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At least 235 records · Page 13Linked to original sources
PubMed1987

Recent views on the pathogenesis of gastro-oesophageal reflux disease.

The pathogenesis of GORD depends on a mix of factors which vary amongst individual patients. The central issue in the pathogenesis of gastro-oesophageal reflux is understanding of the mechanisms that lead to reflux, since the effects of all other factors depend on this event. Consequently, new information and views about the mechanisms of gastro-oesophageal reflux have been presented in detail. This information suggests that defective lower oesophageal sphincter motility is the most important abnormality that underlies pathological gastro-oesophageal reflux. Two major forms of LOS dysfunction have been identified as responsible for pathological gastro-oesophageal reflux in the horizontal position: (1) an excessively frequent rate of occurrence of transient LOS relaxations; and (2) defective basal LOS tone. Both of these dysfunctions appear to arise from abnormal neural control of the LOS, probably by the central nervous system. The effect of these LOS dysfunctions on gastro-oesophageal competence is probably significantly influenced by non-sphincteric factors, the most important of these apparently being hiatus hernia. Though there is currently poor understanding about the ways in which hiatus hernia impairs gastro-oesophageal competence, measurement techniques have now advanced sufficiently to allow significant accrual of knowledge in this field. Once reflux has occurred, the efficiency of oesophageal acid clearance plays a major role in determining the impact of reflux on the oesophageal mucosa. Recent studies have shown that oesophageal acid clearance depends on both effective volume clearance and neutralization by saliva of residual acid in the oesophageal lumen. The efficiency of oesophageal volume clearance of both stimulated and real reflux has not been studied formally in GORD patients, but the high incidence of peristaltic dysfunction in reflux disease suggests that volume clearance will be defective in some patients. The limited information available about salivation in GORD patients suggests that salivary secretion is no different from that of age-matched controls, but that there is an age-dependent loss of the salivary response to oesophageal acidification. This impairment of salivary response may produce an age-dependent decline of the efficiency of oesophageal acid clearance. Unusually aggressive refluxate and impaired mucosal resistance to injury have been proposed as significant variables which contribute to pathogenesis of reflux disease. The evidence for these factors is circumstantial and scanty. Their importance has probably been overestimated.(ABSTRACT TRUNCATED AT 400 WORDS)

Abdomen↗
PubMed1994

Pathogenesis of tuberculosis: pathway to apical localization.

We have examined the published work of investigators which dealt with the pathogenesis of tuberculosis, especially the following: the infective dose, the yield of bacilli from the primary lesion and primary complex, the predominant location of the minimal lesion, the hypotheses of a vulnerable region in the lung and the specific pathways (endogenous or exogenous) by which tubercle bacilli cause disease. More knowledge of the pathogenic pathway to tuberculosis would provide clues to the development of new vaccines and drug regimens that can intervene at a specific stage in the pathogenesis. Based on the examination of the literature on pathogenesis of human tuberculosis and our findings in a guinea-pig model of experimental airborne tuberculosis, we have proposed an hypothesis which integrates the endogenous and exogenous pathways to tuberculosis. This hypothesis is based on the following observations: 1. The infectious dose is very low, usually 1-5 tubercle bacilli. 2. The first implant can occur anywhere in the lungs. 3. The cavitary lesion, characteristic of tuberculous disease, is often located in the apical regions in the lungs. 4. Whereas the primary implant can occur anywhere in the lungs, for the progression from infection to disease, the tubercle bacilli must gain access to the 'vulnerable' regions in the apex of the lungs. Our hypothesis states that in areas of the world where there is a low risk of infection with tubercle bacilli low incidence of vaccination or sensitization to environmental mycobacteria, or high incidence of high virulent isolates, the virulent tubercle bacilli reach the vulnerable region via a bacillemia during the first infection. In areas of the world where there is a high risk of infection with tubercle bacilli, high incidence of vaccination or sensitization to environmental mycobacteria or a high incidence of low virulent isolates, the tubercle bacilli reach the vulnerable region via the airway, which requires repeated episodes of infection as the probability of a first implant occurring in the vulnerable regions is low.

Animals↗
PubMed2004

Pathogenesis of macular holes and therapeutic implications.

PURPOSE: To review the literature and identify consistencies and inconsistencies in existing theories of pathogenesis and to consider some of their possible therapeutic implications. DESIGN: Presentation of clinical case material with a synthesis of ideas on macular holes. METHODS: The literature of macular hole surgery is reviewed pertinent to pathogenic theories. Clinical examples of evolving macular holes shown on ocular coherence tomography are presented to illustrate issues. RESULTS: The history of pathogenesis and macular holes is interesting in that, in many ways pathogenic theory has come full cycle. Initially, anteroposterior traction was thought to cause direct formation of a macular hole. Subsequently, degenerative and then tangential tractional etiologies were proposed. Current imaging studies have greatly advanced our understanding of anatomic features of full-thickness holes and early full-thickness hole conditions. These are most consistent with a focal anteroposterior traction mechanism, but some inconsistences in clinical cases suggest a role for degeneration of the inner retinal layers. CONCLUSIONS: Degeneration of the inner retinal layers at the central fovea may predispose the eye to macular hole formation. What may otherwise be incidental tractional forces appear to initiate the hole. These tractional elements are oriented perpendicularly to the retinal surface, rather than tangentially. Further observations, especially with sequential observations from ocular coherence tomography, may yield further insights into the pathogenesis of macular holes as well as implications regarding the best repair techniques.

Humans↗
PubMed2004

Gut microflora in the pathogenesis of the complications of cirrhosis.

The gut flora plays an important role in the pathogenesis of the complications of cirrhosis. Cirrhotic patients are prone to develop bacterial infections, mainly the 'spontaneous' infection of ascites or spontaneous bacterial peritonitis. Other complications of cirrhosis, such as variceal haemorrhage and ascites, occur mostly or solely as a consequence of portal hypertension. Portal pressure increases initially as a consequence of an increased intrahepatic resistance but, once collaterals have formed, high portal pressure is maintained by an increased splanchnic blood inflow secondary to vasodilatation. Splanchnic vasodilatation is the initiating event in the hyperdynamic circulatory state that aggravates the complications of cirrhosis. The gut flora plays a role in both the development of infections and in the hyperdynamic circulatory state of cirrhosis and, although less prominently, it also plays a role in the pathogenesis of hepatic encephalopathy. This chapter presents evidence regarding gut flora and its modification in the pathogenesis and management of these complications of cirrhosis.

Ascites↗
PubMed2006

Apolipoprotein E alleles can contribute to the pathogenesis of numerous clinical conditions including HSV-1 corneal disease.

Apolipoprotein E (ApoE) alleles have been reported to affect the clinical outcome of numerous cardiovascular, neurodegenerative, and viral infectious diseases, including atherosclerosis, Alzheimer's disease (AD), hepatitis C, and HIV. The major alleles of ApoE are 2, 3, and 4. ApoE genotypes have been hypothesized to regulate many biological functions, resulting in significant changes in the onset and/or outcome (severity and duration) of several clinical conditions. Based on genetic analyses in human and animal studies using knockout (ApoE -/-) mice and mice transgenic for human 3 and 4, we present evidence that strongly suggests that the ApoE alleles can regulate the pathogenesis of ocular herpes simplex virus type 1 (HSV-1) infections. This review will summarize the major studies that support this hypothesis. Significant gender based differences in HSV-1 pathogenesis have also been reported, suggesting that hormonal regulation combined with ApoE genotype plays a significant role in HSV-1 pathogenesis. Identification of specific mechanisms in ocular HSV-1 infections related to the ApoE alleles and gender could lead to therapeutic intervention based on the properties of the apoE isoforms. While many clinical investigations have been reported and, to a lesser extent, transgenic mouse studies have been conducted, no specific mechanisms of how ApoE induces or alters clinical disease are known.

Alleles↗
PubMed2005

Enteropathogenic Escherichia coli: unravelling pathogenesis.

Enteropathogenic Escherichia coli (EPEC) is a gram-negative bacterial pathogen that adheres to intestinal epithelial cells, causing diarrhoea. It constitutes a significant risk to human health and remains an important cause of infant mortality in developing countries. Although EPEC was the first E. coli strain to be implicated in human disease in the 1940s and 1950s, the mechanisms by which this pathogen induced diarrhoea remained a complete mystery throughout most of the 40 years since its description. It was only during the late 1980s that major advances were made in unravelling the mechanisms behind EPEC pathogenesis. Ever since, progress has been made at a stunning pace and there have been major breakthroughs in identifying the bacterial factors involved in attaching and effacing (A/E) lesion formation, host signal transduction pathways in response to EPEC infection and the genetic basis of EPEC pathogenesis. The rapid pace of discovery is a result of intensive research by investigators in this field and portends that EPEC will soon be among one of the most understood diarrhoea-causing infectious agents. This review aims to trace the progress of EPEC research since its existence was first reported by John Bray in 1945, highlighting the major findings that have revolutionised our understanding of EPEC pathogenesis.

Enteritis↗
PubMed2005

Hepatitis C as a metabolic disease: Implication for the pathogenesis of NASH.

In addition to the link with development of hepatocellular carcinoma (HCC), hepatitis C virus (HCV) infection is associated with several extrahepatic manifestations such as essential mixed cryoglobulinemia, porphyria cutanea tarda or Sjögren's syndrome. A role of hepatic steatosis in the pathogenesis of chronic hepatitis C has also been known, implying hepatitis C as a metabolic disease. In addition, recent epidemiological studies have suggested a linkage between type 2 diabetes and chronic HCV infection. However, the presence of additional factors in patients, such as obesity, aging or cirrhosis, prevents the establishment of a definite relationship between HCV infection and these two conditions, lipid metabolism disturbance and diabetes. In addition to the data indicating the presence of dyslipidemia and diabetes or insulin resistance in our cohort of chronic hepatitis C patients, we found a series of evidence showing the association between the conditions and HCV infection in mouse models that are transgenic for the HCV genes. In patients with chronic hepatitis C, a significant decrease in the serum levels of total cholesterol and apolipoproteins C2 and C3 was observed compared to those with chronic hepatitis B that were comparable in liver function. In an animal model, C18:1 mono-unsaturated fatty acids were significantly increased in the liver from HCV core gene transgenic mice, which was similarly observed in the liver from human hepatitis C patients. Thus, a disturbance in lipid metabolism was observed in both humans and an HCV mouse model, supporting that it is a specific event in HCV infection. A significant increase in the value of an indicator for homeostasis model assessment of insulin resistance (HOMA-IR), was observed in patients with chronic hepatitis C, even at the very early stage of chronic hepatitis. In the animal model, a marked insulin resistance was exhibited from a very young age in HCV core gene transgenic mice. Insulin resistance observed in the core gene transgenic mice was chiefly due to the shortage of insulin action on the suppression of glucose production in the liver. Thus, the ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes. Insulin resistance may be a critical factor in the pathogenesis of chronic hepatitis C as recently suggested in non-alcoholic steatohepatitis (NASH), along with impairment in lipid metabolism. Our results would provide a clue for further understanding of pathobiology of HCV infection, and may provide an implication for the pathogenesis of NASH.

Journal Article↗
PubMed2005

The pathogenesis of migraine - 17th to early 20th century understandings.

The modern understanding of the pathogenesis of migraine, based on the concept that it is a neurovascular disorder, is often thought to have emerged from the work of Harold Wolff in the period 1932-1962. However, over the preceding 300 years, from William Harvey onwards, various hypotheses of the pathogenesis of migraine had been proposed, a few bearing reasonably strong resemblances to Wolff's ideas, though based on less adequate evidence. Many of these earlier hypotheses regarded migraine either primarily as a vascular (e.g., Willis, Wepfer, Latham) or as a neural disorder (e.g., Harvey, Lieving and his 'nerve storms'). There were also variations around these two major themes and in the 19th Century a number of neurovascular type hypotheses emerged assigning a major role in migraine pathogenesis to the autonomic nervous system. In addition, during the three centuries there were a number of other hypotheses based on different postulated pathogenic mechanisms, some quite ingenious, which had relatively brief vogues. No hypothesis has yet proved capable of explaining all the features of migraine satisfactorily.

Cerebrovascular Disorders↗
PubMed2003

Endometriosis from thelarche to midteens: pathogenesis and prognosis, prevention and pedagogy.

John Huffman, a founder of the subspecialty of pediatric and adolescent gynecology in North America, first related the diagnosis of endometriosis to thelarche. Subsequently, endometriosis was diagnosed in early puberty between thelarche and menarche. Based on solid evidence, we suggest that the theory of embryonic mullerian rests be added to currently accepted theories of pathogenesis of endometriosis. This article argues for recognition of embryonic mullerian rests as the pathogenesis of some cases of endometriosis not explained by accepted theories. Along with Huffman, we propose that thelarche be recognized as a developmental benchmark, after which endometriosis is included in the differential diagnosis of chronic pelvic pain. Thus, in an effort to refocus research and patient care to early adolescence, this review is limited to endometriosis occurring in young women from thelarche to their sixteenth birthday. Relating endometriosis to thelarche has fundamental implications for pathogenesis, early diagnosis, prognosis, treatment, education, and long-term care of adolescents.

Adolescent↗
PubMed2006

The pathogenesis of post kala-azar dermal leishmaniasis from the field to the molecule: does ultraviolet light (UVB) radiation play a role?

Post kala-azar dermal leishmaniasis (PKDL) is a dermatosis caused by persistence of Leishmania donovani parasites in the skin following apparently successful treatment of visceral leishmaniasis. The distribution of PKDL lesions in Sudanese patients often mirrors the clothing habits of those affected. It is most severe in or confined to the sun-exposed parts of the skin. It is well established that elimination of Leishmania parasites requires activation of parasitised macrophages by a Th1 immune response and that the latter is depressed by ultraviolet light (UVB). In this paper, we hypothesized that UVB light might be a key player in the pathogenesis of PKDL. This paper links observations made in the field with immunological data that are compatible with this hypothesis. We therefore investigated patients with PKDL immunologically for a possible role of UVB exposure in the pathogenesis of this condition. We marshal evidence that the changes in the tissues are compatible with the effects of UVB light and it is probable that UVB appears to be a key factor in the pathogenesis of PKDL. Immunopathologically the lesions were characterized by an influx of various inflammatory cells. The number of CD1a (Langerhans' cells) was decreased, they lost their dendrites, their HLA-DR and B7-1 expression was down regulated while B7-2 was expressed. Others have shown that Langerhans' cells with these features result from UVB exposure and that such cells are unable to present antigen to Th1 cells while retaining the capacity to present antigen to Th2 cells. Various cytokines known to be induced by UVB radiation could be demonstrated in PKDL lesions. Of these IL-10, TGF-beta, IL-12, IL-4 and TNF-alpha were found in different quantities. The Th-1 cytokine IFN-gamma was constantly present. The tissue origin of the Th-1 cells in PKDL is unknown. We believe that the antagonistic action of the different cytokines is the cause of the inflammation and chronicity of PKDL.

Cytokines↗
PubMed2005

The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses with an unknown etiology. Evidence from animal and human studies has suggested that brain-derived neurotrophic factor (BDNF) function may be implicated in the pathogenesis of MDD. Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that catalyses the generation of zymogen plasminogen from the proteinase plasmin. Recent studies have found that the proteolytic cleavage of proBDNF, a BDNF precursor, to BDNF by the plasmin represents a mechanism by which the direction of BDNF action is controlled. Furthermore, studies using mice deficient in tPA has demonstrated that tPA is important for the stress reaction, a common precipitating factor for MDD. A study of the serum levels of the plasminogen activator inhibitor-1 (PAI-1), the major inhibitor of tPA, found that women with MDD had a higher PAI-1 concentration than normal controls. From these findings, it is proposed that the tPA/plasminogen system may play a role in the pathogenesis of MDD. Attempts to confirm the tPA/plasminogen hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention of this disorder.

Major Depressive Disorder↗
PubMed2006

The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants.

Major depressive disorder (MDD) is a common disabling psychiatric illness with an unknown etiology. Evidence from animal and human studies suggests that a disturbance in serotonergic (5-HT) activity and/or brain-derived neurotrophic factor (BDNF) signaling may be implicated in the pathogenesis of MDD. Recently, a protein, p11, has been found to increase the number of 5-HT(1B) receptors on the surface of cells and enhance 5-HT(1B) receptor function. Furthermore, mice over-expressing p11 acted as if they were undergoing treatment with antidepressants and p11 knockout mice exhibit a depression-like phenotype and reduced behavioural reactions to an antidepressant. As tissue-type plasminogen activator (tPA)/plasminogen proteolytic cascade is implicated in the cleavage of proBDNF to BDNF, and p11, a component of the Annexin II, which can greatly enhance the activation of plasmin by tPA, it is proposed that p11 may act through the tPA/plasminogen/BDNF pathway to achieve its antidepressant effect. Attempts to confirm this hypothesis may lead to new directions in the study of the pathogenesis of MDD and the development of a novel intervention for this disorder. In addition, BDNF is also implicated in several psychiatric diseases such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder and Alzheimer's disease; whether p11 and other components related to the tPA/plasminogen pathway may be related to the pathogenesis of these diseases needs further exploration.

Animals↗
PubMed2006

Potential roles of allograft inflammatory factor-1 in the pathogenesis of hemangiomas.

Hemangiomas are benign tumors of the vascular endothelium and are the most common tumors of infancy. These tumors are characterized by an initial phase of rapid proliferation in the first months of life, which is followed, in most cases, by spontaneous slow involution. Despite their high prevalence, their detailed pathogenesis remains unknown. Recent studies suggest that immunity responses, inflammatory cells and their precursors, myeloid cells, play important roles in the growth and involution of hemangiomas. The allograft inflammatory factor-1 is a powerful gene that is involved in several kinds of inflammatory response-related diseases. Studies also show that it is implicated in angiogenesis, proliferation and differentiation of stem cells, and development of tumors. Taken all these evidences into consideration, we hypothesize that allograft inflammatory factor-1 plays potential roles in pathogenesis, proliferation and involution of hemangioma. Investigating the role of allograft inflammatory factor-1 in the proliferation and involution of hemangioma will lead to a better understanding of pathogenesis of this lesion. Furthermore, the subtle regulation of allograft inflammatory factor-1 in the involution of hemangiomas will help design a new anti-angiogenic therapy for some tumors.

Calcium-Binding Proteins↗
PubMed2005

Volumetric neuroimaging and low-dose early-life exposures: loose coupling of pathogenesis-brain-behavior links.

The interface of developmental neuroimaging with developmental neurotoxicology can, broadly speaking, address two complementary concerns. The first is to study the impact of specific exposures on brain development. The second is to study known neurobehavioral disorders with an eye to discerning toxicological contributions to pathogenesis. Pathogenesis targets brain based upon physical properties (receptors, growth factors, etc.) while behavior is modulated by regional and neural systems alterations. The distribution of pathogenesis-brain relationships overlaps only partially with that of brain-behavior relationships. The goal of this paper is to highlight methodological issues involved in designing and interpreting volumetric neuroimaging studies in the light of this loose coupling.

Behavior↗
PubMed2006

Common mechanisms of amyloid oligomer pathogenesis in degenerative disease.

Many age-related degenerative diseases, including Alzheimer's, Parkinson's, Huntington's diseases and type II diabetes, are associated with the accumulation of amyloid fibrils. The protein components of these amyloids vary widely and the mechanisms of pathogenesis remain an important subject of competing hypotheses and debate. Many different mechanisms have been postulated as significant causal events in pathogenesis, so understanding which events are primary and their causal relationships is critical for the development of more effective therapeutic agents that target the underlying disease mechanisms. Recent evidence indicates that amyloids share common structural properties that are largely determined by their generic polymer properties and that soluble amyloid oligomers may represent the primary pathogenic structure, rather than the mature amyloid fibrils. Since protein function is determined by the three-dimensional structure, the fact that amyloids share generic structures implies that they may also share a common pathological function. Amyloid oligomers from several different proteins share the ability to permeabilize cellular membranes and lipid bilayers, indicating that this may represent the primary toxic mechanism of amyloid pathogenesis. This suggests that membrane permeabilization may initiate a core sequence of common pathological events leading to cell dysfunction and death that is shared among degenerative diseases, whereas pathological events that are unique to one particular type of amyloid or disease may lie in up stream pathways leading to protein mis-folding. Although, these upstream events may be unique to a particular disease related protein, their effects can be rationalized as having a primary effect of increasing the amount of mis-folded, potentially amyloidogenic proteins.

Amyloid↗
PubMed2024

Acute MeCP2 loss in adult mice reveals transcriptional and chromatin changes that precede neurological dysfunction and inform pathogenesis.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we profiled genome-wide histone modifications and found that a decrease in histone H3 acetylation (ac) at downregulated genes is among the earliest molecular changes occurring well before any measurable deficiencies in electrophysiology and neurological function. These data reveal a molecular cascade that drives disease independent of any developmental contributions or secondary pathogenesis.

Animals↗
PubMed2005

Pathogenesis of nigral cell death in Parkinson's disease.

Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.

Cell Death↗
PubMed2006

The Na(+)/K(+)-ATPase as [K(+)](o) sensor: Role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids.

Current evidence demonstrates that augmented production of endogenous cardiotonic steroids (CTS) such as ouabain and marinobufagenin is involved in the pathogenesis of hypertension and other cardiovascular diseases associated with volume expansion. It is also well documented that the development of hypertension and the cardiovascular complications of this disease are provoked by hypokalemia and suppressed by high-K(+) diet. We hypothesized that altered extracellular K(+) (K(+))(o) handling contributes to the pathogenesis of hypertension via modulation of interaction of endogenous CTS with Na(+)/K(+)-ATPase. To examine this hypothesis, experiments were performed with C7-Madin-Darby canine kidney epithelial cells at [K(+)](o) detected in plasma under control conditions (4.5mM), severe hypokalemia (2mM), and hyperkalemia (7mM). Elevation of [K(+)](o) from 2 to 7mM increased the threshold of modulation of intracellular (Na(+))(i) and (K(+))(i) content by ouabain from 1 to 10nM, which corresponds to the range of endogenous CTS detected in plasma from patients with volume-expanded disorders. In control medium, approximately 30% activation of cell proliferation was observed with 3nM ouabain, whereas the addition of 0.3nM ouabain was sufficient to induce about the same increment of cell proliferation in K(+)-depleted medium. [K(+)](o) elevation up to 7mM completely abolished the proliferative effect of ouabain. At [K(+)](o)=2, 4.5 and 7mM, the death of ouabain-treated cells was indicated in the presence of 10, 30 and 300nM ouabain, respectively. In conclusion, our results showed that modulation of [K(+)](o) in a pathophysiologically reasonable range sharply affected efficacy of endogenous CTS in the elevation of the [Na(+)](i)/[K(+)](i) ratio and in triggering (Na(+))(i),(K(+))(i)-independent signaling resulting in cell proliferation and death. We propose that Na(+)/K(+)-ATPase may be considered as a [K(+)](o) sensor involved in the crosstalk of (K(+))(o) handling with the pathogenesis of cardiovascular diseases.

Journal Article↗