• The Korean Journal of Pharmacology
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• v.31 no.1 s.57
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• pp.123-133
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• 1995

A number of tricyclic antidepressants appear to have inhibitory action on calmodulin. Although amitriptyline, imipramine and doxepine have been shown to inhibit calcium uptake, oxidative phosphorylation and ATPase activities, effects of amitriptyline, imipramine and doxepine on functional responses of human neutrophils have not been elucidated. In this study, effects amitriptyline, imipramine and doxepine on superoxide and hydrogen peroxide generation, myeloperoxidase release, leukocriene B4 formation and intracellular calcium level were investigated. Superoxide and hydrogen peroxide production in heat aggregated IgG-activated neutrophils were inhibited by amitriptyline, imipramine and doxepine. EDTA, EGTA, verapamil and bepredil inhibited heat aggregated IgG-induced superoxide production. Chlorpromazine, trifluoperazine, staurosporine and H-7 also inhibited it. PMA-induced superoxide production was inhibited by amitriptyline, imipramine, doxepine, chlorpromazine and H-7. Amitriptyline, imipramine, chlorpromazine and trifluoperazine inhibited the myeloperoxidase release by heat aggregated IgG. Productions of $LTB_4$, and 5-HETE in heat aggregated IgG-activated neutrophils were inhibited by amitriptyline, imipramine and doxepine. In neutrophils, elevation of intracellular calcium induced by heat aggregated IgG was inhibited by amitriptyline, imipramine, doxepine, chlorpromazine and EGTA, while verapamil slightly inhibited increase of intracellular calcium and H-7 did not inhibit it. These results suggest that the inhibitory effect of amitriptyline, imipramine and doxepine on respiratory burst, myeloperoxidase release and LTB4 production in heat aggregated IgG-activated neutrophils appears to be ascribed to the inhibition of calcium mobilization, calmodulin and protein kinase C.

• Childhood Kidney Diseases
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• v.8 no.2
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• pp.129-137
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• 2004

Purpose : Nocternal enuresis is a common disorder. Tricyclic antidepressant and desmopressin have been accepted pharmacological treatment for this disorder We conducted a cooperative study to investigate the efficacy and adverse reactions of imipramine, desmopressin and combination treatment in children with primary monosymptomatic nocturnal enuresis(PMNE). Methods: Data from a large multicenter study were analysed. In the period of 8 months in 2002, the study comprised of 168 children(78 boys and 90 girls, 5 to 15 years old) with PMNE for imipramine, desmopressin or combination treatment. Before treatment a history, physical examination and laboratory tests were performed and the children were observed for 2 weeks. Response rate, adverse reactions and enuresis episodes after stopping drug administration were evaluated after 12-weeks of imipramine, desmopressin or combination of both. Results: After 4 weeks, the frequency of bed wetting in all treated patients decreased during treatment significantly Even though a 30-50%, reduction in the number of wet nights were 68.6%, 74.4% and 86.1% during 12 weeks treatment by imipramine, desmopressin and both of them respectively, there was no significant difference between them. The most common adverse reaction was decreased appetite from imipramine administration. But no serious drug-related adverse events were reported. Conclusion: Efficacy of the combination therapy of imipramine and desmopressin in PMNE appears not to be better than either drug alone. It is necessary to pay attention on account of adverse reactions during imipramine treatment even though imipramine and desmopressin were generally well tolerated.

• The Korean Journal of Pharmacology
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• v.28 no.1
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• pp.81-89
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• 1992

Enuresis is a common voiding disorder among children. There are several therapeutic regimens for the disorder available today; behavioral therapies, psychotherapy, bladder training, sleep interruption, hypnosis and drug therapy. Recently, the efficacy of drug therapy has been acknowledged, particularly of antidepressants. Among the tricyclic antidepressants, imipramine is most frequently employed for the treatment of enuresis. Present study was undertaken to investigate the mechanism of imipramine on the contractility of urinary bladder in relation to the calcium modulation using isolated strips of rat detrusor urinae. 1. The electric fileld stimulation-induced contraction was abolished by imipramine, but partially inhibited by atropine. 2. Imipramine reduced the basal tone and diminished the phasic activity of detrusor muscle concentration-dependently, which was similar to that of diltiazem, a calcium channel blocker. 3. Imipramine suppressed the maximal responses and shifted the concentration-response curves of bethanechol and ATP to right. 4. Imipramine inhibited the calcium-induced recovery of tension in calcium-free physiologic salt solution (PSS) with a mode of action similar to that of diltizaem. 5. A23187, a calcium ionophore recovered the basal tone which had been reduced by imipramine in normal PSS. 6. In calcium-free PSS, A23187 could recover the abolished basal tone with the pretreatment of imipramine, but it exerted a partial recovery with the pretreatment of TMB-8, an inhibitor of intracellular calcium release. Based on these results, it is suggested that the inhibitory action of imipramine on the detrusor muscle exerted in part by blockade of the muscarinic and purinergic receptors, and interference with the influx of extracellular calcium, but not with the release of intracellular stored calcium, is involved in its mechanism of action.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.4
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• pp.439-445
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• 1999

This study is to investigate the mechanism of inhibitory effect of imipramine on the calcium utilization in single cells isolated from canine detrusor. 2 mm thick smooth muscle chops were incubated in 0.12% collagenase solution at $36^{circ}C,$ and aerated with 95% $O_2/5%\;CO_2,$ and then cell suspension was examined. Acetylcholine (ACh) evoked a concentration-dependent contraction of the isolated detrusor cells in normal physiologic salt solution (PSS), and the ACh-induced contraction was significantly inhibited by imipramine. In $Ca^{2+}-free$ PSS, ACh-induced contraction was less than those in normal PSS and it was not affected by the pretreatment with imipramine. $Ca^{2+}-induced$ contraction in $Ca^{2+}-free$ PSS was supressed by imipramine, but addition of A 23187, a calcium ionophore, overcomed the inhibitory effect of imipramine. High potassium-depolarization (40 mM KCl) evoked cell contraction, which was inhibited by imipramine. Caffeine, a releasing agent of the stored $Ca^{2+}$ from sarcoplasmic reticulum, evoked a contraction of the cells that was not blocked by the pretreatment with imipramine. These results suggest that imipramine inhibits the influx of calcium in the detrusor cells through both the receptor-operated- and voltage-gated-calcium channels, but does not affect the release of calcium from intracellular storage site.

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.195-206
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• 1995

The study was undertaken to examine the possibility of the involvement of $K^+$ channels in the mechanism of relaxant-action of imipramine on the isolated canine detrusor muscle strips. Canine urinary bladder were isolated, and smooth muscle strips of 15 mm long and 2 mm wide from the mid-portion of anterior wall were made in the Tyrode solution of $0{\sim}4^{\circ}C$. The strips were prepared for isometric myography in Biancani's isolated muscle chamber containing 1 ml of Tyrode solution, which was maintained with pH 7.4 by aeration with $95%\;O_2/5%CO_2\;at\;37^{\circ}C$. RP 52891, a non-specific $K^+$ channel opener, concentration-dependently suppressed the spontaneous phasic contractions of the detrusor strips. Imipramine, a tricyclic antidepressant, also reduced the spontaneous contractions in a concentration-dependent manner. RP 52891 was more potent than imipramine(p<0.05), and Imipramine was more efficient than RP 52891(p<0.05).Procaine, a voltage-dependent $K^+$ channel blocker, glibenclamide, an ATP-dependent $K^+$ channel blocker, and apamin, a calcium-dependent $K^+$ channel blocker antagonized the relaxant effect of RP 52891, but not of imipramine. Imipramine reduced the electric field stimulation (EFS) -induced contractions concentration-dependently. None of the $K^+$ channel blockers employed for this study, procaine, glibenclamide or apamin antagonized the inhibitory action of imipramine on the EFS-induced contraction. These results suggest that in canine detrusor, the $K^+$ channels of the characteristics of voltage-dependent, ATP-dependent and/or calcium-dependent are exist, and the inhibitory action of imipramine on the contractility of the detrusor is independent from the $K^+$ channels.

• The Korean Journal of Pharmacology
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• v.20 no.2
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• pp.7-14
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• 1984

In pithed rats, rising in diastolic blood pressure by clonidine, when intravenously injected, is expressed as the postsynaptic action, and inhibitory action on electrical stimulation-induced tachycardia by clonidine is expressed as the presynaptic inhibitory action. In this study it was aimed to observe the inhibitory effect of imipramine caused by a single and chronic administration on both postsynaptic and presynaptic action of clonidine in pithed rats, and discussed in relation with the mechanism of antidepressant action of imipramine. 1) A rise of diastolic blood pressure by clonidine was not antagonized by prazosin, but by both phentolamine and piperoxan. 2) The inhibition by clonidine of tachycardia which was induced by electrical stimulation was also antagonized by phentolamine and piperoxan, but not by prazosin. 3) The increase in diastolic blood pressure in response to clonidine was inhibited by both a single or chronic administration with imipramine (20 mg/kg). It was more pronounced in the latter. 4) The inhibitory action of clonidine on the tachycardia was markedly inhibited by both types of administration with imipramine, between which there showed little difference. It is concluded that the presynaptic ${\alpha}_2-adrenoceptor$ is rather sensitively affected by a single administration with imipramine, and a long-term imipramine treatment may inhibit both pre- and postsynaptic ${\alpha}_2-adrenoceptors$, simultaneously. Furthermore, it was seemed unlikely that these results provide the evidence :to support the fact that the subsensitivity of presynaptic ${\alpha}_2-adrenoceptor$ may be the mechanism of action of tricyclic antidepressant.

• Archives of Pharmacal Research
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• v.29 no.11
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• pp.998-1005
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• 2006

The effects of imipramine on A-type delayed rectifier $K^{+}$ currents and ATP-sensitive $K^{+}\;(K_{ATP)$ currents were studied in isolated murine proximal colonic myocytes using the whole-cell patch-clamp technique. Depolarizing test pulses between-80 mV and +30 mV with 10 mV increments from the holding potential of-80 mV activated voltage-dependent outward $K^{+}$ currents that peaked within 50 ms followed by slow decreasing sustained currents. Early peak currents were inhibited by the application of 4-aminopyridine, whereas sustained currents were inhibited by the application of TEA. The peak amplitude of A-type delayed rectifier $K^{+}$ currents was reduced by external application of imipramine. The half-inactivation potential and the half-recovery time of A-type delayed rectifier $K^{+}$ currents were not changed by imipramine. With 0.1 mM ATP and 140 mM $K^{+}$ in the pipette and 90 mM $K^{+}$ in the bath solution and a holding potential of -80 mV, pinacidil activated inward currents; this effect was blocked by glibenclamide. Imipramine also inhibited $K_{ATP}$ currents. The inhibitory effects of imipramine in A-type delayed rectifier $K^{+}$ currents and $K_{ATP}$ currents were not changed by guanosine 5-O-(2-thiodiphosphate) ($GDP{\beta}S$) and chelerythrine, a protein kinase C inhibitor. These results suggest that imipramine inhibits A-type delayed rectifier $K^{+}$ currents and $K_{ATP}$ currents in a manner independent of G-protein and protein kinase C.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.2
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• pp.161-167
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• 1997

This study compares the subtypes of central beta adrenergic receptors (ARs) of brains of untreated rats with those of imipramine-treated rats. Beta adrenergic receptors were measured by quantitative autoradiography of the binding of $^3H$-dihydroalprenolol ($^3H$-DHA) in coronal sections of rat brain. Repeated treatment of rats with imipramine significantly reduced the binding of $^3H$-DHA to beta-1 AR in many brain areas, especially throughout the cerebral cortex, hippocampus, thalamus, and amygdala. Significant reductions of the binding of $^3H$-DHA to beta-2 AR were not found in any area of the brain. These data suggests that a selective down-regulation of beta-1 AR may be involved in the adaptive changes occurring after prolonged imipramine treatment.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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• pp.109-117
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• 1998

Role of $Ca^{2+}$/calmodulin complex in intracellular $Ca^{2+}$ mobilization in neutrophils has not been clearly elucidated. In this study, effects of chlorpromazine, trifluoperazine and imipramine on the intracellular $Ca^{2+}$ mobilization, including $Ca^{2+}$ influx, in C5a-activated neutrophils were investigated. Complement C5a- stimulated superoxide production and myeloperoxidase release in neutrophils were inhibited by chlorpromazine, trifluoperazine and imipramine, except no effect of imipramine on myeloperoxidase release. A C5a-elicited elevation of [$Ca^{2+}$]i in neutrophils was inhibited by chlopromazine, trifluoperazine, imipramine, staurosporine, genistein, EGTA, and verapamil but not affected by pertussis toxin. The intracellular $Ca^{2+}$ release in C5a-activated neutrophils was not affected by chlorpromazine and imipramine. Chlorpromazine and imipramine inhibited $Mn^{2+}$ influx by C5a-activated neutrophils. Thapsigargin-evoked $Ca^{2+}$ entry was inhibited by chlorpromazine, trifluoperazine, imipramine, genistein, EGTA and verapamil, while the effect of staurosporine was not detected. The results suggest that $Ca^{2+}$/calmodulin complex is involved in the activation process of neutrophils. The depressive action of calmodulin inhibitors on the elevation of cytosolic $Ca^{2+}$ level in C5a-activated neutrophils appears to be accomplished by inhibition of $Ca^{2+}$ influx from the extracellular medium.

• Journal of Yeungnam Medical Science
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• v.11 no.2
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• pp.293-302
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• 1994

The objective of this study was to establish a good methodology to isolate single smooth muscle cells that are alive and respond properly to pharmacological agents. Canine urinary bladders were employed as the source of single cells, and acetylcholine, atropine and imipramine were used as indicators of pharmacological responsiveness. Imipramine, an antidepressant drug exhibited the anticholinergic and calcium antagonizing properties on rat detrusor muscle. To establish a control value for a further experiment to elucidate the mechanism of action of imipramine on detrusor muscle, we measured the concentration-response of single cells to acetylcholine in the presesnce of imipramine by length of the cells and compared the result with the response in the presence of atropine. Tiny chops of smooth muscle taken from anesthetized canine urinary bladder were incubated in collagenase solution at $36^{\circ}C$ for 17-20 minutes. The collagenase solution included collagenase 1.2 mg/ml, soybean tryspin inhibitor 0.08 mg/ml, bovine serum albumin 2% in 10 ml Krebs-Henseleit buffer solution aerated with a consistent breeze of 95/5% $O_2/CO_2$, to maintain the pH at 7.4. After washing with plain K-H solution on 450 mesh, cells were dissociated from the digested tissue for 12-15 minutes. Cell suspension was transfered in 5 ml test tubes and acetylcholine was added for the final concentration to be $10^{-14}M{\sim}10^{-9}M$. To find the optimal time to fix the cells to determine the contractile responses, 1% acrolein was added 5, 10, 20, 30, 60 and 120 seconds after the administration of ACh. The length of cells fixed by acrolein were measured by microscaler via CCTV camera on phaes-contrast microscope. The average length of 50 cells from a slide glass was taken as the value of a sample at the very concentration point. Single cells were isolated from canine detrusor. The length of untreated cells varied from 82 ${\mu}m$ to 94 ${\mu}m$. The maximal response to actylcholine $10^{-9}M$ was accomplished within 5 seconds of exposure, and the shortening was $19{\pm}3$%. Atropine reduced the contraction of the cells concentration-dependently. Imipramine which exerts a cholinergic blocking action on some smooth muscles also reduced the contraction concentration-dependently and by a similar pattern as atropine. These findings document that imipramine may exerts a cholinergic blocking activity in the single smooth muscle cells isolated from canine urinary bladder.