+/-1 s (P < 0.001). Pretreatment with each of the four test drugs limited the reduction in reflex facilitation after pentobarbital to 1.3 s or less, similar to the reduction seen after saline injection, without altering sedation. L-NAME increased plasma pentobarbital concentrations by 10% without changing the concentration associated with return of responsiveness. CONCLUSIONS: Pentobarbital-induced nocifensive reflex facilitation was inhibited by all four tested drugs without evidence of increased sedation. The results are consistent with a role for GABA(A) receptor-mediated depolarization in barbiturate-induced hyper-reflexia.  (+info)

Effects of exogenous [Arg8]-vasopressin on borderline-hypertensive Hiroshima rats. (7/924)

The interaction between [Arg8]-vasopressin and a vasopressin receptor antagonist, [d(CH2)5(1), O-Me-Tyr2, Arg8]-vasopressin, was examined in Hiroshima rats and normotensive control rats under pentobarbital anesthesia. [Arg8]-vasopressin dose-dependently increased the arterial pressure in both the Hiroshima and control rats, the pressor effect being greater in the Hiroshima rats. After the administration of a vasopressin antagonist (0.01 mg/kg), which by itself decreased arterial pressure only in the Hiroshima rats, the dose-response curve for [Arg8]-vasopressin was much more greatly shifted to the right in the control rats. These results indicate that with or without a vasopressin antagonist, the exogenous [Arg8]-vasopressin induced more powerful pressor actions in the Hiroshima rats compared to the control rats.  (+info)

Distinct molecular sites of anaesthetic action: pentobarbital block of human brain sodium channels is alleviated by removal of fast inactivation. (8/924)

Fast inactivation of sodium channel function is modified by anaesthetics. Its quantitative contribution to the overall anaesthetic effect is assessed by removing the fast inactivation mechanism enzymatically. Sodium channels from human brain cortex were incorporated into planar lipid bilayers. After incorporation, channels were exposed to increasing concentrations of pentobarbital (pentobarbitone), either before or after fast inactivation had been enzymatically removed using trypsin. Anaesthetic suppression of these channels with or without the fast inactivation site was compared by analysing single channel currents. Treatment with cytoplasmic trypsin alleviated two-thirds of the pentobarbital block on open channel probability (fractional channel open time). The hyperpolarizing shift in steady-state activation caused by pentobarbital was not affected by treatment with trypsin. Extracellular trypsin was ineffective. These results support a model of general anaesthetic action on sodium channels in which anaesthetics produce a concentration-dependent shift in the distribution between activated and inactivated states towards fast inactivation. Some pentobarbital effects remained after removal of inactivation. The results support a multi-mechanistic model of anaesthetic action on brain sodium channels.  (+info)