[Antipsychotic Treatment of Alcohol Withdrawal Syndrome with Focus on Delirium Tremens: a Systematic Review]. / Systematische Übersichtsarbeit Antipsychotische Behandlung des Alkoholentzugssyndroms: Fokus Delirium Tremens.

BACKGROUND: Delirium tremens (DT) is a common complication of alcohol withdrawal. Pharmacological treatment of hospitalized patients with DT is important in addiction medicine but also in other medical disciplines where DT can occur as a complication of hospitalization. Patients suffering from DT require treatment with benzodiazepines (short-acting benzodiazepines for elderly patients to reduce accumulation), and in cases of psychotic symptoms, treatment with antipsychotics. Benzodiazepines are a first-line treatment for DT. A specific guideline for the use of antipsychotics has yet to be developed. This review discusses the current guidelines and literature on the antipsychotic treatment options in DT. AIM: Systematic presentation of relevant antipsychotics for the treatment of DT. METHODS: A systematic literature search was conducted using Scopus and PubMed. The last search was conducted on May 22nd 2022. Original articles and reviews on antipsychotic treatment in alcohol withdrawal and DT were included in this review. Further, international guidelines were also considered. The review was registered using the PROSPERO database (https://www.crd.york.ac.uk/prospero/); CRD42021264611. RESULTS: Haloperidol is mainly recommended for use in the intensive care unit. There is little literature on the use of atypical antipsychotics to treat DT. Treatment with antipsychotics always should be combined with benzodiazepines, and physicians should watch out for complications like neuroleptic malignant syndrome, QTc interval prolongation, extrapyramidal symptoms and withdrawal seizures resulting from lowering the threshold for seizures. CONCLUSION: Antipsychotic treatment should depend on the experience of the physician. Beside haloperidol, no other clear recommendations are available.

Mechanisms of N-oleoyldopamine activation of central histaminergic neurons.

Histaminergic (HA) neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus fire exclusively during waking and support many physiological functions. We investigated the role of the endovanilloid N-oleoyldopamine (OLDA) in TMN, where dopamine synthesis and its conjugation with oleic acid likely occur. We show that several known targets of OLDA including TRPV1 and cannabinoid receptors are expressed in HA neurons. In contrast to capsaicin, which failed to increase firing of HA neurons in TRPV1 knockout mice (TRPVI KO), OLDA was still able to induce excitation. This excitation was not sensitive to the blockade of cannabinoid receptors 1 and 2 and could result from OLDA interaction with GPR119, as the ligand of GPR119, oleoylethanolamide (OEA), also increased the firing of HA neurons. However, we ruled out this possibility as OEA- (but not OLDA-) excitation was abolished by the PPAR (peroxisome proliferator activated receptor) alpha antagonist MK886. The dopamine uptake blocker nomifensine blanked OLDA-excitation and dopamine receptor antagonists abolished the OLDA action in TRPV1 KO mice. Therefore OLDA excites HA neurons through multiple targets suggesting a central role of the histaminergic system in the behavioral stimulation seen after systemic OLDA application.

Effects of varenicline on alpha4-containing nicotinic acetylcholine receptor expression and cognitive performance in mice.

Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4ß2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4ß2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated. Protein and mRNA expression of both the α4 and ß2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The ß2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine). Varenicline dose-dependently increased protein expression of both the α4 and ß2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice. In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction.

Preservation of Endothelial and Smooth Muscle Function of Human Saphenous Vein Transplants.

OBJECTIVES: Methods for conservation and preservation of vascular grafts are often controversially discussed. Furthermore, immunologic monitoring or immunotherapy for allogeneic graft is not considered necessary in many cases. The present study was initiated to examine the cellular vitality and functional efficiency of vein transplant during preservation. MATERIALS AND METHODS: Twenty-seven human vein segments (vena saphena magna) were stored after explant in University of Wisconsin solution or histidine-tryptophan-ketoglutarate solution at 4 °C. After 3, 24, 48, 72, and 96 hours, vein functionality was tested. Ring segments were fixed by triangles in Krebs-Henseleit buffer. Contractile function was measured after addition of potassium chloride solution (80 mM) and phenylephrine (0.2, 2, or 20 µM). To investigate endothelium-dependent vasorelaxation, 1 µM acetylcholine was added. RESULTS: Of 27 segments, 5 showed endothelium-dependent relaxation. Vasorelaxation continued for up to 48 hours after administration of acetylcholine in University of Wisconsin solution and for up to 24 hours in histidine-tryptophane-ketoglutarate solution. At 48 hours, potassium chloride solution-induced vasocontraction was 17% more effective than phenylephrine in University of Wisconsin solution. University of Wisconsin solution was significantly more effective than histidine-tryptophane-ketoglutarate solution in terms of preservation of phenylephrine (0.2, 2 µM)-induced vasocontraction. Phenylephrine (2 µM)-induced contraction was retained in University of Wisconsin solution after 24 hours by 81% and after 48 hours by 55%, with comparable results in histidine-tryptophane-ketoglutarate solution of only 62% and 34% after 24 and 48 hours. CONCLUSIONS: At 48 hours, human saphenous vein transplants had better endothelium and smooth muscle function when preserved in University of Wisconsin solution versus histidine-tryptophane-ketoglutarate solution.

Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice.

OBJECTIVE: Hyaluronan (HA) is a polymeric glucosaminoglycan that forms a provisional extracellular matrix in diseased vessels. HA is synthesized by 3 different HA synthases (HAS1, HAS2, and HAS3). Aim of this study was to unravel the role of the HAS3 isoenzyme during experimental neointimal hyperplasia. APPROACH AND RESULTS: Neointimal hyperplasia was induced in Has3-deficient mice by ligation of the carotid artery. HA in the media of Has3-deficient mice was decreased 28 days after ligation, and neointimal hyperplasia was strongly inhibited. However, medial and luminal areas were unaffected. Cell density, proliferation, and apoptosis were not altered, suggesting a proportional decrease of both, the number of cells and extracellular matrix. In addition, endothelial function as determined by acetylcholine-induced relaxation of aortic rings, immunoblotting of endothelial nitric oxide synthase, and arterial blood pressure were not affected. Furthermore, the oxidative stress response was not affected as determined in total protein extracts from aortae. Transcriptome analysis comparing control versus ligated carotid arteries hinted toward a mitigated differential regulation of various signaling pathways in Has3-deficient mice in response to ligation that were related to vascular smooth muscle cell (VSMC) migration, including focal adhesions, integrins, mitogen-activated protein kinase, and phosphatidylinositol signaling system. Lentiviral overexpression of HAS3 in VSMC supported the migratory phenotype of VSMC in response to platelet-derived growth factor BB in vitro. Accordingly, knockdown of HAS3 reduced the migratory response to platelet-derived growth factor BB and in addition decreased the expression of PDGF-B mRNA. CONCLUSIONS: HAS3-mediated HA synthesis after vessel injury supports seminal signaling pathways in activation of VSMC, increases platelet-derived growth factor BB-mediated migration, and in turn enhances neointimal hyperplasia in vivo.

Identification of histaminergic neurons through histamine 3 receptor-mediated autoinhibition.

Using a reporter mouse model with expression of the tomato fluorescent protein under the dopamine transporter promoter (Tmt-DAT) we discovered a new group of neurons in the histaminergic tuberomamillary nucleus (TMN), which, in contrast to tuberoinfundibular dopaminergic neurons of the dorsomedial arcuate nucleus, do not express tyrosine hydroxylase but can synthesize and store dopamine. Tmt-DAT neurons located within TMN share electrophysiological properties with histaminergic neurons: spontaneous firing at a membrane potential around -50 mV and presence of hyperpolarization-activated cyclic nucleotide-gated ion channels. Histamine (30 µM) depolarizes and excites Tmt-DAT neurons through H1R activation but inhibits histaminergic neurons through H3R activation thus allowing a pharmacological identification of the different neurons. Single-cell RT-PCR revealed that all histaminergic neurons expressing histidine decarboxylase (HDC) also express H3R. This includes neurons retrogradely traced from the striatum whose inhibition by a selective H3R agonist was indistinguishable from the whole population. Prolonged depolarization reduces the autoinhibition. The potency of histamine at H3R depends on membrane potential and on extracellular and intracellular calcium. Autoinhibition can be impaired by preincubation with capsaicin, a ligand of the calcium-permeable TRPV1 channel or by blockade of Ca(2+)-ATPase with thapsigargin. The pharmacology of autoinhibition is revisited and physiological conditions for its functionality are determined. Usage of reporter mouse models for the safe identification of aminergic neurons under pathophysiological conditions is recommended. This article is part of the Special Issue entitled 'Histamine Receptors'.

Impact of eNOS-Dependent Oxidative Stress on Endothelial Function and Neointima Formation.

AIMS: Vascular oxidative stress generated by endothelial NO synthase (eNOS) was observed in experimental and clinical cardiovascular disease, but its relative importance for vascular pathologies is unclear. We investigated the impact of eNOS-dependent vascular oxidative stress on endothelial function and on neointimal hyperplasia. RESULTS: A dimer-destabilized mutant of bovine eNOS where cysteine 101 was replaced by alanine was cloned and introduced into an eNOS-deficient mouse strain (eNOS-KO) in an endothelial-specific manner. Destabilization of mutant eNOS in cells and eNOS-KO was confirmed by the reduced dimer/monomer ratio. Purified mutant eNOS and transfected cells generated less citrulline and NO, respectively, while superoxide generation was enhanced. In eNOS-KO, introduction of mutant eNOS caused a 2.3-3.7-fold increase in superoxide and peroxynitrite formation in the aorta and myocardium. This was completely blunted by an NOS inhibitor. Nevertheless, expression of mutant eNOS in eNOS-KO completely restored maximal aortic endothelium-dependent relaxation to acetylcholine. Neointimal hyperplasia induced by carotid binding was much larger in eNOS-KO than in mutant eNOS-KO and C57BL/6, while the latter strains showed comparable hyperplasia. Likewise, vascular remodeling was blunted in eNOS-KO only. INNOVATION: Our results provide the first in vivo evidence that eNOS-dependent oxidative stress is unlikely to be an initial cause of impaired endothelium-dependent vasodilation and/or a pathologic factor promoting intimal hyperplasia. These findings highlight the importance of other sources of vascular oxidative stress in cardiovascular disease. CONCLUSION: eNOS-dependent oxidative stress is unlikely to induce functional vascular damage as long as concomitant generation of NO is preserved. This underlines the importance of current and new therapeutic strategies in improving endothelial NO generation.

Angiotensin-(1-7) modulates renal vascular resistance through inhibition of p38 mitogen-activated protein kinase in apolipoprotein E-deficient mice.

Apolipoprotein E-deficient (apoE(-/-)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)-(1-7) treatment ameliorates endothelial dysfunction in apoE(-/-) mice. However, the mechanism of Ang-(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang-(1-7) function, we used apoE(-/-) and wild-type mice fed on Western diet that were treated via osmotic minipumps either with Ang-(1-7) (82 µg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(-/-) compared with wild-type mice. This apoE(-/-)-specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC(20)), causing renal vasoconstriction. Here, we provide evidence that chronic Ang-(1-7) treatment attenuated the renal pressor response to Ang II in apoE(-/-) mice to wild-type levels. Ang-(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogen-activated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogen-activated protein kinase inhibitor SB203580 (5 µmol/L), causing a reduced renal pressor response to Ang II in apoE(-/-) but not in apoE(-/-) mice treated with Ang-(1-7). Moreover, Ang-(1-7) treatment had no effect in Mas(-/-)/apoE(-/-) double-knockout mice confirming the specificity of Ang-(1-7) action through the Mas-receptor. In summary, Ang-(1-7) modulates vascular function via Mas-receptor activation that attenuates pressor response to Ang II in apoE(-/-) mice by reducing reactive oxygen species-mediated p38 mitogen-activated protein kinase activity.

Epidemiology, symptoms, and treatment characteristics of hyponatremic psychiatric inpatients.

Hyponatremia is a common phenomenon in psychiatry occurring as an adverse effect to drugs or following polydipsia. We performed a retrospective in-depth analysis of hyponatremia cases in a large unselected population of psychiatric inpatients. During a 3-year period, all cases of hyponatremia were identified among patients admitted to a large psychiatric state and university hospital by the institution's electronic laboratory database. Demographic, treatment-related, and laboratory data were obtained by consecutive chart review, respectively. Hyponatremia occurred in 347 (4.9%) of 7113 cases, of which the majority (78%) displayed only a mild manifestation. Symptoms were recorded in 28.8% of cases, already occurred in mild forms, and comprised gait impairment (45%, including falls), confusion (30%), sedation (26%), and dyspepsia (41%). Age, female sex, nonpsychiatric drug polypharmacy-particularly with thiazides and/or angiotensin-converting enzyme inhibitors-and diagnosis of a mood disorder were associated with more severe hyponatremia, respectively. The proportion of hyponatremic patients treated with venlafaxine, trazodone, carbamazepine, oxcarbazepine, and first-generation antipsychotics, respectively, was significantly higher in the hyponatremia sample than in the normonatremic population. This was, surprisingly, not the case with selective serotonin reuptake inhibitors or any other antidepressant drug class. We found prescription with second-generation antipsychotics to be significantly associated with less severe hyponatremia.Hyponatremia may be mainly attributed to the syndrome of inappropriate antidiuretic hormone secretion, as indicated by decreased serum osmolarity in our sample. Besides old age and female sex, treatment with certain drugs-rather than whole drug classes-carries a substantially increased risk.

Critical role of endothelial hydrogen peroxide in post-ischemic neovascularization.

BACKGROUND: Reactive oxygen species (ROS) play an important role in angiogenesis in endothelial cells (ECs) in vitro and neovascularization in vivo. However, little is known about the role of endogenous vascular hydrogen peroxide (H2O2) in postnatal neovascularization. METHODOLOGY/PRINCIPAL FINDINGS: We used Tie2-driven endothelial specific catalase transgenic mice (Cat-Tg mice) and hindlimb ischemia model to address the role of endogenous H2O2 in ECs in post-ischemic neovascularization in vivo. Here we show that Cat-Tg mice exhibit significant reduction in intracellular H2O2 in ECs, blood flow recovery, capillary formation, collateral remodeling with larger extent of tissue damage after hindlimb ischemia, as compared to wild-type (WT) littermates. In the early stage of ischemia-induced angiogenesis, Cat-Tg mice show a morphologically disorganized microvasculature. Vascular sprouting and tube elongation are significantly impaired in isolated aorta from Cat-Tg mice. Furthermore, Cat-Tg mice show a decrease in myeloid cell recruitment after hindlimb ischemia. Mechanistically, Cat-Tg mice show significant decrease in eNOS phosphorylation at Ser1177 as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in ischemic muscles, which is required for inflammatory cell recruitment to the ischemic tissues. We also observed impaired endothelium-dependent relaxation in resistant vessels from Cat-Tg mice. CONCLUSIONS/SIGNIFICANCE: Endogenous ECs-derived H2O2 plays a critical role in reparative neovascularization in response to ischemia by upregulating adhesion molecules and activating eNOS in ECs. Redox-regulation in ECs is a potential therapeutic strategy for angiogenesis-dependent cardiovascular diseases.

Nitric oxide and the CABG patient.

The post surgery success of coronary artery bypass grafting (CABG) is counteracted by thrombosis and de-endothelialization, intimal hyperplasia and, over the long term, atherosclerosis. There are many reasons to assume that in CABG patients vascular bioavailability of NO generated by the endothelium plays an important role for graft function. This holds true for factors such as graft type, harvesting and storage, the type of surgery, non-pharmacologic prevention of risk factors, for example, regular physical activity (if feasible), and drug therapy. Although the precise role of graft endothelial NO bioavailability for graft patency and clinical endpoints is still uncertain, current data rather speak in favor of NO indicating that the potential of vasoprotective activities of NO in the CABG patient deserves further investigation.

Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice.

Clinical studies revealed unfavorable effects of hormone replacement therapy in postmenopausal women despite strong evidence for vasoprotective effects of estrogen in animal models. Therefore, an attempt was made to address adverse effects of estradiol on atherosclerosis, endothelial function, and thrombosis in a murine model of atherosclerosis. ApoE(-/-) mice were bilaterally ovariectomized (OVX) and substituted with placebo or 17-beta-Estradiol (E(2), 1.1 and 6.6 microg/day) on Western diet for 90 days. Low-dose E(2) (1.1 microg/day) treatment significantly increased atherosclerotic plaque score, whereas high-dose E(2) (6.6 microg/day) reduced aortic plaque burden. The proatherosclerotic effects of low-dose E(2) were associated with decreased total collagen in aortic root lesions and impaired acetylcholine (ACh)-induced vasorelaxation of aortic rings. On the contrary, OVX compared with control reduced atherosclerosis, increased fibrillar collagen and improved endothelial function. The thrombotic response as measured in a photothrombosis model was not significantly altered by E(2) or OVX. Taken together, differential effects on atherosclerosis of the clinical relevant low-dose E(2) compared with high-dose E(2) were demonstrated. Importantly, the presented experimental conditions provide a model to study the untoward vascular effects of E(2) in the context of accelerated and advanced atherosclerosis.

Hydrogen peroxide inhibits exercise-induced increase of circulating stem cells with endothelial progenitor capacity.

The number of circulating stem cells with endothelial progenitor capacity (EPCs) inversely correlates with the number of cardiovascular risk factors. In this study we sought to investigate the effects of vascular H(2)O(2) on circulating EPC levels. In C57BL/6 mice 3 weeks of freely moving or forced physical activity or voluntary exercise failed to increase circulating EPCs defined as double positive for Flk-1 and CD34, CD133 or Sca-1. Likewise, neither insertion of additional genes encoding for catalase (cat(++)) or eNOS nor eNOS knock-out changed EPCs in resting mice. In striking contrast, inhibition of catalase by aminotriazole strongly reduced circulating EPCs in sedentary cat(++) and their transgen-negative littermates (cat(n)), while forced or voluntary exercise training of cat(++) mice significantly increased the number of circulating EPCs. The latter effect was completely inhibitable by aminotriazole. These data suggest that endogenous vascular H(2)O(2) likely contributes to the impairment of important stem cell-induced vascular repair mechanisms in cardiovascular disease.

Differential effects of medroxyprogesterone acetate on thrombosis and atherosclerosis in mice.

BACKGROUND AND PURPOSE: The risk for cardiovascular events including venous and arterial disease and stroke is elevated after treatment with estrogen and medroxyprogesterone acetate (MPA) in postmenopausal women. Here, we have investigated the effect of MPA on arterial thrombosis and atherosclerosis in a murine model of atherosclerosis. EXPERIMENTAL APPROACH: Apolipoprotein E (ApoE)-/- mice were bilaterally ovariectomized and treated with placebo, MPA (27.7 microg day(-1)) and MPA + 17-beta-oestradiol (E2; 1.1 microg day(-1)) for 90 days, on a Western-type diet. Thrombotic response was measured in a photothrombosis model, platelet activation by fluorescence activated cell sorting (FACS) analysis (CD62P) and thrombin generation by the endogenous thrombin potential (ETP). Furthermore, aortic plaque burden and aortic root plaque composition were determined. KEY RESULTS: MPA and MPA + E2-treated animals showed an aggravated thrombotic response shown by significantly reduced time to stable occlusion. The pro-thrombotic effect of MPA was paralleled by increased ETP whereas platelet activation was not affected. Furthermore, MPA + E2 reduced the number of cells positive for alpha-smooth muscle actin and increased hyaluronan in the plaque matrix. Interestingly, total plaque burden was reduced by MPA but unchanged by MPA + E2. CONCLUSION AND IMPLICATIONS: Long-term treatment with MPA and MPA + E2 increased arterial thrombosis despite inhibitory effects of MPA on atherosclerosis in ApoE-deficient mice. Increased thrombin formation, reduced smooth muscle content and remodelling of non-collagenous plaque matrix may be involved in the pro-thrombotic effects. Thus, MPA exhibits differential effects on arterial thrombosis and on atherosclerosis.

Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes.

Reduced activity and expression of endothelial NO synthase (eNOS) is observed in cardiomyocytes from pressure-overloaded hearts with heart failure. The present study was aimed to investigate whether reduced eNOS-derived NO production contributes to the hypertrophic growth and phenotype of these cardiomyocytes. Cultured ventricular cardiomyocytes from adult rats were exposed to Nomega-nitro-l-arginine (l-NNA) to inhibit global NO formation, and cultured cardiomyocytes derived from eNOS-deficient mice were used as a model of genetic knockout of eNOS. Cell growth, formation of oxygen-derived radicals (reactive oxygen species [ROS]), activation of p38 mitogen-activated protein (MAP) kinase phosphorylation, and cytokine expression in cardiomyocytes were investigated. l-NNA caused a concentration-dependent acceleration of the rate of protein synthesis and an increase in cell size. This effect was sensitive to p38 MAP kinase inhibition or antioxidants. l-NNA induced a rapid increase in ROS formation, subsequent activation of p38 MAP kinase, and p38 MAP kinase-dependent increases in the expression of transforming growth factor-beta and tumor necrosis factor-alpha. Similar changes (increased ROS formation, p38 MAP kinase phosphorylation, and cytokine induction) were also observed in cardiomyocytes derived from eNOS+/+ mice when exposed to l-NNA. Cardiomyocytes from eNOS-/- mice displayed higher p38 MAP kinase phosphorylation and cytokine expression under basal conditions, but neither these 2 parameters nor ROS formation were increased in the presence of l-NNA. In conclusion, our data support the hypothesis that reduced eNOS activity in cardiomyocytes contributes to the onset of myocardial hypertrophy and increased cytokine expression, which are involved in the transition to heart failure.

Evaluation and management of angioedema of the head and neck.

PURPOSE OF REVIEW: Sudden occurrence of subcutaneous or submucosal swelling, the so-called angioedema, is an established and potentially life-threatening condition. Several forms of angioedema show a great variety of tissue localizations and different underlying mechanisms such as genetic mutations, allergic reactions and nonallergic reactions exist. Unfortunately, angioedema is often unrecognized and/or incorrectly treated. To change this situation, a better understanding of angioedema and possible therapeutic approaches appears necessary. RECENT FINDINGS: Recent investigations have shed new light on the pathomechanism of nonallergic drug-induced angioedema and new therapeutic options targeting the kallikrein-kinin system have become available for patients in clinical trials. Furthermore, extensive clinical evaluations of commonly used inhibitors of the renin-angiotensin system have provided reliable data on the incidence of angioedema induced by these drugs. Accordingly, several thousand patients worldwide experience severe fatal attacks although timely medical care would have saved their lives. SUMMARY: Current data suggest that the nonapetide bradykinin plays a crucial role in the pathogenesis of most forms of nonallergic angioedema, while histamine acts as the main biogenic mediator in allergic angioedema. Thus, correct diagnosis is crucial for effective treatment. Standard antiallergic drugs such as glucocorticoids and antihistamines are most probably ineffective in nonallergic angioedema forms.

Vasoprotection by nitric oxide: mechanisms and therapeutic potential.

Endothelial production of nitric oxide (nitrogen monoxide, NO) has become a major research area in vascular biology. Some of the most important effects that NO exerts in the vascular wall are potentially vasoprotective, because these effects maintain important physiological functions such as vasodilation, anticoagulation, leucocyte adhesion, smooth muscle proliferation, and the antioxidative capacity. During the last 2 decades it has become apparent that a variety of diseases are associated with an impairment of endothelium-dependent NO activity. One of the major causes is believed to be an increased production of reactive oxygen species, in particular superoxide, which have been shown to interfere with many steps of the NO--cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has been found in diverse conditions such as atherosclerosis, hypertension, diabetes, hypercholesterolemia, heart failure, and cigarette smoking. The aim of this review is to examine the cellular and molecular mechanisms whereby NO exerts potentially vasoprotective effects and to discuss pharmacologic approaches targeting the NO pathway in view of their potential to improve endothelial function and to reduce the progression of atherosclerotic vascular disease. We conclude that there is compelling evidence for vasoprotective actions of NO which are mediated by cGMP-dependent and cGMP-independent mechanisms. These effects may contribute to the beneficial effects of established drugs such as ACE inhibitors or statins. Unfortunately, clinical data on the effect of long-term treatment with nitrates on the progression of coronary artery disease are lacking. Finally, L-arginine or new activators of the NO pathway may become therapeutic options in the future.