Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DESIPRAMINE”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,513 records · Page 84Linked to original sources
PubMed1998

The effects of T-588, a novel cognitive enhancer, on noradrenaline uptake and release in rat cerebral cortical slices.

Previously, we reported that (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)-ethoxy]e thanol hydrochloride (T-588), a novel cognitive enhancer, stimulated noradrenaline (NA) release from rat cerebral cortical slices. In this study, we investigated the effects of T-588 on NA uptake and release, compared to the effects of desipramine, a blocker of the NA carrier on the plasma membrane. Both T-588 and desipramine caused dose-dependent inhibition of [3H]NA uptake into the slices. Addition of 3 mM T-588 stimulated [3H]NA release from the prelabeled slices even in the presence of 10 microM desipramine, which inhibited NA uptake completely. Tyramine, which accelerates NA carrier-mediated release, also stimulated [3H]NA release, and tyramine-stimulated release was inhibited by desipramine. These findings indicated that T-588-stimulated NA release was not mediated by 1) inhibition of reuptake or 2) reverse transport mediated by NA carriers. Reserpine, which interacts with the intracellular vesicular transport system, increased [3H]NA efflux from slices. High K+-, not T-588-, stimulated [3H]NA release was shifted upward by reserpine. These findings suggest that T-588 evokes NA release by a mechanism similar to that induced by reserpine. T-588 might act as a cognitive enhancer via neurotransmitter release in the brain.

Adrenergic Uptake Inhibitors↗
PubMed1993

Analysis of imipramine and three metabolites produced by isozyme CYP2D6 expressed in a human cell line.

1. A commercially-available human cytochrome P450 isozyme (CYP2D6) preparation was used in imipramine metabolism studies. This isozyme catalysed both aromatic C-oxidation and N-demethylation. 2-Hydroxyimipramine was the major metabolite; desipramine was isolated in a significant amount and 2-hydroxydesipramine was a trace metabolite. 2. To prevent decomposition of metabolites during the analytical procedure, the metabolism mixture was derivatized with acetic anhydride prior to extraction, and the derivatized metabolites were separated and quantified by g.l.c. with N/P detection. The analytical procedure had excellent sensitivity and was capable of routinely quantifying imipramine and its metabolites down to the 0.36 nmol level. 3. In excess of 90% of drug and metabolites was consistently recovered when metabolism was conducted over a 5-60-min duration. 4. The formation of the secondary metabolite, 2-hydroxydesimipramine, from imipramine proceeds by two pathways, via desipramine and via 2-hydroxyimipramine; the former is the preferred pathway. 5. CYP2D6 catalyses C-hydroxylation of imipramine to 2-hydroxyimipramine more efficiently than its N-demethylation to desipramine. Also, the C-hydroxylation of imipramine to 2-hydroxyimipramine proceeds more efficiently than the conversion of desipramine to 2-hydroxydesipramine.

Catalysis↗
PubMed2001

Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice.

The development of serotonin receptor knockout mice has provided an opportunity to study antidepressant drug effects in animals with targeted genetic deletion of receptors involved in antidepressant responses. In the current study, the effects of two types of antidepressant drugs, the selective serotonin reuptake inhibitors fluoxetine and paroxetine and the selective norepinephrine reuptake inhibitor desipramine, were examined in 5-hydroxytryptamine (5-HT)(1A) and 5-HT(1B) receptor mutant mice using the tail suspension test (TST). Under baseline conditions, the immobility of 5-HT(1A) receptor mutant mice, but not 5-HT(1B) receptor mutant mice, was significantly lower than that of wild-type mice. The decreased baseline immobility in 5-HT(1A) receptor mutant mice was reversed by pretreatment with alpha-methyl-para-tyrosine, but not by para-chlorophenylalanine, suggesting mediation by enhanced catecholamine function. In wild-type mice, fluoxetine (10.0--20.0 mg/kg i.p.) and desipramine (5.0--20.0 mg/kg i.p.) both significantly decreased immobility in the TST. In 5-HT(1A) receptor mutant mice, desipramine (20.0 mg/kg i.p.) significantly decreased immobility, whereas fluoxetine (20.0 mg/kg i.p.) and paroxetine (20.0 mg/kg i.p.) had no effect. The immobility of 5-HT(1B) receptor mutant mice was decreased similarly by desipramine (5.0--20.0 mg/kg i.p.). However, the effect of low doses of fluoxetine were significantly augmented in the 5-HT(1B) receptor mutant mice (2.5--20.0 mg/kg i.p.) compared with wild-type mice. Administration of selective 5-HT receptor antagonists in wild-type mice partially reproduced the phenotypes of the mutant mice. These results suggest that 5-HT(1A) and 5-HT(1B) receptors have different roles in the modulation of the response to antidepressant drugs in the TST.

Amphetamine↗
PubMed1975

Effects of perphenazine on imipramine metabolism in man.

In previous studies we have shown that perphenazine inhibits the metabolism of nortriptyline and imipramine. In this study the metabolism of 14C-imipramine and 14C-desipramine was studied before and during treatment with perphenazine. Studies on the imipramine and desipramine metabolites in urine showed that the major effect of perphenazine is an inhibition of the 2-hydroxylation of imipramine and desipramine. This causes a decreased formation and excretion of non-conjugated and glucuronide bound hydroxy metabolites and accumulation of imipramine and desipramine. There was some relationship between the dose of perphenazine and the decrease in total urinary excretion but the individual variations in response were pronounced (2-3-fold).

Adult↗
PubMed1990

Antinociceptive action of tricyclic antidepressant drugs in the rat.

The antinociceptive effects of controlled release amitriptyline, desipramine, and placebo pellets were studied over 3 weeks using the hot plate method in 45 rats. Animals treated with desipramine at total doses of 50 mg (8 mg/kg/day) and 100 mg (16 mg/kg/day) displayed analgesia for up to 48 hours compared with the matching placebo groups. Amitriptyline did not produce significant analgesia at the same doses. By 72 hours until the final evaluation period at 21 days, the antinociceptive action of desipramine was no longer evident. These results suggest that relatively small continuously released doses of desipramine produce analgesia within 24 hours in this animal model, but an apparent analgesic tolerance develops within 3 days.

Amitriptyline↗
PubMed1990

Fluvoxamine in the treatment of tricyclic-resistant depression.

Following an initial double-blind, randomized, parallel treatment group comparison of fluvoxamine, desipramine, and placebo in 89 outpatients with major depression at two centers, double-blind crossover to fluvoxamine was offered to 13 of 22 desipramine-treated completers of the initial phase who were considered failures on desipramine. Twelve elected to cross over to blinded fluvoxamine, and eleven continued on fluvoxamine for at least eight weeks. Nine of these eleven improved, and overall there was a statistically significant decrease in average Hamilton Depression Scores, from 24 to 13, for these fluvoxamine-treated desipramine-resistant patients.

Adult↗
PubMed1990

A scale for rating tricyclic response in major depression: the TRIM.

We describe the construction and validation of the TRIM, an empirically derived scale designed to rate tricyclic antidepressant response in major depression. Symptoms selected were those that improved in direct association with therapeutic desipramine plasma levels, were frequently present, were substantially correlated with the scale total, could be reliably rated, and for which interview ratings were concordant with observed behavior. Eight symptoms met these criteria and were included. The sensitivity of the TRIM was tested and compared with the Hamilton Rating Scale for Depression (HAM-D) and the Montgomery Asberg Depression Scale (MADS) in a new 4-week prospective desipramine study of nonpsychotic unipolar inpatients with major depression. TRIM 4-week totals were significantly associated with total desipramine plus hydroxydesipramine plasma concentrations, r = -0.32, p less than 0.05, but HAM-D and MADS scores were not. Using multiple regression to control for pretreatment severity, TRIM scores were significantly associated with desipramine plus hydroxydesipramine levels, while HAM-D and MADS scores were not. The data appear to validate the sensitivity of the TRIM and illustrate that scales designed for drug response may detect drug effects that global scales do not.

Antidepressive Agents, Tricyclic↗
PubMed1986

Human fibroblast cultures as a tool for the study of antidepressant drug action.

Studies and interpretations of results of antidepressant drug action in brain are hampered by the complexity of the target organ. Biochemical and physiological effects of these drugs can, however, be studied profitably in cultured cells. We have investigated the effects of the tricyclic antidepressant desipramine on cultured human fibroblasts. The desipramine-induced changes were compared with effects of further antidepressants and of drugs with other therapeutic indications. In addition to the drug uptake and release, effects on phospholipid metabolism and on beta-adrenoceptor density were studied. The results showed an accumulation of desipramine within the lysosomal compartment and an inhibition of the phospholipid degradation resulting in a specific change of the cellular phospholipid-pattern. Chronic but not single dose exposure to desipramine reduced the number of beta-adrenoceptors and the isoproterenol-stimulated cAMP-response. This beta-adrenoceptor desensitization is thought to be causally related to the specific change of the phospholipid-pattern induced by the drug. It can be speculated that such a drug specific change of the phospholipid-matrix may be responsible for the alterations of a number of neurotransmitter receptors and of other membrane-associated functions, observed in brains of chronically drug treated animals.

Antidepressive Agents↗
PubMed1985

Neuronal and postjunctional components in the blood pressure effects of dopamine and bromocriptine in rabbits.

We have studied the contribution of neuronal and postjunctional dopamine (DA) receptors and of the DA1 and DA2 receptor subtypes to the blood pressure effects of DA and bromocriptine in the rabbit. The norepinephrine release rate, i.e., the rate of entry of endogenous norepinephrine into the plasma, was derived from the plasma level of endogenous norepinephrine and the plasma [3H]norepinephrine clearance. Bromocriptine (40 micrograms kg-1) lowered the norepinephrine release rate and the arterial blood pressure both in anesthetized rabbits and in pithed rabbits with electrically stimulated sympathetic outflow. These effects were antagonized by the selective DA2 antagonist domperidone but not by the selective DA1 antagonist SCH 23390. DA (10-160 micrograms kg-1 min-1) dose-dependently increased the norepinephrine release rate and caused only transient hypotension in anesthetized rabbits. However, after treatment with desipramine, DA did not change the norepinephrine release rate and produced a persistent fall in blood pressure. When DA and domperidone were given simultaneously to desipramine-treated rabbits, the hypotensive effect of DA was unchanged, but now DA increased the norepinephrine release rate. When DA and SCH 23390 were given simultaneously to desipramine-treated rabbits, DA failed to lower blood pressure and decreased the norepinephrine release rate. Propranolol did not change the effects of DA in desipramine-treated rabbits. These results suggest that bromocriptine decreases blood pressure by activating ganglionic and/or prejunctional, inhibitory DA2 receptors in the peripheral sympathetic nervous system. DA also activates these receptors, but in addition releases norepinephrine in the manner of an indirectly acting sympathomimetic amine and activates postjunctional vascular DA1 receptors, and the latter seems to be the main component in DA-induced hypotension.

Anesthesia↗
PubMed1987

Dihydroxyphenylglycol and intraneuronal metabolism of endogenous and exogenous norepinephrine in the rat vas deferens.

To elucidate the origin and significance of dihydroxyphenylglycol (DHPG) as a metabolite of norepinephrine (NE), the isolated rat vas deferens was preloaded with tracer amounts of tritiated NE and examined for the release of radioactive and endogenous NE and DHPG before and during electrical stimulation or stimulation with excess K+. Tissues were incubated with desipramine or reserpine to determine the effects of blockade of neuronal uptake and of interference with vesicular translocation of NE. Radioactive NE appeared to distribute differently from endogenous NE into at least two pools, but for the most part endogenous NE and DHPG behaved similarly in response to pharmacological manipulations. Desipramine blocked completely the increased appearance of both radioactive and endogenous DHPG in the medium during electrical stimulation or K+ stimulation; DHPG responses to stimulation are thus dependent on recapture of NE at the synapse. Basal release of DHPG was increased by reserpine, and this increase was not affected by desipramine; therefore, reserpine-induced release of DHPG is independent of neuronal uptake consistent with formation of DHPG from NE leaking into the cytosol from vesicular stores. Reserpine enhanced the release of DHPG during stimulation, and concomitant desipramine treatment blocked this effect; thus, interference with NE translocation into storage vesicles increases the availability of recaptured NE for intraneuronal metabolism. During stimulation of NE release between 70 to 80% of the recaptured NE was estimated to be sequestered into storage vesicles for rerelease. Combined measurement of endogenous and labeled NE and DHPG provides a useful tool for examining neuronal uptake and intraneuronal disposition of NE.

Animals↗
PubMed1984

Effect of age and sex on the plasma binding of acidic and basic drugs.

Protein binding of chlorpromazine, propranolol, meperidine, desipramine, salicylic acid and phenytoin was determined in plasma of 64 healthy volunteers (35 males and 29 females). An attempt was made to identify factors affecting the plasma protein binding of these drugs. Whereas plasma albumin levels decreased as a function of age in both sexes, alpha 1-acid glycoprotein levels increased with age, but the increase was more pronounced in males. The free plasma fraction of the acidic drugs (salicylic acid, phenytoin) and desipramine (a base) showed a significant (p less than 0.005) negative correlation with plasma albumin levels. The free fractions of the other three basic drugs (chlorpromazine, propranolol, meperidine) in plasma showed a significant (p less than 0.005) negative correlation with alpha 1-acid glycoprotein plasma levels. Plasma protein binding of salicylic acid, phenytoin and desipramine decreased as a function of age. Plasma protein binding of chlorpromazine, propranolol and meperidine was virtually unaffected by age or was slightly increased (chlorpromazine). Only in the case of salicylic acid could a statistically significant difference be demonstrated between males and females in the free fraction-age relationship. Stepwise multiple linear regression analysis, including age and blood chemistry values such as hematocrit, bilirubin, cholesterol, triglycerides, creatinine, BUN, albumin and alpha 1-acid glycoprotein as independent variables, identified age as the variable explaining most of the variability in plasma binding of salicylic acid, phenytoin and desipramine. For chlorpromazine, propranolol and meperidine alpha 1-acid glycoprotein was the most important determinant of plasma protein binding.

Adolescent↗
PubMed1994

Tricyclic antidepressant concentrations in plasma: an estimate of their sensitivity and specificity as a predictor of response.

An analysis of the literature on tricyclic antidepressant level in blood using receiver operating characteristics curves as the primary statistical tool was performed. For nortriptyline, a significant curvilinear relationship between therapeutic response and nortriptyline was observed that ranged from 58 to 148 ng/ml. The sensitivity and specificity for the nortriptyline therapeutic window were 78 and 61%, respectively. The response rate within the therapeutic range was 66% versus 26% outside the therapeutic range. For desipramine, a significant linear relationship between therapeutic response and desipramine concentration in plasma was observed. The threshold concentration in plasma for therapeutic response was 116 ng/ml. The sensitivity and specificity for the desipramine threshold level in blood were 81 and 59%, respectively. The response rate above the threshold level was 51% versus 15% below the therapeutic threshold concentration. For imipramine, a significant curvilinear relationship between therapeutic response and total imipramine (imipramine+desipramine) concentration in plasma was observed between 175 and 350 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 52 and 74%, respectively. The response rate within the therapeutic range was 67% versus 39% outside the therapeutic range. For amitriptyline, a significant curvilinear relationship between therapeutic response and total amitriptyline (amitriptyline+nortriptyline) concentration in plasma was observed between 93 and 140 ng/ml. The sensitivity and specificity for the total imipramine concentrations in plasma were 37 and 80%, respectively. The response rate within the therapeutic range was 50% versus 30% outside the therapeutic range.

Adolescent↗
PubMed1977

Neurochemical properties of 3,3-dimethyl-1-[3-(methylamino) propyl]-1-phenylindan HCl (LU 3-049) and selected tricyclic antidepressants.

Lu 3-049 was compared to certain antidepressants on biogenic amine metabolism. Like desipramine, Lu 3-049 was found to possess potent and selective inhibitory effects on norepinephrine uptake. In rat brain and mouse heart, both agents were found to be considerably more potent than imipramine and chlorimipramine. Unlike the latter, Lu 3-049 and desipramine possessed weak inhibitory effects on serotonin uptake in brain or spleen. Brain norepinephrine levels were unaltered following single or repeated doses of either agent. Desipramine caused a marked increase in norepinephrine turnover; Lu 3-049 caused no change or a slight decrease in turnover. Lu 3-049 had neither inhibitory effects on monoamineoxidase activity in brain or liver nor affected norepinephrine release from brain slices. Presumptive of inhibition of amphetamine metabolism, and in decreasing order of potency, iprindole, desipramine and Lu 3-049 elevated brain levels of amphetamine. Thus, Lu 3-049 shares some but not all of the biochemical properties of tricyclic antidepressants.

Amphetamines↗
PubMed1996

Role of noradrenaline uptake inhibition and alpha-adrenoceptors in reperfusion ventricular arrhythmias in vivo and in vitro.

In view of the importance of sympathetic nervous system in the genesis of cardiac arrhythmias during reperfusion following coronary occlusion, the role of noradrenaline uptake inhibitor desipramine in the prevention of reperfusion arrhythmias was investigated in intact rabbit heart and isolated rat heart. For both the paradigms, ischaemia was produced by coronary artery ligation for 30 min followed by reperfusion for 60 min with drug administration at the time of reperfusion. Desipramine was used at three dose levels (0.2, 0.6 and 2.0 mg/kg) in the in vivo study while in vitro it was used at a concentration of 7 microM. Further, to investigate the status of adrenergic receptors during ischaemia and reperfusion, ischaemia was simulated by superfusing lactate physiological solution in isolated rabbit aortic strip preparation, which has well characterized alpha-receptors. Cumulative dose response curves (DRC) of selective alpha 1 agonist, phenylepherine (PE) were recorded during normal, ischaemic and reperfused conditions. Desipramine showed dose dependent anti-arrhythmic effect in vivo as well as in vitro. In intact heart studies desipramine offered protection against reperfusion arrhythmias in a dose related manner i.e. 50, 67.5 and 100% whereas in isolated studies, 50% protection was observed in the overall incidence of arrhythmias. DRC of PE shifted towards right during both ischaemia and reperfusion with a significant elevation of maximal response only during reperfusion.

Adrenergic Uptake Inhibitors↗
PubMed2001

Antidepressants for cocaine dependence.

BACKGROUND: Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. The past decade has witnessed a sustained search for an effective pharmacotherapeutic agent for the treatment of cocaine dependence. While administration of cocaine acutely increases intercellular dopamine, serotonin, and norepinephrine levels by blocking their presynaptic reuptake, chronic cocaine abuse leads to down-regulation of monoamine systems. Post-cocaine use depression and cocaine craving may be linked to this down-regulation. Antidepressant pharmacotherapy, by augmenting monoamine levels, may alleviate cocaine abstinence symptomatology, as well as relieving dysphoria and associated craving by general antidepressant action. OBJECTIVES: To conduct a systematic review of all RCTs on the use of antidepressants for treating cocaine dependence. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, issue 4, 2000), MEDLINE (from 1966 - 2000), EMBASE (from 1980 - 2000), LILACS (from 1982 - 2000), PsycLIT (from 1974 - 2000), Biological Abstracts (1982 to 2000). Other searches:reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. SELECTION CRITERIA: The inclusion criteria for all randomised controlled trials were that they should focus on the use of antidepressants on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. DATA COLLECTION AND ANALYSIS: The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. MAIN RESULTS: 18 studies were included in the review, with 1177 people randomised. Positive urine sample for cocaine metabolites was the main efficacy outcome, with no significant results obtained regardless the type of antidepressant. Compared to other drugs, desipramine performed better but showing just a non significant trend with heterogeneity present as revealed by the chi-square test (8.6, df=3; p=0.04). One single trial showed imipramine performed better than placebo in terms of clinical response according to patient's self-report. A similar rate of patients remaining in treatment was found for both patients taking desipramine or placebo. Results from one single trial suggest fluoxetine patients on SSRIs are less likely to dropout. Similar results were obtained for trials where patients had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. REVIEWER'S CONCLUSIONS: There is no current evidence supporting the clinical use of antidepressants in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding psychotherapeutic supportive measures aiming to keep patients in treatment.

Antidepressive Agents↗
PubMed1986

Effects of combined administration of diazepam and imipramine hydrochloride in rats.

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50 mg/kg) and/or diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5 mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100 g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydrochloride plus diazepam treatment group did not show increased imipramine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Tricyclic antidepressants inhibit the Ca(2+)-dependent ATPase activity from plasma membrane.

Tricyclic antidepressants are moderately potent inhibitors of the plasma membrane Ca(2+)-ATPase activity measured in erythrocyte ghosts. For the calmodulin-activated activity, half-maximal inhibition was observed in the presence of 0.25 mM clomipramine. Desipramine, imipramine, and trimipramine show half-maximal inhibition in the range of 0.8 to 1 mM. The inhibition dependence on clomipramine concentration is the same whether the enzyme is activated by exogenous calmodulin or by tryptic digestion. A similar behavior was observed for desipramine. The inhibition mechanisms utilized by clomipramine and desipramine are different. The clomipramine effect is associated with the Ca(2+)-bound enzyme conformation and can be attributed to a decrease in the rate of phosphorylation by ATP. The desipramine effect appears more related to the Ca(2+)-free conformation, since the partial reaction involved in the release of inorganic phosphate is perturbed by this drug. There is also little or no effect of tricyclics on the enzyme's affinity for ligand (Ca(2+) or ATP) binding.

Adenosine Triphosphate↗
PubMed1994

Cardiac noradrenaline release accelerates adenosine formation in the ischemic rat heart: role of neuronal noradrenaline carrier and adrenergic receptors.

In the present study the hypothesis was tested that local noradrenaline release contributes to adenosine formation in myocardial ischemia. Therefore, in ischemic non-working rat hearts either adrenergic receptors or ischemia-evoked noradrenaline release were blocked. Noradrenaline and adenosine were determined in the effluent using HPLC-methods. Following 20 min of stop of perfusion flow both the beta-adrenergic receptor antagonist bisoprolol (91.6 +/- 10.5 nmol/g) and the inhibitor of ischemia-induced noradrenaline release desipramine (108.5 +/- 12.5 nmol/g) caused a suppression of adenosine release (control: 140.9 +/- 7.3 nmol/g). To examine the time-course of the release, further experiments were performed at constant perfusion flow with energy metabolism blocked by cyanide together with removal of glucose from the perfusion buffer. This condition resulted in a nearly simultaneous release of adenosine and noradrenaline from the hearts. The beta-adrenoceptor blocking agents atenolol and bisoprolol postponed the release of adenosine, whereas the alpha-antagonists prazosin and yohimbine had no effect on adenosine release induced by cyanide. None of the adrenergic receptor blockers affected the release of noradrenaline. The inhibitors of the neuronal noradrenaline carrier (uptake1) desipramine, oxaprotiline, and cocaine suppressed the release of noradrenaline during cyanide administration, indicating a carrier-mediated efflux of noradrenaline. Reduction of extracellular noradrenaline by these agents coincided with a delay of adenosine release (cumulative release within 20 min--control: 251.2 +/- 13.9, desipramine: 172.1 +/- 15.3, oxaprotiline 36.5 +/- 5.8, cocaine: 111.8 +/- 23.6 nmol/g). Desipramine and cocaine were also used during administration of exogenous noradrenaline in normoxic hearts, to confirm specificity of their action.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗