Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alcoholism is a prevalent problem of contemporary society, yet there are virtually no clinically effective drugs for the management of this disorder. A previous study demonstrating the ability of angiotensin-converting enzyme (ACE) inhibitors to attenuate voluntary alcohol intake in rats prompted the suggestion that these drugs, currently marketed for the treatment of hypertension, may also be useful in dealing with human alcohol abuse. The present experiments explored in more detail the effect and possible mechanisms of action of this class of drug on alcohol consumption in rats. Experiment one demonstrated that Abutapril, a new ACE inhibitor, significantly reduced alcohol intake and that this effect could not be blocked by either an ANG II or an opiate receptor antagonist suggesting that neither the peripheral renin-angiotensin system (RAS) nor the endogenous enkephalins are involved in the ability of ACE inhibition to attenuate alcohol intake. Experiments two and three showed that ACE inhibition effectively reduced alcohol drinking faster in animals with elevated RAS activity and not at all in animals with suppressed RAS activity indicating that initial levels of RAS activity may determine the speed and ability of ACE inhibition to attenuate alcohol intake. ACE inhibitors may reduce alcohol intake by elevating a nonapeptide fragment or by elevating central ANG II levels. The assessment of this class of drugs to reduce alcohol intake in humans should include a monitoring of the initial level of activity in the renin-angiotensin system since this may be a predictor of the effectiveness of treatment with the ACE inhibitors.
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PMID:Angiotensin converting enzyme inhibitors reduce alcohol consumption: some possible mechanisms and important conditions for its therapeutic use. 217 80

The prevalence of heavy alcohol consumption is a major problem of increasing proportions throughout the world. Although alcohol sensitizing drugs and more recently serotonin uptake inhibitors are drug interventions with some following, their long term beneficial consequences have yet to be demonstrated. In recent years, we have demonstrated that manipulating activity in the renin-angiotensin system will dramatically alter voluntary alcohol consumption in rats. Based on these findings, the present study evaluated the ability of a class of drugs known as the angiotensin converting enzyme inhibitors to reduce voluntary alcohol drinking in laboratory animals. These drugs prevent the conversion of angiotensin I to angiotensin II. They have been licensed for use in Europe and North America and are indicated in the treatment of hypertension. Our experiments showed that both captopril (Capoten, Squibb) and enalapril (Vasotec, Merck Sharpe & Dohme) can reduce alcohol drinking in both normotensive and hypertensive animals regardless of whether the pattern of intake is in a bout or of a less exaggerated nature. Furthermore, this change in alcohol intake can occur without concomitant changes in blood pressure, plasma renin activity, overall fluid balance, or the distribution and metabolism of alcohol. Taken together these findings suggest that the angiotensin converting enzyme inhibitors should be evaluated in a clinical setting for they may prove to be a useful new treatment or treatment adjunct for alcohol abuse in humans.
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PMID:Angiotensin converting enzyme inhibitors: animal experiments suggest a new pharmacological treatment for alcohol abuse in humans. 283 50

This review examines some particular approaches that have been used to investigate factors that facilitate or constrain the self-administration of ethanol by rats. A technique for increasing ethanol self-administration in rats, the prandial drinking method, was examined and the effect of body-weight reduction on drug intake was discussed. Emphasis was placed on how ethanol intake may be controlled by processes in addition to the direct pharmacological actions of the drug in the CNS. These processes may be physiological. Evidence was presented for a relationship between activity in the renin-angiotensin system and the self-administration of ethanol. These processes may also be environmental. Using the place-conditioning technique, demonstrations were presented of how the context or situation in which ethanol is experienced may determine whether preference or aversion for the drug develops. Such a diversity in the factors that can potentially control ethanol intake may complicate the identification of the causes of alcohol abuse, but this same diversity also holds out greater hope that manipulations may be found to reduce excessive drinking in humans.
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PMID:Ethanol as a reinforcer for rats: factors of facilitation and constraint. 306 1

Angiotensin converting enzyme plays a key role in the regulation of blood pressure and inhibitors of the enzyme are effective antihypertensive agents. An association between hypertension and alcohol abuse has long been recognized and manipulations of the renin-angiotensin system in laboratory animals has been shown to alter their consumption of ethanol. Procedures that decrease the renin-angiotensin system increase ethanol consumption. Paradoxically, inhibitors of angiotensin converting enzyme also diminish drinking. Several possible explanations for this observation have been proposed. However, observations on the relationship between stress-induced drinking and the antidipsogenic action of a fragment of adrenocorticotropic hormone suggest another possibility: angiotensin converting enzyme may be involved in the metabolism of this peptide and thereby exert an influence on drinking behavior.
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PMID:Angiotensin converting enzyme inhibitors and alcohol abuse. 803 63

Extensive research has shown that manipulations that augment activity in the renin-angiotensin system can reduce alcohol intake. Inhibition of aminopeptidase B and M can prolong the action of angiotensin (ANG) II and ANG III by preventing their degradation. This study assessed the ability of bestatin, an aminopeptidase B and M inhibitor, to decrease alcohol intake. Bestatin produced a dose-dependent reduction in alcohol intake without altering water intake. The angiotensin antagonist Sar1Thr3-ANG II, however, did not attenuate the effect of bestatin, suggesting that the reduction in alcohol intake was mediated by a system other than the renin-angiotensin system. Bestatin (Ubenimex) is used extensively in Japan as an anticancer agent. It has a low toxicity and is readily absorbed after oral administration. Although further research is needed to uncover the mechanism of its effect, the potential of this drug as an adjunct for the treatment of alcohol abuse should be evaluated.
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PMID:Bestatin, an aminopeptidase B inhibitor, selectively reduces alcohol intake in rats. 848 90

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-beta1 (TGF-beta1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-beta1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-beta1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-beta1 expression. The glutathione precursor procysteine also prevented TGF-beta1 expression, suggesting that TGF-beta1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-beta1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-beta1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
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PMID:Angiotensin II mediates glutathione depletion, transforming growth factor-beta1 expression, and epithelial barrier dysfunction in the alcoholic rat lung. 1590 76

Alcohol abuse increases the incidence of acute respiratory distress syndrome and causes oxidative stress and cellular dysfunction in the lung. The mechanisms of ethanol (EtOH)-induced oxidative stress in the lung remain to be defined. Chronic alcohol ingestion has been associated with increased renin-angiotensin system (RAS) activity. Therefore, the current study investigated the ability of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, to modulate oxidative stress in the lung after chronic EtOH ingestion in a well-established rat model. Male Sprague-Dawley rats were fed liquid diets containing EtOH (36% of calories) or maltose-dextrin as an isocaloric substitution for EtOH (Control) for 6 wk. Selected animals were also treated with lisinopril (3 mg/liter) for 6 wk. Chronic EtOH ingestion increased bronchoalveolar lavage fluid glutathione disulfide levels and superoxide formation in lung parenchyma. These effects of EtOH were attenuated by lisinopril treatment. Chronic EtOH ingestion failed to increase ACE expression or angiotensin II levels in lung homogenates, but increased angiotensinogen, angiotensin II type 1 and type 2 receptor levels, and ACE activity. Chronic EtOH ingestion also increased the levels of the NADPH oxidase subunit, gp91phox, an effect that was attenuated by lisinopril, but had no effect on lung p22phox or p47phox levels. These findings suggest that EtOH-mediated RAS activation plays an important role in pulmonary oxidative stress and provide new insights into mechanisms by which EtOH causes oxidative stress in the lung and potential strategies of lung protection through ACE inhibition.
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PMID:Chronic ethanol ingestion increases superoxide production and NADPH oxidase expression in the lung. 1628 59

ARDS is a severe form of lung injury characterized by increased permeability of the alveolar capillary membrane, diffuse alveolar damage, the accumulation of proteinaceous interstitial and intra-alveolar edema, and the presence of hyaline membranes. These pathological changes are accompanied by physiological alterations, including severe hypoxemia, an increase in pulmonary dead space, and decreased pulmonary compliance. Approximately 200,000 individuals develop ARDS in the United States each year, and nearly 50% of these patients have a history of alcohol abuse. We have identified alcohol abuse as an independent risk factor for the development of ARDS, and more recent studies have validated these findings in patients following lung resection and blood transfusion. In ARDS survivors, alcohol abuse is also associated with an increased duration of mechanical ventilation and prolonged ICU length of stay. Despite studies aimed at improving outcomes in patients with ARDS, the mortality remains high at > 40%]. For those who abuse alcohol, the mortality is even higher, at 65%. In this review, we will discuss the relationship between alcohol abuse and ARDS, the effects of alcohol abuse on pulmonary function, and future directions and potential therapeutic targets for patients at risk for ARDS as a result of alcohol abuse, which impairs immune function, decreases pulmonary antioxidant capacity, decreases alveolar epithelial cell function, alters activation of the renin angiotensin system, and impairs GM-CSF signaling. These pathways represent potential therapeutic targets for patients at risk for ARDS as a result of alcohol abuse.
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PMID:Alcohol abuse and pulmonary disease. 1960 70

Bipolar affective disorder (BD) diagnosis and initiation of appropriate treatment are often delayed, and this is associated with poorer outcomes, such as rapid cycling or cognitive decline. Therefore, identifying certain warning signs of a probable successive episode during the inter-episode phase is important for early intervention. We present the retrospective data of three cases of BD. Our first case had a history of alcohol use disorder (AUD), where he drank in a dipsomaniac manner, and the other two cases had dipsomaniac alcohol use before their manic attacks, and none of them had any AUD after the mood episode was over. Two brothers also had hypertensive episodes during the manic attacks. None of the cases reported increased fluid intake when they were euthymic. We suggest that polydipsia in BD may be a warning sign of an upcoming manic episode, especially in those patients with AUD. Polydipsia in BD may be caused or facilitated by a combination of hyperdopaminergic activity, hypothalamic dysfunction, and dysregulated renin-angiotensin system. To be able to prevent new episodes, a patient's drinking habits and change in fluid intake should be asked at every visit. Those patients with a history of alcohol abuse should especially be informed about polydipsia and manic episode association.
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PMID:Polydipsia as a Precursor of Manic Episode in Bipolar Affective Disorder Patients with Alcohol Use Disorder. 2939 74