atrial-natriuretic-factor and Substance-Withdrawal-Syndrome

Abrupt cessation of long-term alcohol consumption produces well-defined symptoms called alcohol withdrawal (AW). The exact pathophysiological mechanisms involved in the appearance of AW symptoms and particularly those related to the precipitation of delirium tremens (DT), still await clarification in spite of the fact that the prediction of complicated AW is essential to guarantee that appropriate therapies may be planned in advance. Changes in central nervous system (CNS) glutamate- and GABA-transmission and a role of voltage-operated calcium channels are equally important elements of neuroadaptation to the chronic presence of alcohol. In addition to the CNS regulation, however, changes in peripheral fluid and electrolyte homeostasis may accompany, and are expected to modify the clinical symptoms of AW. In an early phase of acute withdrawal, plasma levels of atrial natriuretic peptide (ANP), plasma renin activity and aldosterone are high. In patients with DT, elevated levels of ANP were observed days before the actual onset of DT. It is concluded that the altered plasma ANP secretion might be associated with, and therefore used as an indicator of the onset of DT. However, ANP is present in and produced by the brain and thus it can be regarded as a neuropeptide. The role of CNS ANP was studied in mice, rendered tolerant to and physically dependent on alcohol. Intracerebroventricular injections of ANP attenuated, whereas those of an antiserum against ANP intensified hyperexcitability during AW. ANP in the brain - the content of which undergoes sensitive changes in the hippocampus during AW appears to interact primarily with glutamate transmission through the NMDA-receptors. This brain structure is of utmost importance for the generation of withdrawal-related hyperexcitability. It is concluded that peripheral secretion of ANP might be a diagnostics indicator, whereas ANP in the CNS might be a modulator of AW.

Topics: Alcohol Withdrawal Delirium; Aldosterone; Amino Acid Sequence; Animals; Atrial Natriuretic Factor; Biomarkers; Ethanol; Humans; Molecular Sequence Data; Neurotransmitter Agents; Receptors, Atrial Natriuretic Factor; Renin; Substance Withdrawal Syndrome

Changes in fluid and electrolyte homeostasis may accompany and are likely to modify the clinical symptoms of alcohol-withdrawal reactions. It was of obvious theoretical and practical interest therefore to investigate the changes in the secretion of hormones, which regulate the fluid and electrolyte homeostasis (atrial natriuretic peptide, aldosterone and plasma renin activity) during alcohol withdrawal in chronic alcoholic patients. In a phase of severe withdrawal, there were increased plasma renin activity and aldosterone levels observed. In a phase of partial recovery, on the other hand, the elevated plasma renin activity and aldosterone levels were back to the normal range. In 60% of the patients, delirium tremens was gradually developing during the observation period. In these patients, an elevated level of atrial natriuretic peptide was observed at the time of hospital admission, i.e. days before the actual onset of delirium tremens. It is concluded that the disturbed volume homeostasis and the consequently altered plasma atrial natriuretic peptide secretion might be associated with, and therefore used as an indicator of the onset of delirium tremens. To study the role of central nervous atrial natriuretic peptide, mice were rendered tolerant to and dependent on alcohol with an alcohol-liquid diet for 14 days. Five hours after withdrawal from alcohol, withdrawal hyperexcitability symptoms were analyzed. Intracerebroventricular (i.c.v.) injection of atrial natriuretic peptide attenuated, whereas that of an antiserum against atrial natriuretic peptide intensified the severity of handling-induced convulsions. N-methyl-D-aspartate induced behavioral seizures in a dose-dependent manner, whose effect was more intensive during the alcohol-withdrawal period than in alcohol-naive animals. I.c.v. injections of atrial natriuretic peptide dose-dependently inhibited, whereas that of antiserum against atrial natriuretic peptide potentiated the seizure-inducing effect of N-methyl-D-aspartate in alcohol-dependent mice. Although tentatively, it is concluded that peripheral secretion of atrial natriuretic peptide may be an indicator, whereas central nervous atrial natriuretic peptide a neuropeptide modulator of alcohol-withdrawal symptomatology.

Topics: Animals; Atrial Natriuretic Factor; Biomarkers; Central Nervous System Depressants; Ethanol; Humans; Neurotransmitter Agents; Substance Withdrawal Syndrome

In heart failure patients, diuretics cause renin-angiotensin-aldosterone system (RAS) activation, which may lead to increased morbidity and mortality despite short-term symptomatic improvement.. To determine changes in RAS activation and clinical correlates following furosemide withdrawal in elderly heart failure patients without left ventricular systolic dysfunction.. We performed clinical assessments and laboratory determinations of aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP), norepinephrine, and endothelin in 29 heart failure patients [aged 75.1+/-0.7 (mean+/-S.E.M.) years], before, 1 and 3 months after placebo-controlled furosemide withdrawal. Recurrent congestion occurred in 2 of 19 patients withdrawn, and in 1 of 10 patients continuing on furosemide. Three months after withdrawal, PRA had decreased -1.61+/-0.71 nmol/l/h (P<0.05). Decreases in aldosterone levels did not reach significance (-0.17+/-0.38 nmol/l). The decreases in PRA after withdrawal correlated with decreases in systolic (r(s)=0.61, P=0.020) and diastolic blood pressure (r(s)=0.80, P=0.01). Successful withdrawal was associated with increases in norepinephrine (+0.58+/-0.22 nmol/l) and ANP (+3.5+/-1.3 pmol/l) (P<0.05) after 1 month, but these changes did not persist after 3 months. Endothelin levels did not change in both groups.. Successful furosemide withdrawal in elderly heart failure patients causes persistent decreases in RAS activation.

Topics: Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diuretics; Double-Blind Method; Echocardiography; Epinephrine; Female; Follow-Up Studies; Furosemide; Heart Failure; Heart Rate; Humans; Male; Neurotransmitter Agents; Norepinephrine; Patient Compliance; Renin; Renin-Angiotensin System; Statistics as Topic; Stroke Volume; Substance Withdrawal Syndrome; Systole; Time Factors; Treatment Outcome; Ventricular Function, Left

Topics: Adrenocorticotropic Hormone; Adult; Alcohol Drinking; Alcoholism; Atrial Natriuretic Factor; Ethanol; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Leptin; Male; Middle Aged; Outpatients; Self Administration; Self Disclosure; Substance Withdrawal Syndrome; Time Factors

Both atrial natriuretic peptide (ANP) and vasopressin (VP) influence alcohol intake and withdrawal as well as craving and are also regulated by epigenetic factors. Disturbances in expression and promoter methylation status have been described in patients suffering from alcohol use disorder and alcohol withdrawal therapy.. In this study, we wanted to map the progression of cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoter of ANP and VP immediately after starting alcohol withdrawal therapy when compared with healthy controls METHODS: We recruited 34 males suffering from alcohol addiction or harmful use alongside 43 healthy male controls. Blood samples for methylation analyses were drawn on days 1, 2, 3, 4, and 7-10.. There was no difference in mean methylation for both VP and ANP during withdrawal. There was no difference at the ANP CpG-sites after correction for multiple testing. Regarding VP, methylation was significantly higher at CpG 033, CpG 064, CpG 103, CpG 118, and CpG 194 and significantly lower at CpG 053, CpG 060, and CpG 214 when compared to healthy controls. Via in silico analysis, we identified transcription factor binding sites that could potentially influence methylation-dependent gene transcription.. While there was no change in methylation status during withdrawal, significant differences in average methylation of specific CpG sites were observed for VP. We also identified the role of transcription factors in the context of promoter methylation as one potential mechanism that could explain the differences in VP levels between alcohol-dependent patients and healthy controls.

Topics: Alcoholism; Atrial Natriuretic Factor; Case-Control Studies; DNA Methylation; Humans; Male; Substance Withdrawal Syndrome; Vasopressins

Atrial natriuretic peptide (ANP) is well known in psychiatric disorders to modulate hypothalamic-pituitary-adrenal axis activity. Disturbances of ANP have been described in early abstinent alcohol-dependent patients. This is the first longitudinal investigation on cytosine-phosphatidyl-guanine (CpG)-island promoter methylation of the ANP gene in the blood of tobacco-dependent patients.. In a longitudinal approach, we investigated whether changes in ANP serum levels correlated to CpG methylation of the respective gene promoters on days 1, 7, and 14 of tobacco withdrawal.. Compared to non-smokers, promoter-related deoxyribonucleic acid methylation of the ANP promoter was significantly elevated on days 7 and 14 of withdrawal in tobacco-dependent patients. Baseline methylation status of the ANP promoter was not significantly different from controls, arguing for an impaired regulation during withdrawal.

Topics: Adolescent; Adult; Atrial Natriuretic Factor; DNA Methylation; Humans; Longitudinal Studies; Middle Aged; Pilot Projects; Promoter Regions, Genetic; Smokers; Smoking; Smoking Cessation; Substance Withdrawal Syndrome; Tobacco Use Disorder; Young Adult

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.

Topics: Adult; Alcoholism; Atrial Natriuretic Factor; Case-Control Studies; CpG Islands; DNA Methylation; Humans; Male; Promoter Regions, Genetic; Substance Withdrawal Syndrome; Vasopressins; Young Adult

Converging evidence from both preclinical and clinical studies suggests atrial natriuretic peptide (ANP) as a potential target for treatment of alcohol withdrawal and dependence. Since ANP tightly interacts with hypothalamic-pituitary-adrenocortical (HPA) axis activity, especially the modulation of stress-related anxiety during alcohol withdrawal might mediate these effects. We have now evaluated the anxiolytic activity of intraperitoneal ANP application during alcohol withdrawal in alcohol-habituated mice (C57/Bl6J). Anxiety related behaviour was attenuated during ethanol withdrawal following application of ANP (60 μg/kg) vs. saline. Our results support that anxiolytic effects of ANP mediate ANP-related gene effects with clinical data on withdrawal symptomatology.

Topics: Alcohol Drinking; Animals; Anti-Anxiety Agents; Anxiety; Atrial Natriuretic Factor; Disease Models, Animal; Ethanol; Exploratory Behavior; Injections, Intraperitoneal; Male; Maze Learning; Mice; Statistics, Nonparametric; Substance Withdrawal Syndrome

Disturbances of volume regulating peptides like vasopressin and atrial natriuretic peptide (ANP) have been described in early abstinent patients. Aim of the present study was to evaluate possible alterations of the promoter-related DNA methylation of the ANP and vasopressin precursor genes and the related mRNA-expression of these genes in early alcohol withdrawal. We analyzed blood samples of 57 healthy controls and of 111 patients suffering from alcohol dependence that were admitted for detoxification treatment. Promoter-related DNA methylation and mRNA-expression of vasopressin and ANP genes were assessed using real-time PCR. Vasopressin mRNA-expression was not statistically different between patients and controls. However, we found a significantly elevated promoter-related DNA methylation of the vasopressin gene in patients with alcohol dependence (Mann-Whitney U-test: Z=-2.178, p=0.029). ANP mRNA-expression was significantly elevated in alcoholic patients (Z=-6.240, p<0.001) while promoter-related DNA methylation of ANP was significantly decreased (Z=-2.282, p=0.023). Furthermore, promoter-related DNA methylation of ANP was significantly correlated to the extent of craving measured with the OCDS (r=-0.197, p=0.040). The findings of the present study show significant alterations of the mRNA-expression and promoter-related DNA methylation of vasopressin and especially ANP precursor genes in patients with alcohol dependence. Further studies focusing on longitudinal changes of epigenetic regulation and gene expression of both peptides are needed to clarify the pathophysiological role of these findings.

Topics: Adult; Alcoholism; Atrial Natriuretic Factor; Case-Control Studies; DNA Methylation; Epigenesis, Genetic; Female; Humans; Male; Middle Aged; Promoter Regions, Genetic; Reference Values; RNA, Messenger; Substance Withdrawal Syndrome; Vasopressins; Water-Electrolyte Balance; Young Adult

Topics: Atrial Natriuretic Factor; Depression; Female; Humans; Selective Serotonin Reuptake Inhibitors; Sexual Dysfunctions, Psychological; Substance Withdrawal Syndrome

Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms.. To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure.. Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months.. At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2+/-10.8 to 39.2+/-10.1 mg/dl at 3 months, p=0.014; creatinine 1.1+/-0.23 to 0.98+/-0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151+/-91 to 122+/-14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80+/-10 to 87+/-13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19+/-5.96 to 2.88+/-4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115+/-87 to 168+/-155 pg/ml, p=0.004).. Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.

Topics: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Diuretics; Female; Heart Failure; Humans; Male; Middle Aged; Pilot Projects; Renin; Sodium Potassium Chloride Symporter Inhibitors; Substance Withdrawal Syndrome

During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long-term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol-dependent men compared with healthy controls.. Vasopressin (AVP), N-terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 +/- 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long-Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 +/- 7 years.. Basal AVP levels were found to be suppressed over the whole study period. In contrast, N-terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study.. Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic-pituitary-adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.

Topics: Adult; Alanine Transaminase; Alcoholism; Aldosterone; Angiotensin II; Aspartate Aminotransferases; Atrial Natriuretic Factor; Blood; Blood Urea Nitrogen; Drinking; gamma-Glutamyltransferase; Humans; Kidney; Liver; Male; Middle Aged; Osmolar Concentration; Protein Precursors; Substance Withdrawal Syndrome; Time Factors; Urea; Urine; Vasopressins; Water-Electrolyte Balance

Atrial natriuretic peptide (ANP) has been shown to inhibit the effects of corticotrophin releasing hormone, corticotrophin and cortisol, and to influence affective and anxiety symptoms in man. We tested the hypothesis of whether ANP is associated with endocrine and psychopathological disturbances during acute alcohol withdrawal.. ANP and cortisol plasma concentrations were studied in alcoholics during in-patient detoxification and in healthy controls. Additionally, craving, depressive mood and anxiety were assessed.. Although mean ANP levels increased significantly in alcoholics between days 1 and 14, they remained diminished compared to controls. Separating a subgroup of alcoholics with a decrease of ANP levels during withdrawal, these individuals revealed significantly elevated scores for mean and maximum craving and a trend to an elevated self-rated anxiety on day 14.. We suggest that a dysregulation of ANP plasma levels during alcohol withdrawal may contribute to symptoms of protracted withdrawal such as craving and anxiety.

Topics: Adult; Anxiety; Atrial Natriuretic Factor; Ethanol; Female; Humans; Hydrocortisone; Male; Substance Withdrawal Syndrome; Time Factors

Different doses (0.2-200 ng) of C-type natriuretic peptide (CNP) were administered into the lateral brain ventricle, and morphine (5 mg/kg) was injected subcutaneously. The analgesic effect was measured in a tail-flick test, in CFLP mice. CNP administered centrally did not itself affect pain sensitivity, but it depressed the acute antinociceptive effect of morphine 30 min after icv (0.2, 2 or 20 ng) CNP administration and the 2 and 20 ng doses also decreased this action after 60 min. CNP in a 0.2 or 200 ng dose blocked the development of acute tolerance to morphine after 30 min, as did the 200 ng dose at 60 min. CNP in a 0.2 ng dose blocked the development of chronic tolerance to morphine after 30 min, but there was no effect at 60 min. Morphine withdrawal signs were studied by injecting naloxone (1 mg/kg sc). There was no significant difference in symptoms between the tolerant group and the animals treated with CNP.

Topics: Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Drug Tolerance; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred Strains; Morphine; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Substance Withdrawal Syndrome; Time Factors

Mice were rendered tolerant to and dependent on ethanol with an ethanol-liquid diet for 14 days. Five hours after withdrawal from ethanol, withdrawal symptoms were analyzed by scoring handling-induced convulsions. Intracerebroventricular (i.c.v.) injection of alpha-atrial natriuretic peptide (alpha-ANP) attenuated, whereas that of an antiserum against alpha-ANP (anti-ANP) intensified the severity of handling-induced convulsions.

Topics: Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Ethanol; Injections, Intraventricular; Male; Mice; Seizures; Substance Withdrawal Syndrome

Atrial natriuretic peptide (ANP) is known to participate in different vegetative functions. The aim of the present study was to investigate the influence of ANP on nociception itself, pain sensitivity to morphine, and the development of acute and chronic tolerance to morphine. Morphine withdrawal signs were also evaluated by injecting naloxone. In adult, male NMRI mice, ANP administered SC or ICV did not affect pain sensitivity itself in a heat-radiant tail-flick test. Peptide treatment, however, depressed the acute nociceptive effect of a single dose of morphine (4 mg/kg, SC) after both SC (20-200 ng/animal) and ICV (5, 10, 20, or 200 ng/animal) ANP administration. ANP given SC and ICV attenuated the development of acute morphine tolerance. Acute morphine tolerance was assessed by giving a bolus injection of morphine (60 mg/kg) 24 h before the pain sensitivity to a challenge dose of morphine (4 mg/kg) was measured. ICV treatment with ANP also blocked the development of chronic morphine tolerance, but did not affect the appearance of naloxone-precipitated withdrawal syndromes. ANP seems to act differently on the development of tolerance to and dependence upon morphine.

Topics: Animals; Atrial Natriuretic Factor; Behavior, Animal; Drug Tolerance; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Morphine; Morphine Dependence; Naloxone; Pain Measurement; Substance Withdrawal Syndrome