Inhibition Of Dopamine Β-hydroxylase Research Articles

Cardiometabolic and Inflammatory Benefits of Sympathetic Down-Regulation with Zamicastat in Aged Spontaneously Hypertensive Rats.

The hyperactivity of the sympathetic nervous system (SNS) plays a major role in the development and progression of several cardiovascular diseases. One strategy to mitigate the SNS overdrive is by restricting the biosynthesis of norepinephrine via the inhibition of dopamine β-hydroxylase (DBH). Zamicastat is a new DBH inhibitor that decreases norepinephrine and increases dopamine levels in peripherally sympathetic-innervated tissues. The cardiometabolic and inflammatory effects of sympathetic down-regulation were evaluated in 50 week old male spontaneously hypertensive rats (SHRs) receiving zamicastat (30 mg/kg/day) for 9 weeks. After 8 weeks of treatment, the blood pressure (BP) and heart rate (HR) were assessed by tail cuff plethysmography. At the end of the study, 24 h urine, plasma, heart, and kidney were collected for biochemical and morphometric analyses. Zamicastat-induced sympathetic down-regulation decreased the high BP in SHRs, with no observed effect on HR. The heart-to-body weight ratio was lower in SHRs treated with zamicastat, whereas the body weight and kidney-to-body weight ratio were similar between both SHR cohorts. Zamicastat-treated SHRs showed reduced 24 h urine output, but the urinary amount of protein excreted and creatinine clearance rate remained unchanged. Zamicastat treatment significantly decreased plasma triglycerides, free fatty acids, and aspartate aminotransferase levels. Aged SHRs showed higher plasma levels of inflammatory markers as compared with age-matched normotensive Wistar-Kyoto rats. The inflammatory benefits attained with DBH inhibition were expressed by a decrease in CRP, MCP-1, IL-5, IL-17α, GRO/KC, MIP-1α, and RANTES plasma levels as compared with untreated SHRs. In conclusion, DBH inhibition decreased norepinephrine levels, reduced end-organ damage, and improved cardiometabolic and inflammatory biomarkers in aged male SHRs.

Abstract P477: Effect of Zamicastat on Blood Pressure and Heart Rate - Comparison Between Acute and Repeated Dosing in the SHR

The sympathetic nervous system (SNS) can alter blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalyses the conversion of dopamine to NE in sympathetic nerves. Zamicastat is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS. In order to compare the effect of zamicastat on blood pressure and heart rate after acute and repeated dosing in spontaneously hypertensive rats (SHR), male adult SHR were implanted with telemetry devices (TA11PA-C40, DSI). Zamicastat (30 mg/kg p.o.) was given either as a single dose (n=8) or once a day for five days (n=6). On day 1, the maximal effect (E max ) of zamicastat on systolic blood pressure (SBP) was attained 15h after dosing. E max was similar in the acute and repeated dosing groups: -21.1±3.9 and -22.0±8.2 mmHg, respectively. In the acute treatment group, a gradual return of the SBP to the high baseline levels was observed over time. On the other hand, in the repeat dosing group the E max were consistent across the five administrations -22.0±8.2, -25.2±7.9, -22.0±7.5, -20.0±6.0 and -16.1±2.8 mmHg, respectively day 1 to 5. On day 5, after reaching E max a gradual return of SBP to baseline levels was also observed. The effect of zamicastat on diastolic blood pressure was similar with an E max of -18.4±3.5 mmHg in the acute dosing group and -18.8±8.7, -19.2±7.2, -18.2±6.6, -19.6±6.6 and -15.7±4.7 mmHg over the five days of administration in the repeated dosing group. Zamicastat did not affect heart rate under each dosing regimen. In conclusion, there is no tachyphylaxis or sensitization to the cardiovascular effects of zamicastat in this model and blood pressure returns to basal levels after zamicastat treatment discontinuation.

Dopamine β-hydroxylase inhibition decreases renal AT1R and normalizes hypertension of human GRK4γ 142V transgenic mice

Dopamine β-hydroxylase inhibition decreases renal AT1R and normalizes hypertension of human GRK4γ 142V transgenic mice

Abstract P224: Zamicastat Prevents the Deterioration of Cardiometabolic and Inflammatory Biomarkers in a Genetic Model of Salt-sensitive Hypertension

The Dahl salt-sensitive (Dahl/SS) rat, a genetic model of salt-sensitive hypertension and heart failure, develops left ventricle (LV) hypertrophy after five to six weeks and cardiac failure with LV dilation and contractile dysfunction after 10 to 12 weeks of high-salt (HS) intake. The aim of the present study was to evaluate the effect of zamicastat, a selective peripheral dopamine β-hydroxylase inhibitor, on cardiometabolic and inflammatory biomarkers in Dahl/SS during chronic HS intake. Eight week-old Dahl/SS rats were randomized into three groups; two groups received for 10 weeks a HS (8% NaCl) diet, one of which received 30 mg/kg/day zamicastat (HS+ZAMI); a third cohort received normal-salt diet (NS-0.3% NaCl) and served as controls. In the last week of treatment, 3 out of 10 animals from the HS group and 1 out of 10 from HS+ZAMI group were found dead. All animals from the NS group survived (n=8). Rats in the HS and HS+ZAMI groups showed heart and kidney hypertrophy as indicated by higher heart/body weight ratios (3.86±0.05 and 3.63±0.09 vs 2.96±0.05 mg/g) and kidney/body weight ratios (5.23±0.29 and 4.80±0.24 vs 3.41±0.06 mg/g), as compared to the NS group. A multiplex inflammatory cytokine assay was used to profile expression of 23 inflammatory mediators. Plasma levels of IL-1β, IL-4, IL-5, IL-7 and GM-CSF were significantly increased in the HS, but not in the HS-ZAMI group. Plasma levels of monocyte chemoattractant protein (MCP)-1 were higher in the HS and HS+ZAMI than in NS group (105.0±10.4 and 85.2±5.9 vs 67.6±2.8 pg/ml). The HS group, but not HS+ZAMI, showed hypercholesterolemia (4.45±0.23 and 3.72±0.37 vs 3.07±0.22 mmol/l). Both HS and HS+ZAMI cohorts had reduced levels of free fatty acids (0.23±0.02 and 0.23±0.02 vs 0.35±0.02 mmol/l) and normal levels of triglycerides in plasma (1.87±0.29 and 1.69±0.18 vs 1.28±0.15 mmol/l). Insulin plasma levels in HS and HS+ZAMI groups were lower than in NS group (1.45±0.26 and 1.90±0.22 vs 4.03±0.40 ng/ml), but the glucose levels were similar in all three groups (162±5 and 168±7 vs 150±7 mg/dl). In conclusion, chronic HS intake deteriorates several cardiometabolic and inflammatory biomarkers in Dahl/SS rats, which can be prevented by dopamine β-hydroxylase inhibition with zamicastat.

Blood pressure decrease in spontaneously hypertensive rats folowing renal denervation or dopamine β-hydroxylase inhibition with etamicastat.

Overactivity of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. Catheter-based renal nerve ablation for the treatment of drug-resistant hypertension has recently been developed. An alternative strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of noradrenaline (NA) by inhibiting dopamine β-hydroxylase (DβH), the enzyme that catalyzes the conversion of dopamine (DA) to NA in the sympathetic nerves. Renal denervation (RDN) surgery was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on the DA and NA levels and on blood pressure over a 28-day period. The selective peripheral DβH inhibitor etamicastat (30 mg kg (-1)day(-1)) was administered to another cohort of SHR. RDN and etamicastat treatment had no effect on the renal function, as assessed by measuring the water balance response, renal function and urinary electrolyte levels. RDN significantly decreased the systolic blood pressure (SBP) and the diastolic blood pressure (DBP). A gradual return of the SBP and the DBP to the high baseline levels was observed over time. Conversely, treatment with etamicastat resulted in a significant decrease in the SBP and the DBP at all time points. On the last day of the assessment, NA levels in renal tissue were significantly decreased in both RDN and etamicastat-treated groups. In contrast, the NA levels in the left ventricle were decreased only in the etamicastat-treated group. Thus, RDN produces transitory decreases in blood pressure, whereas prolonged downregulation of sympathetic drive with the DβH inhibitor etamicastat results in a sustained decrease in the SBP and the DBP.

Abstract 526: Blood Pressure in the SHR Following Renal Denervation or Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor

Overactivity of the sympathetic nervous system plays an important role in the development and progression of hypertension. Catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been recently developed. An alternative strategy for modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalysis the conversion of dopamine to NE in sympathetic nerves. Renal denervation (RDN) was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on NE levels and blood pressure throughout a 28-day period. Chronic oral treatment with the peripheral selective DβH inhibitor etamicastat (30 mg/kg/day) was performed in another cohort of SHR. RDN and chronic oral treatment with etamicastat did not affect renal function, as assessed by urinary protein, creatinine and urea levels. RDN significantly decreased mean arterial blood pressure (MAP, in mm Hg) 7 days post-surgery (139±6, P<0.01) versus baseline values (158±6). A gradual MAP return to high baseline levels was observed overtime; 139±7 at day 14, 151±12, at day 21 and 155±12 at day 28 after RDN. Treatment with etamicastat decreased baseline MAP (150±5) in a sustained and significant (P<0.01) manner at all-time points: 141±5 at day 7, 139±5 at day 14, 138±5 at day 21 and 143±5 at day 28. At day 28, NE levels (in pmol/mg tissue) in renal tissue were significantly decreased in both RDN (0.12±0.08, P=0.001) and etamicastat-treated group (0.48±0.04, P=0.01) as compared to vehicle group (0.88±0.13). On the other hand, left ventricle NE levels were decreased only after treatment with etamicastat (1.24±0.12, P=0.04) but not in the RDN group (2.53±0.24, P=0.9) when compared to controls (2.59±0.58). It is concluded that RDN produces transitory decreases in MAP, whereas prolonged down regulation of sympathetic drive with the DβH inhibitor etamicastat results in sustained decreases in MAP.

Effects of pharmacologic dopamine β-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys.

Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies.

Abstract 532: BIA 5-1058, Beyond Blood Pressure, Improves Cardiometabolism and Decrease End-organ Damage

The sympathetic nervous system (SNS) can alter blood pressure (BP) by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH). BIA 5-1058 is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS. In order to evaluate the cardiometabolic effects of BIA 5-1058 in aged spontaneously hypertensive rats (SHR), 12 male SHR 50-week-old were randomized into two groups and one group was treated with BIA 5-1058 (30 mg/Kg/day) mixed in the diet for 9 weeks. During week 8 of treatment, blood pressure (BP) and heart rate (HR) were measured by tail cuff. At the end of the study, 24-hour urine and plasma was collected and organs weight was recorded. BIA 5-1058 treatment reduced systolic BP (224±5 vs 183±8 mmHg, p<0.05) with no significant effect on HR. The heart/body weight ratio was decreased in animals treated with BIA 5-1058 (3.66±0.08 vs 3.45±0.04 mg/g, p<0.05), while the ratio kidney/body weight was unchanged. BIA 5-1058 significantly decreased plasma levels of the inflammatory markers CRP (447.3±7.1 vs 401.2±7.1 μg/ml, p<0.05), MCP-1 (90.3±10.5 vs 58.2±9.0 pg/ml, p<0.05) and ASAT (91.7±8.0 vs 67.3±4.0 U/l, p<0.05) but no significant effect on ALAT was observed. Concerning lipid metabolism, there was a decrease in plasma triglycerides (0.94±0.05 vs. 0.70±0.05 mmol/l, p<0.05) and free fatty acids levels (0.23±0.03 vs 0.11±0.01 mmol/l, p<0.05) induced by BIA 5-1058, while total cholesterol plasma levels was similar in both groups. BIA 5-1058 significantly reduced the 24-hour urine excretion (13.5±1.6 vs 8.9±1.2 ml, p<0.05), but had no significant effect in the amount of protein excreted in urine nor in the creatinine clearance rate. In conclusion, the new DBH inhibitor, BIA 5-1058, presents cardiometabolic benefits in aged SHR.

Abstract 454: Hypertension Control by Decrease of Sympathetic Hyperactivity in SHR Rats: Comparison Between Renal Denervation and Dopamine ß-hydroxylase Inhibition

Activation of the sympathetic nervous system has been described in the development and progression of systemic hypertension. Recently, catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been developed. An alternative strategy for modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalysis the conversion of dopamine (DA) to NE in sympathetic nerves. Renal denervation was assessed in the rat by transient (90 sec) ischemia of renal tissues. Bilateral renal artery occlusion (RAO) was assessed in spontaneously hypertensive rats (SHR) to evaluate the effect of renal denervation on NE levels and blood pressure throughout a 28-day period. Oral treatment with the selective peripheral DβH inhibitor etamicastat (30 mg/Kg body weight) was performed in a second cohort of SHR and NE levels and blood pressure was assessed. Renal denervation resulted in marked depletion of NE levels, selective for the renal sympathetic innervations, 5 days after RAO in renal cortex (16.5±7.7% of control values, P<0.0001). Decreased NE levels persisted up to 28 days after RAO (40.8±19.4% of control values, P<0.0001). No differences in left ventricle NE levels were observed. Renal denervation significantly decreased systolic blood pressure (SBP) 5 days (165±6 vs. 187±2 mmHg, P<0.05) and 14 days post-surgery (194±3 vs. 204±2 mmHg, P<0.05), but had no effect on heart rate. Systolic blood pressure recovered to basal values 28 days post-surgery. Likewise, etamicastat treatment resulted in a depletion of NE levels in both renal cortex (70.9±9.1% of control values, P<0.05) and left ventricle (55.8±3.9% of control values, P<0.01). Etamicastat treatment decreased SBP (228±7 vs. 174±9 mmHg, P<0.001) without effects on heart rate. In conclusion, these results suggest that renal denervation and DβH inhibition similarly decreases sympathetic hyperactivity and high blood pressure in the SHR. Downregulation of sympathetic drive with DβH inhibitors may be useful in the treatment of hypertension.

1164 – Manic episode in the context of treatment with disulfiram: description of clinical case

The prescription of disulfiram for the treatment of alcohol dependence is common in clinical practice. This drug is an inhibitor of aldehyde dehydrogenase, which interferes in the alcohol metabolism by increasing blood levels of acetaldehyde and promoting an intense physical discomfort, thus reinforcing the need for alcohol withdrawal. Additionally, one metabolite of disulfiram is responsible for the inhibition of dopamine β-hydroxylase, and may potentiate psychotic or mood disorders even in the absence of personal or family history of psychiatric illness. This paper aims to describe the clinical case of a 45 year old man with a history of alcoholism who presented the first manic episode after initiation of treatment with disulfiram and discuss, based on a literature review, the possible association between symptoms and treatment with this drug.

814 ANTIHYPERTENSIVE EFFECT OF BIA 5–1058 A NEW SELECTIVE PERIPHERAL DOPAMINE β-HYDROXYLASE INHIBITOR

Background: Sympathetic nervous system tone alters blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is reduction of biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH; EC 1.14.17.1), the enzyme that catalyses the conversion of dopamine (DA) to NE in sympathetic nerves. BIA 5-1058 is a reversible DβH inhibitor that decreases NE levels in peripheral sympathetically innervated tissues, without effect in brain tissues. Methods: In telemetry transmitter implanted SHR single administration of BIA 5-1058 demonstrates dose (3, 30 and 100 mg/Kg) and time dependent blood pressure effects with no significant effect on heart rate (HR) and total activity monitored over 96-hours. Results: The maximum reductions of systolic blood pressure (SBP) were -10.8, -21.1 and -35.2 mmHg for 3, 30 and 100 mg/Kg, respectively and diastolic blood pressure (DBP) were -9.9, -18.4 and -24.8 mmHg, respectively. Antihypertensive effects of BIA 5-1058 (30 mg/Kg) was further evaluated in combination with efficacious doses of well-known antihypertensive drugs, like the ACE inhibitor captopril, the AT1 receptor antagonist losartan, the diuretic hydrochlorothiazide, beta-blocker metoprolol, the alpha-1 receptor antagonist prazosin, and the calcium channel blocker diltiazem. All drugs were administered orally (single dose) in a cross-over design and the effect was monitored for 72 hours. Combination of BIA 5-1058 the tested antihypertensive drugs caused a stronger and prolonged blood pressure decrease than any single compound. Conclusions: In conclusion, peripheral DβH inhibitors can be used, alone or in combination with others antihypertensive drugs, to reduce blood pressure.

Abstract 291: Antihypertensive Effect Of Bia 5-1058 a New Selective Peripheral Dopamine β-hydroxylase Inhibitor

The sympathetic nervous system can alter blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH; EC 1.14.17.1 ), the enzyme that catalyses the conversion of dopamine (DA) to NE in sympathetic nerves. BIA 5-1058 is a reversible DβH inhibitor that decreases NE levels in peripheral sympathetically innervated tissues slowing down sympathetic nervous system drive, without effect in brain tissues. In freely moving SHR implanted with radio-telemetry transmitters single administration of BIA 5-1058 showed a dose (3, 30 and 100 mg/Kg) and time dependent effect on blood pressure with no significant effect on heart rate (HR) and total activity monitored over a 96-hour period. The maximum reduction on systolic blood pressure (SBP) was -10.8, -21.1 and -35.2 mmHg for 3, 30 and 100 mg/Kg, respectively and the maximum reduction on diastolic blood pressure (DBP) was -9.9, -18.4 and -24.8 mmHg for 3, 30 and 100 mg/Kg, respectively. The antihypertensive effect of BIA 5-1058 (30 mg/Kg) was further evaluated in combination with efficacious doses of well-known antihypertensive drugs, like the ACE inhibitor captopril, the AT1 receptor antagonist losartan, the diuretic hydrochlorothiazide, beta-blocker metoprolol, the alpha-1 receptor antagonist prazosin, and the calcium channel blocker diltiazem. All drugs were administered orally (single dose) in a cross-over design and the effect was monitored for 72 hours. The combination of BIA 5-1058 with any of the tested antihypertensive drugs caused a stronger and prolonged blood pressure decrease than any of the compounds alone.In conclusion, peripheral DβH inhibitors can be used, alone or in combination with others antihypertensive drugs, to reduce blood pressure.

Some effects of caffeine and aminophylline on the turnover of catecholamines in the brain.

Abstract The effect of caffeine and aminophylline on the turnover of noradrenaline and dopamine in the mouse brain was studied by two different methods: estimation of the rate of disappearance of the transmitter after inhibition of synthesis and measurement of the accumulation of [3H]noradrenaline (3H-NA) and [3H]dopamine (3H-DA) after administration of [3H]tyrosine. After inhibition of the tyrosine hydroxylase the xanthines had little or no effect on the disappearance of both catecholamines. After inhibition of dopamine β-hydroxylase, both xanthines increased the rate of disappearance of noradrenaline. When given in sufficiently large doses both xanthines increased the yield of 3H-NA and 3H-DA from [3H]tyrosine. Pretreatment with a monoamine oxidase inhibitor caused a decrease in the yield of the tritiated catecholamines, which could be counteracted by the xanthines. Stimulation of the noradrenaline receptors by clonidine appeared to cause a decrease in the yield of 3H-NA and an increase in the amount of 3H-DA formed from [3H]tyrosine. Conversely, stimulation of the dopamine receptors by apomorphine caused a decrease in the yield of 3H-DA and an increase in that of 3H-NA. Also, in caffeine-treated animals, clonidine and apomorphine decreased the yield of 3H-NA and 3H-DA respectively. However clonidine could not increase 3H-DA concentrations, nor apomorphine the 3H-NA concentrations more than did caffeine alone. Thus, caffeine and aminophylline appear to increase the rate of turnover of both catecholamines in the brain.

Disulfiram Attenuates Drug-Primed Reinstatement of Cocaine Seeking via Inhibition of Dopamine β-Hydroxylase

The antialcoholism medication disulfiram (Antabuse) inhibits aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde upon ethanol ingestion and produces the aversive 'Antabuse reaction' that deters alcohol consumption. Disulfiram has also been shown to deter cocaine use, even in the absence of an interaction with alcohol, indicating the existence of an ALDH-independent therapeutic mechanism. We hypothesized that disulfiram's inhibition of dopamine β-hydroxylase (DBH), the catecholamine biosynthetic enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons, underlies the drug's ability to treat cocaine dependence. We tested the effects of disulfiram on cocaine and food self-administration behavior and drug-primed reinstatement of cocaine seeking in rats. We then compared the effects of disulfiram with those of the selective DBH inhibitor, nepicastat. Disulfiram, at a dose (100 mg/kg, i.p.) that reduced brain NE by ∼40%, did not alter the response for food or cocaine on a fixed ratio 1 schedule, whereas it completely blocked cocaine-primed (10 mg/kg, i.p.) reinstatement of drug seeking following extinction. A lower dose of disulfiram (10 mg/kg) that did not reduce NE had no effect on cocaine-primed reinstatement. Nepicastat recapitulated the behavioral effects of disulfiram (100 mg/kg) at a dose (50 mg/kg, i.p.) that produced a similar reduction in brain NE. Food-primed reinstatement of food seeking was not impaired by DBH inhibition. Our results suggest that disulfiram's efficacy in the treatment of cocaine addiction is associated with the inhibition of DBH and interference with the ability of environmental stimuli to trigger relapse.

Disulfiram: An Old Therapeutic with New Applications

Disulfiram treatment, despite its limitations, remains a viable option as a treatment for alcohol dependence and has shown recent promise in treating (1) those with co-morbid alcohol dependence and post-traumatic stress disorder, (2) those with co-morbid cocaine- and alcohol-dependence, and (3) those with cocaine-dependence alone. Although disulfiram's mechanism of action in alcohol dependence was long thought to be its effects as a psychological deterrent, more recent studies have uncovered potential anti-craving effects as well as direct effects of disulfiram on cocaine abuse, highlighting a few of the many potential and unique benefits disulfiram may have through its inhibition of dopamine beta-hydroxylase. This article will review the major clinical trials of disulfiram spanning nearly 60 years. We will discuss the pharmacodynamics and pharmacokinetics of disulfiram, indications and limitations of its use, suggestions for appropriate patient populations, and monitoring for compliance and adverse effects. We will also review recent literature on newer potential applications for disulfiram use via its unique action on dopamine beta-hydroxylase.

Effects of disulfiram and dopamine beta-hydroxylase knockout on cocaine-induced seizures

The antialcoholism drug disulfiram has shown recent promise as a pharmacotherapy for treating cocaine dependence, probably via inhibition of dopamine β-hydroxylase (DBH), the enzyme that catalyzes the conversion of dopamine (DA) to norepinephrine (NE). We previously showed that DBH knockout ( Dbh −/−) mice, which lack NE, are susceptible to seizures and are hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, suggesting that disulfiram might exacerbate cocaine-induced seizures (CIS) by inhibiting DBH. To test this, we examined CIS in wild-type and Dbh −/− mice following administration of disulfiram or the selective DBH inhibitor nepicastat. We found that Dbh genotype had no effect on CIS probability or frequency, whereas disulfiram, but not nepicastat, increased the probability of having CIS in both wild-type and Dbh −/− mice. Both disulfiram and nepicastat increased CIS frequency in wild-type but not Dbh −/− mice. There were no genotype or treatment effects on serum cocaine levels, except for an increase in disulfiram-treated Dbh −/− mice at the highest dose of cocaine. These results suggest that disulfiram enhances CIS via two distinct mechanisms: it both increases CIS frequency by inhibiting DBH and increases CIS frequency in a DBH-independent manner.

Inhibition of dopamine β-hydroxylase by captopril

Inhibition of dopamine β-hydroxylase by captopril

Inhibition of Dopamine β-Hydroxylase by Goitrin, a Natural Antithyroid Compound

RS-Goitrin can be conveniently prepared by a simplification of the Ettlinger procedure. Goitrin is a moderate inhibitor of purified bovine adrenal dopamine beta-hydroxylase. The administration of goitrin leads to a depression of brain norepinephrine and to an elevation of heart and adrenal dopamine.

Noradrenaline turnover after left coronary artery ligation in rat heart

The levels and the turnover of noradrenaline were measured in the left and right ventricles following left coronary artery ligation for 2 h in untreated, adrenalectomized or hexamethonium-treated rats. Noradrenaline in the left ventricles was decreased by ligation and unaffected in the right ventricles, whether of untreated, adrenalectomized or hexamethonium-treated animals. Turnover in the left ventricles, as estimated by the decrease of noradrenaline under dopamine β-hydroxylase inhibition with bis-(4-methyl-1-homo-piperazinyl-thiocarbonyl)-disulfide (FLA-63), was unaffected by ligation whether in untreated, adrenalectomized, or hexamethonium-treated rats. Ligation accelerated turnover in the right ventricles of untreated rats or attenuated it in adrenalectomized rats and caused no changes in hexamethonium-treated rats. These results suggest that noradrenaline turnover in ischemic myocardium is not affected by regional ischemia and that such ischemia might accelerate turnover in the non-ischemic area, probably as a result of increased activity of sympatho-adrenal reflexes.

Inhibition of dopamine β-hydroxylase by 2-mercapto-1-methylimidazole

The inhibition of bovine dopamine β-hydroxylase (dopamine β-monooxygenase, EC 1.14.17.1) BY 2-mercapto-1-methylimidazole has been studied using a simple, ‘metal-free’ assay system. 2-Mercapto-1-methylimidazole is an uncompetitive inhibitor of dopamine β-hdyroxylase with respect to ascorbate and a mixed type of inhibitor with respect to tyramine. These findings are consistent with 2-mercapto-1-methylimidazole interacting exclusively with the reduced form of dopamine β-hydroxylase.