Dopamine Beta-hydroxylase Inhibitor Research Articles

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects.

Dopamine beta-hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS). A single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects. Cold pressor test (CPT) was performed at screening and each treatment period on Days -1 and 10. Plasma and 24 h-urine levels of dopamine (DA), epinephrine (EPI) and norepinephrine (NE), and plasma DβH activity, were measured. Compared to placebo, zamicastat showed a - 4.62 mmHg decrease in systolic blood pressure during the cold stimulus vs. rest phases on Day 10 of CPT (P = .020). Zamicastat decreased mean arterial pressure response to cold stimulus during CPT (-2.62 mmHg; P = .025). At Day 10, zamicastat significantly increased plasma DA, before CPT (12.63 ng/L; P = .040) and after CPT (19.22 ng/L; P = .001) as well as the estimated plasma EPI change from baseline after CPT (P = .040). Inhibition of plasma DβH activity ranged from 19.8% to 25.0%. At Day 10, significant reductions in 24-h urinary excretion of EPI (P = .002) and NE (P = .001) were observed. Zamicastat Cτ geometric mean ± GSD ranged from 45.86 ± 1.46 ng/mL on Day 3 to 58.64 ± 1.52 ng/mL on Day 10, with moderate inter-individual variability (CV: 32.6%-36.6%). Steady state was already achieved on Day 6. Our results demonstrated the effect of zamicastat on the overdrive sympathetic response to cold stimulus, confirming its potential as SNS modulator.

Disulfiram Induced Psychosis in Patients Seeking Over the Counter Treatment

Disulfiram is a deterrent in the management of alcohol use associated with neuropsychiatric manifestations, of which psychosis is common. The postulated mechanism is being its metabolite diethyldithiocarbamate being an inhibitor of dopamine beta-hydroxylase (DBH), an enzyme that catalyses the metabolism of dopamine (DA) to norepinephrine (NE) which results in an increase of DA concentrations in mesolimbic system resulting in psychosis. Other mechanisms are also postulated, like direct CNS toxicity, free radical damage. Here, are the two cases that were dependent to opioid given disulfiram surreptitiously land up with psychosis. Keywords: Substance use disorders, Disulfiram, Psychosis, over the counter medicine

Dopamine β-hydroxylase shapes intestinal inflammation through modulating T cell activation

BackgroundInflammatory bowel disease (IBD) is a chronic and relapsing disease characterized by immune-mediated dysfunction of intestinal homeostasis. Alteration of the enteric nervous system and the subsequent neuro-immune interaction are thought to contribute to the initiation and progression of IBD. However, the role of dopamine beta-hydroxylase (DBH), an enzyme converting dopamine into norepinephrine, in modulating intestinal inflammation is not well defined. MethodsCD4+CD45RBhighT cell adoptive transfer, and 2,4-dinitrobenzene sulfonic acid (DNBS) or dextran sodium sulfate (DSS)-induced colitis were collectively conducted to uncover the effects of DBH inhibition by nepicastat, a DBH inhibitor, in mucosal ulceration, disease severity, and T cell function. ResultsInhibition of DBH by nepicastat triggered therapeutic effects on T cell adoptive transfer induced chronic mouse colitis model, which was consistent with the gene expression of DBH in multiple cell populations including T cells. Furthermore, DBH inhibition dramatically ameliorated the disease activity and colon shortening in chemically induced acute and chronic IBD models, as evidenced by morphological and histological examinations. The reshaped systemic inflammatory status was largely associated with decreased pro-inflammatory mediators, such as TNF-α, IL-6 and IFN-γ in plasma and re-balanced Th1, Th17 and Tregs in mesenteric lymph nodes (MLNs) upon colitis progression. Additionally, the conversion from dopamine (DA) to norepinephrine (NE) was inhibited resulting in increase in DA level and decrease in NE level and DA/NE showed immune-modulatory effects on the activation of immune cells. ConclusionModulation of neurotransmitter levels via inhibition of DBH exerted protective effects on progression of murine colitis by modulating the neuro-immune axis. These findings suggested a promising new therapeutic strategy for attenuating intestinal inflammation.

Limited modulation of the abuse-related behavioral effects of d-methamphetamine by disulfiram.

Disulfiram (Antabuse), an acetaldehyde dehydrogenase and dopamine-beta hydroxylase inhibitor, has shown promise in preclinical and clinical studies as a pharmacotherapy for cocaine addiction. However, the extent to which disulfiram may alter the abuse-related behavioral effects of related psychostimulants, such as methamphetamine, is unknown. Here, the therapeutic potential of disulfiram was evaluated by examining its impact on the reinforcing and discriminative stimulus effects of d-methamphetamine in adult rhesus monkeys (N = 4 per group). In subjects trained to respond for injections of methamphetamine or food delivery, i.v. methamphetamine (.001-.032 mg/kg) maintained dose-related and stable levels of self-administration in all subjects. Pretreatment with disulfiram (5.6 mg/kg) produced a significant downward shift in the d-methamphetamine dose-response function; surprisingly, lower and higher pretreatment doses (3.0 mg/kg; 10 mg/kg) were ineffective. Also, disulfiram (3-10 mg/kg) did not significantly alter food-maintained responding or, in subjects trained to discriminate the effects of cocaine from vehicle, the ability of d-methamphetamine (.032-.32 mg/kg) to substitute for cocaine. Taken together, the present data reveal dose-dependent effects of disulfiram in modifying some of the abuse-related effects of d-methamphetamine and provides support for future investigations examining the capacity of disulfiram as a treatment for d-methamphetamine abuse. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Dopamine beta-hydroxylase participate in the immunoendocrine responses of hypothermal stressed white shrimp, Litopenaeus vannamei

Dopamine beta-hydroxylase (DBH) plays a critical role in catecholamine (CA) synthesis of neuroendocrine regulatory network, and is suggested to be involved in the immunoendocrine responses of invertebrate against bacterial challenge. DBH has been identified in white shrimp, Litopenaeus vannamei, and further investigation on its potential function was conducted after hypothermal stress, pharmaceutical inhibition and gene silencing in the present study. Cloned DBH L. vannamei (LvDBH), belonging to the Copper type II, ascorbate-dependent monooxygenases, was characterized by a DOMON domain, a Cu2_monooxygen domain and three glycosylation sites, and its expression was abundant in thoracic ganglia and haemocytes determined by quantitative real-time PCR. The effects of hypothermal stress showed that LvDBH expression in thoracic ganglia, haemocytes and hepatopancreas as well as the DBH contents in haemocytes and dopamine (DA) and norepinephrine (NE) levels in haemolymph are obviously up-regulated. L. vannamei receiving disulfiram for 30–120 min revealed the inhibition of DBH and NE contents in haemocytes and haemolymph respectively, but high level of DA in haemolymph was noticed. Besides, a significant decrease of LvDBH expression in thoracic ganglia, haemocytes and hepatopancreas were also observed. Subsequently, LvDBH expression was successfully silenced in thoracic ganglia, haemocytes and hepatopancreas of shrimp that received LvDBH-dsRNA for 3 days, and meanwhile, a decrease of DBH contents in haemocytes accompanied by decreased levels of NE and DA in haemolymph were also observed. These results indicate that LvDBH possesses the functional domains responsible for CAs synthesis, and therefore, inhibiting DBH contents in haemocytes by disulfiram and by LvDBH-dsRNA resulted in the impaired synthesis of NE from DA in haemolymph. These also suggest that the increased release of DA and NE in haemolymph for potential modulation of physiological or immunological responses is the consequence of the upregulated LvDBH expression and DBH contents in L. vannamei exposed to hypothermal stress.

Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after exvivo tissue extraction or invivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The results indicate that nepicastat enhances DA release from noradrenergic terminals supposedly by removing NA from α2-autoreceptors. In addition to the inhibition of DA uptake, the latter mechanism may explain the synergistic effect of cocaine on nepicastat-induced DA release.

Effects of dopamine beta‐hydroxylase (DBH) inhibition on cocaine‐induced reinstatement in squirrel monkeys

Disulfiram (Antabuse) has shown promise in clinical trials as a pharmacotherapy for cocaine dependence. One of many biochemical actions of disulfiram is inhibition of dopamine beta‐hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine (NE); consequently, reducing brain NE levels. It is believed that this mechanism is responsible for the therapeutic effects of disulfiram. In rats, disulfiram blocks cocaine‐primed reinstatement (an animal model of relapse), corroborating with clinical results. Furthermore, nepicastat, a selective DBH inhibitor also blocks cocaine‐primed reinstatement in rats, supporting the therapeutic use of DBH inhibitors. In this study, we attempted to replicate these results in non‐human primates. Squirrel monkeys trained to self‐administer cocaine under a second‐order schedule were pretreated with disulfiram or nepicastat prior to cocaine‐primed reinstatement sessions. Neither pretreatment altered cocaine‐primed reinstatement. Unexpectedly, nepicastat alone was sufficient to induce a modest reinstatement effect. The discrepancies found between squirrel monkeys and rats may be explained by differences in pharmacokinetic or metabolic profiles in the two species. Ongoing studies are investigating whether metabolic differences are present, which will ultimately be instrumental in influencing the translation of these therapies to a human population.Support: DA00517, DA12514, 5T32DA015040, UL1 RR025008, RR00165

2-mercaptobenzothiazole, an inhibitor of dopamine beta-hydroxylase.

Journal Article 2-Mercaptobenzothiazole, an inhibitor of dopamine β-hydroxylase Get access G A Johnson, G A Johnson CNS Research, The Upjohn Company, Kalamazoo, Michigan 49001, USA Search for other works by this author on: Oxford Academic Google Scholar S J Boukma, S J Boukma CNS Research, The Upjohn Company, Kalamazoo, Michigan 49001, USA Search for other works by this author on: Oxford Academic Google Scholar P A Platz P A Platz CNS Research, The Upjohn Company, Kalamazoo, Michigan 49001, USA Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 22, Issue 9, September 1970, Pages 710–712, https://doi.org/10.1111/j.2042-7158.1970.tb12761.x Published: 25 January 2012 Article history Received: 16 June 1970 Published: 25 January 2012

Pharmacological inhibition of dopamine beta‐hydroxylase blocks cocaine‐induced reinstatement in rats

Disulfiram (Antabuse) has recently shown promise as a pharmacotherapy for cocaine dependence, though the mechanisms underlying its efficacy are unclear. One of the many biochemical actions of disulfiram is inhibition of dopamine beta‐hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine (NE); consequently, disulfiram reduces brain NE levels. Noradrenergic signaling is required for reinstatement of drug seeking in rats, a paradigm which is thought to model drug relapse. We therefore hypothesized that DBH inhibition underlies the therapeutic effects of disulfiram. To test this hypothesis, cocaine self‐administration studies were conducted in rats (N=5–8 per group) given pretreatments of vehicle, disulfiram (100 mg/kg i.p.) or the selective DBH inhibitor nepicastat (50 mg/kg i.p.). We found that neither disulfiram nor nepicastat altered lever pressing behavior during the maintenance phase of self‐administration. In contrast, both drugs blocked cocaine‐primed reinstatement of lever pressing following extinction. These results suggest that pharmacological DBH inhibition may be an effective treatment for cocaine dependence, potentially by preventing relapse.

Mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse.

The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine beta-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.

Norepinephrine Signaling Through β-Adrenergic Receptors is Critical for Expression of Cocaine-Induced Anxiety

Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.

Synthesis and Biological Evaluation of Novel, Peripherally Selective Chromanyl Imidazolethione-Based Inhibitors of Dopamine β-Hydroxylase

A novel series of dopamine beta-hydroxylase (DBH) inhibitors was designed and synthesized incorporating modifications to the core structure of nepicastat 3, with the principal aim of discovering potent DBH inhibitors exerting minimal effects on dopamine (DA) and noradrenaline (NA) levels in the central nervous system. This study resulted in the identification of a potent, peripherally selective DBH inhibitor, (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride 54 (BIA 5-453). In experiments in mice and rats at T(max) (9 h after administration), 54 reduced NA levels in a dose-dependent manner in both the left atrium and the left ventricle, with the maximal inhibitory effect attained at a dose of 100 mg/kg. In contrast to that found in the heart, 54 failed to affect NA tissue levels in the brain. Compound 54 is thus presented as a candidate for clinical evaluation for the treatment of chronic heart failure and hypertension.

Dopamine β-Hydroxylase Knockout Mice have Alterations in Dopamine Signaling and are Hypersensitive to Cocaine

Multiple lines of evidence demonstrate that the noradrenergic system provides both direct and indirect excitatory drive onto midbrain dopamine (DA) neurons. We used DA beta-hydroxylase (DBH) knockout (Dbh-/-) mice that lack norepinephrine (NE) to determine the consequences of chronic NE deficiency on midbrain DA neuron function in vivo. Basal extracellular DA levels were significantly attenuated in the nucleus accumbens (NAc) and caudate putamen (CP), but not prefrontal cortex (PFC), of Dbh-/- mice, while amphetamine-induced DA release was absent in the NAc and attenuated in the CP and PFC. The decrease in dopaminergic tone was associated with a profound increase in the density of high-affinity state D1 and D2 DA receptors in the NAc and CP, while DA receptors in the PFC were relatively unaffected. As a behavioral consequence of these neurochemical changes, Dbh-/- mice were hypersensitive to the psychomotor, rewarding, and aversive effects of cocaine, as measured by locomotor activity and conditioned place preference. Antagonists of DA, but not 5-HT, receptors attenuated the locomotor hypersensitivity to cocaine in Dbh-/- mice. As DBH activity in humans is genetically controlled and the DBH inhibitor disulfiram has shown promise as a pharmacotherapy for cocaine dependence, these results have implications for the influence of genetic and pharmacological DBH inhibition on DA system function and drug addiction.

Effects of dopamine β-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice

Dopamine beta-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), thus playing a critical role in catecholamine metabolism. We examined the effects of Dbh gene dosage and the DBH inhibitor disulfiram in mice with zero, one, or two null Dbh alleles (+/+, +/-, and-/- mice). DBH protein levels in adrenal and prefrontal cortex (PFC) and adrenal DBH activity were proportional to number of wild-type alleles. Adrenal DA was slightly increased in+/- mice and markedly increased (80-fold) in -/- mice compared to wild-type animals. While adrenal NE and epinephrine (EPI) were undetectable in -/- mice, adrenal concentrations of NE and EPI were similar in +/+ and +/- mice, suggesting that the increase in DA maintains the normal rate of beta-hydroxylation in Dbh +/- mice. Disulfiram had little effect on adrenal catecholamine levels, regardless of genotype or dose. NE was absent in the PFC of -/- mice, but only slightly reduced in +/- animals compared to wild-type animals. PFC DA was increased twofold in +/- mice and fivefold in -/- mice, and the NE to DA ratio was reduced ( approximately 35%) in +/- mice, compared to wild-type mice. Disulfiram significantly decreased PFC NE and increased DA in +/+ and +/- animals, with the disulfiram and genotype effects on the PFC NE to DA ratio apparently additive. The data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

Enhanced Ligand Affinity for Receptors in which Components of the Binding Site Are Independently Mobile

Using calmodulin antagonism as a model, it is demonstrated that, under circumstances in which binding sites are motionally independent, it is possible to create bifunctional ligands that bind with significant affinity enhancement over their monofunctional counterparts. Suitable head groups were identified by using a semiquantitative screen of monofunctional tryptophan analogs. Two bifunctional ligands, which contained two copies of the highest-affinity head group tethered by rigid linkers, were synthesized. The bifunctional ligands bound to calmodulin with a stoichiometry of 1:1 and with an affinity enhancement over their monofunctional counterparts; the latter bound with a stoichiometry of 2:1 ligand:protein. A lower limit to the effective concentrations of the domains of calmodulin relative to each other (0.2-2 mM) was determined. A comparable effective concentration was achieved for bifunctional ligands based on higher-affinity naphthalene sulphonamide derivatives.

Nonparametric regression applied to quantitative structure-activity relationships

Several nonparametric regressors have been applied to modeling quantitative structure-activity relationship (QSAR) data. The simplest regressor, the Nadaraya-Watson, was assessed in a genuine multivariate setting. Other regressors, the local linear and the shifted Nadaraya-Watson, were implemented within additive models--a computationally more expedient approach, better suited for low-density designs. Performances were benchmarked against the nonlinear method of smoothing splines. A linear reference point was provided by multilinear regression (MLR). Variable selection was explored using systematic combinations of different variables and combinations of principal components. For the data set examined, 47 inhibitors of dopamine beta-hydroxylase, the additive nonparametric regressors have greater predictive accuracy (as measured by the mean absolute error of the predictions or the Pearson correlation in cross-validation trails) than MLR. The use of principal components did not improve the performance of the nonparametric regressors over use of the original descriptors, since the original descriptors are not strongly correlated. It remains to be seen if the nonparametric regressors can be successfully coupled with better variable selection and dimensionality reduction in the context of high-dimensional QSARs.

The local minima method (LMM) of pharmacophore determination: a protocol for predicting the bioactive conformation of small, conformationally flexible molecules.

Software has been developed for potential energy surface analysis and the local minima method of pharmacophore determination. LMM is rigorous and systematic and employs multiple conformations which are the local minima from the potential energy surface of each compound in the data set. It produces a series of possible pharmacophores from a postulated set of pharmacophore elements. The best pharmacophore is then determined by performing a comparative molecular field analysis (CoMFA) on each one. The pharmacophore which produces the most self-consistent model is deemed the best. Local minima on the gas-phase potential energy surface are shown to be a reasonably close approximation to protein bound conformations, and these conformations can be found through systematic conformational searches followed by minimization of the local minima. LMM was used to develop a 3D-QSAR model for dopamine beta-hydroxylase (DBH) inhibitors which was highly predictive (predictive R2 = 0.71 and standard error of predictions = 0.41). The model predicted that the phenyl and thienyl series of inhibitors were acting as bioisosteres. Examination of compounds overlayed in the model indicated a possible hydrogen bond acceptor in the DBH active site. Three tyrosine residues previously labeled by mechanism based inhibitors may be acting as the acceptor and therefore represent excellent candidates for site-directed mutagenesis studies.

Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor.

Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of dopamine beta-hydroxylase, which modulates catecholamine levels (reduces norepinephrine and elevates dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of nepicastat. Acute oral administration of nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In inactin-anesthetized SHRs, the antihypertensive effects of nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs, nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex tachycardia. Long-term, concurrent administration of nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of enalapril (1 mg/kg/day, p.o.) produced greater antihypertensive effects than those produced by nepicastat alone. In normal dogs, nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to tyramine. These findings suggest that nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as hypertension and congestive heart failure.

Dopamine Beta-Hydroxylase Inhibition: A Potential Therapy for the Treatment of Congestive Heart Failure

Chronic sympathetic activation in congestive heart failure (CHF) is considered a maladaptive response. Consequently, therapeutic interventions that inhibit sympathetic nerve function are likely to favorably alter the natural course of the disease. Inhibition of sympathetic nerve function with β-blockers is a promising approach that is currently under clinical evaluation. The therapeutic value of β-blockers, however, may be limited by their propensity to cause acute hemodynamic deterioration, which results from abrupt withdrawal of sympathetic support. Thus, although the introduction of β-blockers represents an important advance in the treatment of CHF, a better-tolerated means of interrupting the sympathetic nervous system would be highly desirable.

Blockade of noradrenergic neurotransmission with diethyldithiocarbamic acid decreases the mRNA level of gonadotropin-releasing hormone in the hypothalamus of ovariectomized, steroid-treated prepubertal rats.

We have previously found that progesterone (P) augmented gonadotropin-releasing hormone (GnRH) mRNA levels in the hypothalamus of ovariectomized, estradiol-treated (OVX + E) prepubertal rats. In order to determine whether noradrenergic neurotransmission is involved in the stimulatory effect of P on GnRH gene expression, diethyldithiocarbamic acid (DDC, 500 mg/kg), a dopamine beta-hydroxylase inhibitor was administered i.p. 1 h before P (1 mg) injection into OVX + E treated rats, and the effect of DDC on the P-induced GnRH mRNA levels was examined. A single injection of P into OVX + E primed rats augmented norepinephrine (NE) content, while the administration of DDC effectively blocked the P-induced increase in NE content, along with the increase in dopamine content. Suppression of NE neurotransmission with DDC resulted in a marked decrease in the P-induced GnRH mRNA levels as well as GnRH release in vitro. These results clearly demonstrate that noradrenergic neurotransmission is involved in P-stimulated GnRH gene expression in the rat hypothalamus.