Effect of psychotropic drugs on caudate spindle in cats.
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)
Imipramine blocks the transient outward potassium current in rat ventricular myocytes.
AIM: To examine the effects of imipramine on transient outward potassium current (I(to) in rat ventricular myocytes. METHODS: The patch-clamp whole-cell recording techniques were used. RESULTS: Imipramine resulted in a concentration-dependent inhibition of I(to) with the IC50 of 6.0 mumol.L-1 and a concentration-dependent acceleration of I(to) inactivation. The blocking showed no difference at different testing membrane potentials. Imipramine produced slight effects (about 3 and 4 mV, respectively) on steady-state activation and inactivation curves of I(to), and tended to prolong the recovery of I(to) from inactivation (tau control = 37 +/- 11 ms; tau drug = 58 +/- 17 ms), but not significant (n = 4, P > 0.05). The inhibitory effect of imipramine on Ito was increased when the prepulses were prolonged progressively from 0 to 120 ms. (tau control = 22 +/- 8 ms; tau drug = 14 +/- 5 ms). CONCLUSIONS: Imipramine blocked Ito in concentration-dependent but voltage-independent manners, and with "open channel blocking" properties. (+info)
Antagonistic effects of trifluoperazine, imipramine, and chlorpromazine against acetylcholine-induced contractions in isolated rat uterus.
AIM: To examine the effects and affinity of some phenothizines (trifluoperazine, Tri and chlorpromazine, Chl) and antidepressant (imipramine, Imi) drugs on acetylcholine (ACh)-induced uterine contraction. METHODS: Isotonic contractions of rat uterine strips were recorded. ACh was administrated to induce maximal contraction before exchange of nutrient solution. ACh was added 5 min after the testing drugs. The nutrient solution was exchanged 4 times after each agonist (ACh or other agents) to produce maximal contraction. RESULTS: Atropine (Atr, 0.029-2.9 mumol.L-1), 4-DAMP (3.6-360 nmol.L-1), pirenzepine (Pir, 0.23-23.5 mumol.L-1), and AF-DX 116 (0.7-35.6 mumol.L-1) competitively antagonized the muscular uterine concentration induced by ACh (0.068-36068 mumol.L-1). The Schild plot was linear (r = 1.00). The pKB and slopes values (95% confidence limits) were 9.28 +/- 0.12 and 1.00 +/- 0.10 to Atr, 9.06 +/- 0.10 and 1.10 +/- 0.08 to 4-DAMP, 7.03 +/- 0.15 and 0.99 +/- 0.12 to Pir, and 5.60 +/- 0.08 and 1.00 +/- 0.19 to AF-DX 116. Tri 0.01-2 mumol.L-1 (pKB = 8.39 +/- 0.04) and Imi 94-940 nmol.L-1 (pKB = 7.21 +/- 0.10) produced also a competitive antagonism of the muscular uterine contraction induced by ACh (r = 1.00), but the slope was only 0.60 +/- 0.03 to Tri or 0.83 +/- 0.16 to Imi. Chl 2.8-5.6 mumol.L-1 produced a weak antagonism on amplitude of muscular contraction induced by the cholinomimetic. CONCLUSION: The muscarinic receptors on uterus behaved as M3 subtype. Tri and Imi, but not Chl, were competitive antagonist of muscarinic receptors of uterus. Imi behaved a simple competitive antagonist at a single site on myometrium, but Tri was not a simple competitive agent at a single site. (+info)
Studies on the uptake, metabolism, and release of endogenous and exogenous chemicals by use of the isolated perfused lung.
The isolated perfused lung is a valuable tool for studying many lung functions. The kinds of information one can obtain from the isolated perfused lung are illustrated by examples from our studies on the uptake, accumulation, and metabolism of endogenous and exogenous chemicals. (+info)
Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases.
Fas/CD95/Apo-I has been shown to stimulate a variety of molecules including several members of the caspase family and the acidic sphingomyelinase (Martin and Green 1995; Gulbins et al, 1995). Here, we demonstrate that Fas receptor-triggered activation of the acidic sphingomyelinase, consumption of sphingomyelin, release of ceramide, and subsequent activation of JNK and p38-K are regulated by caspases. Inhibition of caspases by Ac-YVAD-chloromethylketone or transient CrmA transfection prevented stimulation of acidic sphingomyelinase, release of ceramide and activation of JNK and p38-K upon Fas-receptor crosslinking. Likewise, Fas triggered apoptosis was almost completely blocked by Ac-YVAD-chloromethylketone or CrmA mediated inhibition of caspases. The results suggest a new signalling cascade from the Fas receptor via caspases to acidic sphingomyelinase, ceramide and JNK/p38-K. (+info)
Depressive state with anxiety in repeated cold-stressed mice in forced swimming tests.
The effects of various types of stress and drugs were studied to assess mouse performance in forced swimming tests, following characterization of SART (specific alternation of rhythm in environmental temperature) stress. Immobility time in the test decreased in mice subjected to SART, acute cold and restraint stress. No change was noted due to chronic cold stress or repeated fasting. The shortened time did not recover even 24 hr after the end of SART and chronic restraint stress. The time in SART-stressed mice finally recovered at 5-7 days. Shortening of immobility time in SART-stressed mice was inhibited by diazepam and repeated imipramine but not by lithium carbonate. In chronic restraint-stressed mice, this time was inhibited by repeated lithium carbonate but not diazepam or imipramine. SART stress would thus appear related to anxiety and depression and may be useful for detecting new types of antidepressants. (+info)
Effects of imipramine, an uptake inhibitor, on double-peaked constrictor responses to periarterial nerve stimulation in isolated, perfused canine splenic arteries.
Using a cannula insertion method, periarterial nerve electrical stimulations were performed at 1 and 10 Hz in the isolated, perfused canine splenic artery. Electrical nerve stimulation readily caused double-peaked vasoconstrictions. The 1st-peak response at 1 Hz was not influenced by treatment with imipramine but the 2nd one was significantly enhanced by it. The 2nd-peak response was markedly blocked by prazosin. An additional treatment with alpha,beta-methylene ATP, a P2X-purinoceptor desensitizer, abolished electrical stimulation-induced vascular responses that remained. At 10 Hz, the responses to electrical stimulation were not significantly influenced by imipramine. On the other hand, the imipramine treatment inhibited the tyramine-induced vasoconstriction but potentiated the noradrenaline-induced one. ATP-induced responses were not modified by imipramine. From these results, it is concluded that 1) the 1st-peaked constriction is mainly due to a P2X-purinoceptor-dependent mechanism, 2) the 2nd one is mainly due to an alpha1-adrenoceptor-dependent mechanism, and 3) presynaptic uptake mechanisms may perform an important role in the regulation of vascular reactivity, especially at a low frequency. (+info)
Transmembrane domain I contributes to the permeation pathway for serotonin and ions in the serotonin transporter.
Mutation of a conserved Asp (D98) in the rat serotonin (5HT) transporter (rSERT) to Glu (D98E) led to decreased 5HT transport capacity, diminished coupling to extracellular Na+ and Cl-, and a selective loss of antagonist potencies (cocaine, imipramine, and citalopram but not paroxetine or mazindol) with no change in 5HT Km value. D98E, which extends the acidic side chain by one carbon, affected the rank-order potency of substrate analogs for inhibition of 5HT transport, selectively increasing the potency of two analogs with shorter alkylamine side chains, gramine, and dihydroxybenzylamine. D98E also increased the efficacy of gramine relative to 5HT for inducing substrate-activated currents in Xenopus laevis oocytes, but these currents were noticeably dependent on extracellular medium acidification. I-V profiles for substrate-independent and -dependent currents indicated that the mutation selectively impacts ion permeation coupled to 5HT occupancy. The ability of the D98E mutant to modulate selective aspects of substrate recognition, to perturb ion dependence as well as modify substrate-induced currents, suggests that transmembrane domain I plays a critical role in defining the permeation pathway of biogenic amine transporters. (+info)