Anthony P. Zavadil

Effects of desmethylimipramine on plasma norepinephrine, pulse, and blood pressure.

We followed the effects of a tricyclic antidepressant selective for norepinephrine (NE) uptake inhibition, desmethylimipramine (DMI), on blood pressure, heart rate, and plasma NE level in healthy subjects. After a single oral dose of 100 mg DMI, supine systolic and diastolic blood pressure and supine and upright heart rate rose, and there was an increment in heart rate with standing. After long‐term low doses of the drug (mean daily dosage 67.5 mg), the upright level and increment with standing in plasma NE also rose. Supine NE levels also rose after the long‐term higher dose (mean daily dosage 125 mg). No differences in any measures were detected between the short‐ and the two long‐term dose levels of DMI. Our findings suggest that NE uptake inhibition induces physiologic elevation of NE concentration in the sympathetic neuroeffector region. A similar effect at synapses in the CNS might be involved in the mechanism of antidepressant action.

Altered hydroxydesipramine concentrations in elderly depressed patients

Recent reports demonstrate that hydroxy metabolites of desipramine (DMI) have pharmacologic activity and do not just produce side effects. In patients treated with DMI, we determined the ratio of 2‐hydroxydesipramine (2‐OH‐DMI) to drug at steady state. The ratios in the elderly patients were higher than in younger patients, and whereas plasma levels of 2‐OH‐DMI increased with age, urinary clearances decreased. The known decrease in glomerular filtration with age may explain the selective increase of 2‐OH‐DMI concentration in the elderly.

Effect of imipramine on norepinephrine and blood pressure in enuretic boys.

The effect of imipramine, desmethylimipramine, and methscopolamine on blood pressure (BP) and plasma norepinephrine (NE) was measured in enuretic boys in a double‐blind, placebo‐controlled study. Measurements were obtained on the thirteenth day of medication (75 mg at bedtime). The tricyclic drugs induced a rise in diastolic BP as well as an increase in plasma NE but there was no significant relationship between the increments in plasma NE and BP. The plasma concentration of drug correlated with the drug‐induced BP rise. This is the fifth study to demonstrate a hypertensive effect of tricyclic drugs in children in contrast to the systolic hypotension usually seen in adult patients. It is not clear from our data whether children have different cardiovascular compensatory reflexes or whether they experience a greater stimulant effect from the drug.

Hormonal responses to zimelidine and desipramine in depressed patients

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

The effect of oxotremorine on blood pressure and plasma catecholamines in conscious and anesthetized rats.

Abstract Oxotremorine causes a pressor response in conscious rats which is associated with a large increase in circulating catecholamines. This effect is reduced by urethane and abolished by pentobarbital anesthesia. Atropine methyl nitrate antagonises the initial brady-cardia and hypotension induced by oxotremorine and reduces significantly the rise in plasma norepinephrine but not that of epinephrine. Oxotremorine appears to activate the sympathetic nervous system by at least two mechanisms: reflexly through baroreceptors, and directly by stimulation of muscarinic receptors in the central nervous system.

The effect of desmethylimipramine on the metabolism of norepinephrine

Eleven normal volunteers were given an acute and two chronic doses of desipramine (DMI). The plasma norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), and dihydroxyphenylglycol (DHPG) concentrations were measured before and during drug administration. DMI reduced plasma concentrations of MHPG by 13% and DHPG by 17%. After two weeks of drug administration, the MHPG/NE ratio was reduced, and there was a significant negative correlation with the concurrent drug concentration. These results suggest that DMI: (1) reduces the turnover of NE; and (2) diminishes the oxidative deamination of NE. In addition, the drug concentration response relationship indicates that the effects of uptake inhibition may not be maximal until concentrations in the apparent therapeutic range are achieved.

Differential effects of d- and l-propranolol on dopamine turnover stimulated by oxotremorine in striatal and mesolimbic areas of rat brain.

The effects of l-propranolol, d-propranolol and clonidine on homovanillic acid (HVA) concentrations in the corpus striatum and nucleus accumbens of rats were studied under normal conditions and after treatment with oxotremorine or haloperidol. Thile propranolol and clonidine given alone had no significant effect on HVA levels in either area, l-propranolol (1--10 mg/kg) and clonidine (0.1 mg/kg), both significantly inhibited the elevation of striatal HVA, found 60 min after oxotremorine administration. Both l- and d-propranolol (2.5 mg/kg), reduced the effect of oxotremorine in the nucleus accumbens. Neither l-propranolol no clonidine affected the rise in HVA in either brain area seen after haloperidol. Our results suggest that propranolol may reduce cholinergic activation of dopaminergic pathways by two different mechanisms. One is stereospecific for the l-isomer and operates in the striatum and another, which is shared by both isomers, occurs in the nucleus accumbens.

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidin, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.

Norepinephrine in the Affective Disorders: Classic Biochemical Approaches

Publisher Summary This chapter reviews studies which have approached the question of altered noradrenergic function in more classical ways, either by measuring NE or its metabolites in depressed patients or by studying the effects of antidepressantdrugs in these individuals. Animal data show that classic antidepressant drugs increase norepinephrine (NE) in the synapse, and clinical studies report that drugs which deplete NE produce depression in susceptible individuals. At least 50% of patients with affective illness manifest one or more of various neuroendocrine abnormalities, such as, failure of dexamethasone to suppress cortisol, a blunted thyroid-stimulating hormone response to thyrotropin-releasing hormone, or a blunted growth hormone response to insulin-induced hypoglycemia or the administration of clonidine, amphetamine, or desipramine. Many of these altered neuroendocrine responses may relate to some change of NE function. Moreover, alterations of presynaptic and postsynaptic NE receptors in various tissues generally support the notion of abnormal NE Function. This chapter describes the methodologic issues most relevant to investigation of NE function in psychiatric and psychopharmacologic research, highlighting the underlying assumptions that are sometimes ignored in the interpretations of data. It also discusses studies preceding the development of assays sensitive enough to measure NE in plasma and cerebrospinal fluid.