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At least 145 records · Page 8Linked to original sources

PubMed1996

Inhibitory effect of noradrenaline uptake inhibitors on contractions of rat aortic smooth muscle.

1 The effects of noradrenaline (NA) uptake inhibitors on contractions induced by NA, high K+, and 12-O-tetradecanoylphorbol-13-acetate (TPA) in rat isolated aorta were investigated. 2 Protriptyline (0.3 microM) and amitriptyline (0.3 microM) produced an approximately parallel shift to the right in the dose-response curve to NA. Protriptyline (> 0.3 microM), amitriptyline (> 0.3 microM) and xylamine (0.01-1 microM) significantly reduced the maximal contractile response to NA. The IC50 values for inhibition of the contractile response to 3 microM NA were 1.58 microM for xylamine, 1.70 microM for amitriptyline and 2.57 microM for protriptyline. 3 Protriptyline and amitriptyline dose-dependently inhibited the high K+ (60 mM)-induced contraction (IC50 = 0.69 microM for protriptyline and IC50 = 3.15 microM for amitriptyline). In contrast, xylamine did not affect the high K(+)-induced contraction. 4 Protriptyline and amitriptyline dose-dependently inhibited TPA (1 microM)-induced contraction in calcium-free solution; xylamine (up to 30 microM) was without effect. Staurosporine (10 nM) completely inhibited the TPA- and NA-induced contraction. 5. Protriptyline (3 microM) and amitriptyline (3 microM) caused about 54% and 60% inhibition, respectively, of aortic contractions caused by endothelin-1 (10 nM) in the absence of endothelium. Xylamine (10 microM) was without effect. 6 Inhibitory effects of NA uptake inhibitors on contractions were independent of the presence of endothelium and were unaffected by the K+ channel blockers, tetraethylammonium ions (up to 3 mM) and glibenclamide (up to 30 microM). 7 These results indicate that tricyclic antidepressant drugs such as protriptyline and amitriptyline could act as both postsynaptic adrenoceptor antagonists and direct inhibitors of muscle contraction; whereas, xylamine, a structurally distinct NA uptake blocker might principally exert its action only at alpha-adrenoceptors on rat aortic smooth muscle.

Adrenergic Uptake Inhibitors↗

PubMed1976

Relationships between chronotropic effect, 1-3H-noradrenaline uptake and tissue concentrations of desipramine, protripyline and doxepin in rat isolated atria.

The pharmacological effects of three tricyclic antidepressant agents (desipramine, protriptyline and doxepin) are evaluated in rat isolated atria in relation to their accumulation and efflux kinetics. The pharmacological effects studed are: inhibition of 1-3H-noradrenaline uptake, potentiation of 1-noradrenaline chronotropic response, and changes in spontaneous atrial rate. All drugs inhibit noradrenaline uptake and potentiate noradrenaline chronotropic response (desipramine congruent to protriptyline greater than doxepin). Desipramine and protriptyline, at concentrations of 10(-7) -- 10(-6)M stimulate the spontaneous rate; higher concentrations (greater than 10(-6)M) depress it. Doxepin has only a negative chronotropic effect. When the drugs are removed from the incubation medium, the depressing effect starts to disappear immediately for doxepin and desipramine and after 20 min for protriptyline. On the contrary the stimulating effect persists after repeatedly washing the preparations. Desipramine, protriptyline and doxepin extensively accumulate in the myocardial tissue (desipramine larger than or equal to protriptyline greater than doxepin). In the efflux studies doxepin is washed out more rapidly than desipramine and protriptyline. Although the kinetics of uptake and efflux of the three compounds are not sufficient to interpret their different pharmacological activities in isolated atria, they give useful information on the persistance of the sympathomimetic effect and the rapid disappearing of the negative chronotropic effect after washing.

Animals↗

PubMed1997

Inhibition of contractions by tricyclic antidepressants and xylamine in rat vas deferens.

The effects of noradrenaline uptake inhibitors on contractions evoked by electric field stimulation, noradrenaline, clonidine. 5-hydroxytryptamine, ATP, high K+, and BaCl2 in the epididymal half of rat isolated vas deferens were examined. Protriptyline, amitriptyline and xylamine concentration-dependently inhibited monophasic contractions induced by low frequency electrical stimulation (0.3 Hz, 1 ms duration, 60 V). Protriptyline and xylamine inhibited in a noncompetitive manner the contractile response induced by noradrenaline (3 x 10(-8)-3 x 10(-5) M) and the inhibitory effect of protriptyline was reversible, while xylamine produced long-lasting inhibition. All three noradrenaline uptake blockers inhibited the clonidine (3 x 10(-6) M) or 5-hydroxytryptamine (10(-5) M)-induced contraction. Protriptyline and amitriptyline at concentrations of 3 x 10(-6)-3 x 10(-5) M reversibly inhibited the ATP (10(-4) M)-induced monophasic contraction. In contrast, xylamine ((1-3) x 10(-5) M) had no effect. Protriptyline and amitriptyline but not xylamine concentration-dependently reduced the high K+ (6 x 10(-2) M)-induced sustained contraction with respective IC50 values of 1.81 x 10(-6) M and 8.6 x 10(-7) M. Protriptyline and amitriptyline at 10(-5) M reversibly inhibited BaCl2 (3 x 10(-3) M)-induced phasic contractions and xylamine (10(-5) M) had no effect. These findings demonstrate that tricyclic antidepressants might exert direct inhibitory action on mechanical contraction pathway, whilst xylamine, a structurally different inhibitor of noradrenaline uptake, may act mainly at alpha-adrenoceptors and other amine receptors on the smooth muscle of the rat vas deferens as a long-lasting nonselective antagonist, and it at least in part blocks sympathetic transmission.

Adenosine Triphosphate↗

PubMed1984

Antiarrhythmic action of bethanidine.

Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine the efficacy of bethanidine compared with procainamide in preventing VT induced by programmed electrical stimulation. Before administering bethanidine, 5 to 10 mg/kg, the patients received 15 mg of protriptyline orally 24 and 2 hours before electrophysiologic studies to prevent the orthostatic hypotensive effects of bethanidine. Sustained VT (VT not spontaneously stopping) was induced in 8 and nonsustained VT (10 beats or more, terminating spontaneously) was induced in 4 patients. Bethanidine, 5 mg/kg, protected in 7 patients, and 10 mg/kg protected 1 additional patient. Procainamide, 1,000 and 1,500 mg intravenously, protected 8 of 16 patients. Bethanidine prevented VT induction in 50% of the patients not protected by procainamide. Bethanidine facilitated VT induction in 3 patients, while procainamide facilitated VT induction in 1 patient. Four patients with symptomatic VT have received bethanidine therapy for an average of 11 +/- 1.3 months, without clinical recurrence of their VT. Concomitant administration of protriptyline attenuated the acute hemodynamic changes caused by bethanidine and chronic combined therapy of protriptyline and bethanidine abolished the severe orthostatic changes in blood pressure caused by bethanidine. These studies show that bethanidine is effective in preventing VT induction and, thus, its use may not be restricted only to cases of primary ventricular fibrillation.

Bethanidine↗

PubMedDate not supplied

Anti-nociceptive effect of tricyclic anti-depressants following intrathecal administration.

The anti-nociceptive effects of three tricyclic anti-depressants (desipramine, protriptyline, fluoxetine) were evaluated in mice following intrathecal administration. Nociceptive behavior was produced by intrathecal administration of Substance P and measured for 60 seconds following subcutaneous and intrathecal administration of vehicle and increasing doses of the drugs being tested. Systemically administered protriptyline produced dose related antinociception in this paradigm. A similar effect was seen following systemic desipramine; while fluoxetine was inactive systemically. Both protriptyline and desipramine given intrathecally were antinociceptive while fluoxetine had a biphasic effect, being analgesic only at low doses. These results indicate that tricyclic antidepressants may produce analgesia at the spinal level in rodents. This action may be related to the therapeutic success of tricyclic antidepressants in chronic pain syndromes.

Analgesics↗

PubMedDate not supplied

Effects of tricyclic antidepressant drugs on the electrophysiological properties of drug Purkinje fibers.

Microelectrode techniques were used to study the electrophysiologic effects of the tricyclic antidepressant (TCA) drugs imipramine , amitriptyline, doxepin, desipramine, protriptyline, and nortriptyline on isolated Tyrode's ([K +]o= 4.0 mM) superfused dog Purkinje fibers. Drug concentrations ranged from 10(-7) to 10(-5) M. TCA drug concentrations greater than 10(-6) M resulted in decreases in action potential amplitude, duration, and maximum slope of phase O (Vmax). Simultaneously with decreases in action potential duration, the effective refractory period decreased. In addition, the voltage time course of repolarization between proximally and distally recorded action potentials became less obvious. Imipramine, doxepin, protriptyline, and nortriptyline (10(-6), 10(-5) M) depressed membrane responsiveness. Superfusion of dog Purkinje fibers with 10(-5) M concentrations of TCA drugs resulted in conduction delay, postrepolarization refractoriness and, occasionally, total inexcitability. TCA drugs caused an increase in escape time and a decrease in spontaneous rate of spontaneously automatic Purkinje fibers equilibrated with epinephrine (10(-7) M) in 5 X 10(-5) M EDTA. Imipramine, doxepin, protriptyline, and nortriptyline abolished extra nondriven action potentials, and diminished oscillatory afterpotentials in dog Purkinje fibers exposed to toxic concentrations of ouabain (2 X 10(-7) M).

Action Potentials↗

PubMed1978

Drowsiness, impaired performance and tricyclic antidepressants drugs.

1. The effects of amitriptyline, protriptyline, protriptyline, and a chemically related potential antidepressant, BW247, on performance tests and subjective ratings were studied. 2. Two groups of twelve healthy subjects received drugs and lactose dummy in identical capsules at weekly intervals according to a balanced design, under double-blind conditions, and with standarized tests and environment. 3. Amitriptyline produced the most marked effects, with significant (P less than 0.05) impairment in auditory vigilance after 6.25 mg. Auditory reaction time, tapping rate, arithmetic, and digit symbol substitutions were impaired by amitriptyline 12.5 and 25 mg and all doses produced increased ratings of mental sedation. The effects began 1.5 h after drug and lasted approximately 5 h. 4. Nortriptyline produced fewer effects which were later in onset. Tapping at 1.8 h and auditory vigilance at 3.5 to 4.5 h were impaired by nortriptyline 25 mg whereas reaction time was prolonged by both doses at 5 h. No change in rating of mental sedation occurred. 5. No significant change in performance or subjective ratings followed protriptyline 10 mg or BW247, 12.5 and 25 mg. 6. The findings are discussed in relation to the presence of secondary and tertiary amines on the side chain of the compounds, and their relative abilities to block neuronal uptake of noradrenaline and 5-hydroxytryptamine.

Acoustic Stimulation↗

PubMed1978

The effect of gamma-butyrolactone on locomotor activity in the rat.

The effect of gamma-butyrolactone (GBL) on locomotor activity in the rat was studied. Low doses of GBL (100 and 200 mg/kg) had a biphasic effect on activity. Initially, the activity of the rats was reduced, and this reduction was then followed by a period of hyperactivity. The effect of alpha-flupenthixol (50 microgram/kg alpha-FPT), atropine (10 mg/kg), benztroine (25 mg/kg), protriptyline (15 mg/kg), and clomipramine (25 mg/kg) was investigated on this biphasic effect. alpha-FPT reduced the hyperactivity while benztropine potentiated it; atropine, clomipramine, and protriptyline had little effect. It is concluded that the increase in activity could be due to a release of dopamine.

4-Butyrolactone↗

PubMed1991

Effects of tricyclic drug on induced circular dichroism spectra of dicumarol bound to alpha 1-acid glycoprotein.

Effects of both tricyclic and non-tricyclic drugs on the extrinsic Cotton effects of dicumarol bound to human alpha 1-acid glycoprotein (AGP) have been investigated. Basic tricyclic drugs caused the reversal of the signs of the induced Cotton effects of the circular dichroism (CD) spectra of the dicumarol-AGP system while the basic drugs not possessing tricyclic rings and acidic drugs decreased the observed ellipticities without changing the signs of its CD spectra. There was no reversal of the CD signs of the drugs not containing two hydroxycoumarin rings bound to AGP by basic tricyclic drugs. Raising of pH and temperature, and the addition of guanidine hydrochloride decreased the observed ellipticities of the CD spectra of the dicumarol-AGP system without showing any change in the signs of the Cotton effects. The mutual displacement data showed that protriptyline increased its own binding and that of dicumarol with AGP. The results of CD titration and equilibrium dialysis experiments suggest that dicumarol-AGP and dicumarol-AGP-protriptyline form a 1:1 binary complex and a 1:1:1 ternary complex, respectively.

Antidepressive Agents, Tricyclic↗

PubMed1978

Serotonergic reduction of dorsal central gray area stimulation-produced aversion.

Stimulating electrodes were implanted into the dorsal central gray area (DCG) of rats. The animals were trained to bar press to decrement the aversive DCG stimulation current. Rats treated with 5-hydroxytryptophan (5-HTP), 75 mg/kg or 150 mg/kg, showed a dose-dependent reduction in decremental bar pressing. In a second study, animals received either chlorimipramine, 15 mg/kg, protriptyline, 15 mg/kg, or 5-HTP, 150 mg/kg. Chlorimipramine, a strong blocker of serotonin reuptake, and 5-HTP produced significant reductions in decremental bar pressing. Protriptyline, a weak serotonin reuptake blocker, produced no significant effect. These results suggest that serotonin reduces aversive neural mechanisms associated with the dorsal central gray area.

5-Hydroxytryptophan↗

PubMed1985

Bethanidine sulfate: efficacy in prevention of ventricular tachyarrhythmias during programmed stimulation. Report of a multicenter study of 56 patients.

Twelve cardiac electrophysiology centers conducted an open label prospective trial of bethanidine sulfate, an oral bretylium analog, for the prevention of ventricular tachyarrhythmias during programmed electrical stimulation. The study group included 56 patients (44 men, 12 women; mean age 60 years; 55 with structural heart disease). Sixteen patients had both ventricular tachycardia and fibrillation, 30 had ventricular tachycardia alone and 10 had ventricular fibrillation alone. Programmed stimulation on no antiarrhythmic drugs induced sustained ventricular tachycardia in 46 patients, nonsustained ventricular tachycardia in 4 patients and ventricular fibrillation in 6 patients. During programmed ventricular stimulation after 59 trials of 20 to 30 mg/kg body weight of oral bethanidine (acute dosing in 40 patients, and divided dosing over 24 hours in 19 patients), no ventricular tachyarrhythmias were inducible in 6 patients (11%), sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 3 patients (5%), ventricular tachyarrhythmias remained inducible in 39 patients (70%) and spontaneous ventricular tachyarrhythmias occurred more frequently in 4 patients (7%). Side effects prevented repeat testing in four patients. The 10 patients presenting with only ventricular fibrillation appeared to have a higher response rate: no ventricular tachyarrhythmias were inducible in 2 patients and sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 2 patients. Despite protriptyline administration in 54 of 59 bethanidine trials, symptomatic hypotension occurred in 30 trials (51%). In conclusion, the efficacy of bethanidine for preventing ventricular tachyarrhythmias as assessed by programmed stimulation is low. Patients presenting with only ventricular fibrillation may have a more favorable response to bethanidine sulfate. Symptomatic hypotension occurs frequently despite concomitant use of protriptyline.

Adult↗

PubMed1983

Sleep apnea.

Sleep apnea is characterized by recurrent upper airway obstruction, resulting in periodic apneic episodes that are associated with oxygen desaturation and frequent awakenings. This leads to daytime somnolence and, possibly, pulmonary hypertension and cor pulmonale. Tracheostomy has been the standard treatment for severe sleep apnea with life-threatening complications. Several recent studies have reported benefits of protriptyline in obstructive sleep apnea. The drug does not completely resolve the apnea, but does improve nocturnal oxygenation and reduce daytime hypersomnolence. Protriptyline should be considered an alternative to tracheostomy in patients with benign or moderately severe obstructive sleep apnea.

Humans↗

PubMed1978

Effect of uptake inhibitors on the depletion of brain norepinephrine and serotonin after alpha-methyl-m-tyrosine administration to rats.

The depletion of brain norepinephrine after alpha-methyl-m-tyrosine injection into rats was antagonized by pretreatment with an uptake inhibitor (protriptyline or chlorimipramine) but was not completely prevented. Administration of protriptyline after alpha-methyl-m-tyrosine injection, at a time when norepinephrine had been depleted, partially reversed the depletion. Serotonin depletion after alpha-methyl-m-tyrosine was not altered by pretreatment with fluoxetine, an inhibitor of uptake into serotonin neurons. Apparently part of the norepinephrine (but not serotonin) depletion occurring after alpha-methyl-m-tyrosine injection is due to the action of amine products that enter the norepinephrine neuron via the membrane uptake pump and whose presence within the nerve terminals is maintained by the uptake pump.

Animals↗

PubMed1981

Monoaminergic mechanisms and experimental cataplexy.

The effects of pharmacological alteration of the monoamine systems were investigated in a canine model of narcolepsy. Cataplexy was quantified in eight severely affected dogs by means of the food-elicited cataplexy test. The specific norepinephrine (NE) uptake blocker nisoxetine, and (to a much lesser extent) the specific serotonin (5-HT) uptake blocker fluoxetine, significantly suppressed cataplexy, as did the tricyclic antidepressants protriptyline, amitriptyline, and chlorimipramine. Thus, experimental cataplexy is suppressed more by inhibition of the uptake of NE than of 5-HT. Methylphenidate, the alpha-adrenoreceptor blocker clonidine, and the dopamine receptor blocker pimozide also suppressed cataplexy in dogs. The beta-adrenergic blocker propranolol, the fatty acid gamma-hydroxybutyrate, and the monoamine oxidase inhibitors clorgyline and pargyline had little or no effect. With one exception (pimozide), all the drugs that suppressed cataplexy are known to be potent suppressors of REM sleep. The suppression of cataplexy induced by nisoxetine or protriptyline was reversed by the anticholinesterase physostigmine, further supporting a postulated aminergic-cholinergic interaction in the mechanisms for cataplexy.

Animals↗

PubMed1978

Intrapatient variability of serial steady-state plasma tricyclic antidepressant concentrations.

Nine or 10 serial steady-state plasma measurements of amitryptyline, desipramine, desmethyldoxepin, doxepin, imipramine, nortriptyline, or protriptyline were made in 23 depressed patients. Each patient was monitored for compliance by pill counts, and sampling time was controlled carefully to determine intrapatient variability of steady-state tricyclic levels on a day-to-day basis. The coefficients of variation during serial sampling of the various ingested drugs were: amitriptyline, 21%; desipramine, 26%; doxepin, 21%; imipramine, 14%; nortriptyline, 13%; and protriptyline, 17%. The therapeutic ranges for the tricyclic antidepressants are relatively wide, so coefficients of variation of these magnitudes indicate that the position of an individual patient in relation to the optimal therapeutic range can be reliably determined on a clinical basis.

Antidepressive Agents, Tricyclic↗

PubMed1990

Drug partitioning and release characteristics of tricyclic antidepressant drugs using a series of related hydrophilic-hydrophobic copolymers.

A series of crosslinked polymer networks formed from hydrophilic polyethylene oxide (PEO) and a hydrophobic polysiloxane (PGPMDMS) were studied with respect to the partitioning and release of five tricyclic antidepressants (TCAs) at pH 7.4. The TCAs, chemical analogues of one another, have both nonpolar and ionic characteristics at pH 7.4, but differ considerably in hydrophobicity. In PEO-PGPMDMS copolymer networks, the partition coefficient of protriptyline (the TCA studied most extensively) was observed to be higher than in networks of PEO or PGPMDMS singly. This finding, which may represent adsorption of the amphiphilic drug at interfacial sites between hydrophilic and hydrophobic phases within the copolymeric network, shows that in some cases, higher drug loadings of amphiphilic drugs can be obtained with a hydrophilic-hydrophobic copolymer compared with a material made of only one polymer. As the PEO content in PEO-PGPMDMS networks was increased from 20 to 100%, the release rate of protriptyline increased by greater than 1000-fold. Thus, a key variable in achieving a desired release rate is the PEO content of the copolymer. On the other hand, release rates of the five TCAs from PEO-PGPMDMS networks containing 50% PEO varied by a factor of less than 3. Thus, minimal effect on drug release rates was obtained by using a different TCA analogue.

Antidepressive Agents, Tricyclic↗

PubMed1988

Antidepressants and human memory: an investigation of four drugs with different sedative and anticholinergic profiles.

The effects on memory and psychomotor functions of four antidepressants which differ in sedative and anticholinergic properties were assessed. Amitriptyline (37.5, 70 mg), trazodone (100, 200 mg) viloxazine (100, 200 mg), protriptyline (10, 20 mg) or placebo were administered in a double blind, independent groups design in which 90 subjects participated. Subjects completed a battery of tests before and 2 and 4 h after drug administration. The different antidepressants produced different patterns of effects across tasks. The relatively non-sedating compounds viloxazine and protriptyline produced very similar profiles and did not impair psychomotor or memory functions. In contrast, the two more sedative antidepressants produced global impairments on test of attention, manual motor speed, recording skills and primary memory. Although both amitriptyline and trazodone impaired performance on episodic memory tasks, the effect of amitriptyline was significantly greater and this may reflect specific anticholinergic action over and above global sedative effects.

Adult↗

PubMedDate not supplied

Tricyclic antidepressants: effects on extinction and fear learning.

Rats trained to run an alley for a food reward were extinguished following injections of different antidepressants. When retested several days later, the animals extinguished following pretreatment with the NE reuptake blocker protriptyline showed faster running speeds than did the other groups. Other rats given electrical shocks following pretreatment with protriptyline avoided the compartment in which they had been shocked less than did animals shocked following pretreatment with other antidepressants. This implies an interferance with some aspect of the learning or consolidation process which is correlated with the degree of NE reuptake blockage. It is hypothesized that NE terminals are deactivated following frustrative nonreward or punishment by the conversion and reuptake of the released NE to an altered extinction molecule.

Animals↗