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Biomedical subjects

Heinrich Sauer

Publications and source records attributed to Heinrich Sauer.

At least 19 recordsLinked to original sources
PubMed2006

The role of poly(ADP-ribose) polymerase (PARP) in the autonomous proliferative response of endothelial cells to hypoxia.

OBJECTIVE: The autonomous proliferative response of endothelial cells to hypoxia has been shown to be dependent on activation of NAD(P)H oxidase, on the cytosolic Ca2+ load, and, consequently, on nuclear translocation of extracellular signal-regulated kinase (ERK)1/2 during transient hypoxia. The aim of the present study was to investigate whether poly(ADP-ribose) polymerase (PARP) is a downstream signal of NAD(P)H oxidase, mediating cytosolic Ca2+ load and hence nuclear translocation of ERK1/2 and endothelial cell proliferation. METHODS: Porcine aortic endothelial cells were incubated under hypoxic conditions for 40 min. Cytosolic [Ca2+] and reactive oxygen species (ROS) formation were measured in fura-2- and DCF-loaded cells, respectively. PARP activation was detected by immunocytochemistry, and endothelial cell proliferation was determined 24 h after 60 min of transient hypoxia. RESULTS: Inhibition of NAD(P)H oxidase with antisense oligonucleotide against the p22(phox) subunit, MEK/ERK signalling with UO 126 (30 microM), or PARP with PJ 34 (10 microM) leads to a marked reduction in hypoxia-induced cytosolic Ca2+ load and activation of PARP. Hypoxia-induced translocation of ERK1/2 and endothelial cell proliferation were also prevented when NAD(P)H oxidase or PARP were inhibited; however, hypoxic ROS formation was not affected in the presence of PARP inhibitor. CONCLUSION: PARP represents a downstream effector of NADP(H) oxidase and acts as a necessary intermediate step for the hypoxic proliferative response of endothelial cells.

Animals↗
PubMed2006

Decreased baroreflex sensitivity in acute schizophrenia.

Decreased vagal activity has been described in acute schizophrenia and might be associated with altered cardiovascular regulation and increased cardiac mortality. The aim of this study was to assess baroreflex sensitivity in the context of psychopathology. Twenty-one acute, psychotic, unmedicated patients with a diagnosis of paranoid schizophrenia were investigated after admission to the hospital. Results were compared with 21 healthy volunteers matched with respect to age and sex. Cardiovascular parameters obtained included measures for heart rate variability, baroreflex sensitivity, as well as cardiac output, left ventricular work index, and total peripheral resistance. All parameters investigated were analyzed using linear and novel nonlinear techniques. Positive and negative symptoms were assessed to estimate the impact of psychopathology on autonomic parameters. Subjects with acute schizophrenia showed reduction of baroreflex sensitivity accompanied by tachycardia and greatly increased left ventricular work index. Nonlinear parameters of baroreflex sensitivity correlated with positive symptoms. For heart rate variability, mainly parameters indicating parasympathetic modulation were decreased. Vascular pathology could be excluded as a confounding factor. These results reflect a dysfunctional cardiovascular regulation in acute schizophrenic patients at rest. The changes are similar to adaptational regulatory processes following stressful mental or physical tasks in healthy subjects. This study suggests that hyperarousal in acute schizophrenia is accompanied by decreased efferent vagal activity, thus increasing the risk for cardiovascular mortality. Future studies are warranted to examine the role of the sympathetic system and possible autonomic differences in hyperarousal induced by anxiety and/or external stressful events.

Adult↗
PubMed2006

White matter abnormalities and brain activation in schizophrenia: a combined DTI and fMRI study.

Diffusion tensor imaging (DTI) studies of schizophrenia have revealed white matter abnormalities in several areas of the brain. The functional impact on either psychopathology or cognition remains, however, poorly understood. Here we analysed both functional MRI (during a working memory task) and DTI data sets in 18 patients with schizophrenia and 18 controls. Firstly, DTI analyses revealed reductions of fractional anisotropy (FA) in the right medial temporal lobe adjacent to the right parahippocampal gyrus, likely to contain fibres of the inferior cingulum bundle, and in the right frontal lobe. Secondly, functional MRI revealed prefrontal, superior parietal and occipital relative hypoactivation in patients with the main effect of task. This was accounted for by reduced prefrontal activation during the encoding phase of the task, but not during maintenance or retrieval phases. Thirdly, we found a direct correlation in patients between the frontal FA reduction (but not medial temporal reductions) and fMRI activation in regions in the prefrontal and occipital cortex. Our study combining fMRI and DTI thus demonstrates altered structure-function relationships in schizophrenia. It highlights a potential relationship between anatomical changes in a frontal-temporal anatomical circuit and functional alterations in the prefrontal cortex.

Adult↗
PubMed2006

Polyphenols prevent cell shedding from mouse mammary cancer spheroids and inhibit cancer cell invasion in confrontation cultures derived from embryonic stem cells.

The prognosis of cancer disease is worsened upon shedding of tumor cells from the primary tumor, which escape to the blood stream and form metastases at distant sites within the body. Inhibition of cell shedding from the primary tumor could therefore be exploited to avoid metastasis and delay the progression of the cancer disease. In the present study, we investigated the effects of the polyphenols resveratrol, baicalein, epicatechin, epigallocatechin and polyphenon 60 on cell shedding from multicellular tumor spheroids of the murine mammacarcinoma cell line 4T1, cell invasion into embryonic stem cell-derived tissues, generation of reactive oxygen species (ROS) and expression of matrix metalloproteinase 9 (MMP-9). With increasing tumor spheroid growth MMP-9 expression was upregulated and cells detached from tumor spheroids and formed subspheroids that displayed pronounced ROS generation. Upon incubation with polyphenols tumor growth was arrested and cell shedding was totally abolished. Polyphenol treatment decreased ROS generation and downregulated MMP-9 expression. Furthermore, polyphenols significantly inhibited invasion of tumor cells into embryonic stem cell-derived, vascularized tissues. Our data suggest, that polyphenols inhibit cell shedding and invasion by their anti-oxidative capacity and downregulation of MMP-9 expression.

Animals↗
PubMed2006

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

Adolescent↗
PubMed2006

Temporal changes in neural activation during practice of information retrieval from short-term memory: an fMRI study.

Several findings indicate that practice in working memory tasks leads to signal decreases in task-relevant regions. However, the precise dynamics underlying these signal decreases and how they are correlated with improvements in behavioral performance are still matters of debate. We used functional magnetic resonance imaging (fMRI) to assess the cerebral correlates of the practice-related transition from controlled to automatic processing for the retrieval of information maintained in working memory storage. Exponential signal decreases and increases were modeled as covariates of interest. In addition, a bivariate regression analysis on the change in BOLD signal for two a priori hypothesized prefrontal regions (VLPFC, DLPFC) and the change in behavioral performance was conducted to examine the relationship between practice-related changes in cerebral activation and performance. We found exponential practice-related signal decreases mainly in the right superior frontal gyrus/DLPFC (BA 8/9/46), the middle frontal gyrus bilaterally (BA 10/11), the left precentral gyrus (BA 4/6) and the dorsal part of the right anterior cingulate cortex (BA 32). An exponential signal increase was detectable in the posterior cingulate cortex adjacent to the corpus callosum. In addition, there was a correlation between the practice-related change in BOLD signal in the DLPFC (BA 8/9) and the practice-related change in behavioral performance. These results suggest that the transition from controlled to automatic working memory processing is associated with exponential signal decreases in task-relevant regions. The temporal changes in brain activation patterns could be attributed to enhanced efficiency of information processing as a result of cognitive practice.

Adult↗
PubMed2006

The special involvement of the rostrolateral prefrontal cortex in planning abilities: an event-related fMRI study with the Tower of London paradigm.

Planning abilities are essential for the successful management of everyday life activities. Although several neuroimaging studies provide evidence that the prefrontal cortex is crucially involved in planning, the differential roles of its subregions are still a matter of debate. The aim of this study was to investigate the neural correlates of planning by focusing on the functional differentiation between the dorsolateral and rostrolateral prefrontal cortex using the Tower of London (ToL) task and a parametric event-related functional MRI design. In order to control for activations unspecific to planning, two control conditions were presented, which were matched for the length of single events in the ToL task. Seventeen right-handed healthy subjects participated in this study. All statistics were reported with corrections for multiple comparisons (p < 0.05). Compared to control conditions, activations in the ToL task were observed in the dorsolateral prefrontal cortex bilaterally, the right ventrolateral and left rostrolateral prefrontal cortex along with the thalamus, as well as in the parietal and premotor cortex bilaterally. Task complexity dependent analyses revealed that only the left rostrolateral prefrontal cortex showed a BOLD signal increase over the four planning levels, which could not be observed in the control conditions. Hence, current findings suggest that planning involves an extensive fronto-parieto-thalamic network. Within this network, the rostrolateral prefrontal cortex seems to be the only region that is exclusively reactive to planning specific processes, which we described in terms of simultaneous monitoring of internally generated and externally presented information.

Adult↗
PubMed2006

Reduced baroreflex sensitivity in acute alcohol withdrawal syndrome and in abstained alcoholics.

Acute alcohol withdrawal is often associated with increased sympathetic activity, and a decreased baroreflex sensitivity (BRS) can be assumed. Parameters of heart rate variability (HRV), blood pressure variability (BPV), BRS as well as cardiac index (CI), left ventricular work index (LVWI) and total peripheral resistance (TPR) were investigated in 20 patients undergoing acute alcohol withdrawal and matched controls. Measures were obtained during the peak of withdrawal symptomatology prior to treatment as well as 2 and 24h under continuous clomethiazole treatment. Alcohol withdrawal scores were obtained and correlated with autonomic measures. In addition, parameters were assessed in 15 subjects who abstained from alcohol after long-term intake. We found a severe down-regulation of BRS during acute alcohol withdrawal and to a milder extent in abstained alcoholics. Furthermore, HRV and BPV did not unequivocally reveal signs of elevated sympathetic activity. Non-linear parameters of HRV and parameters of BRS correlated with the severity of AWS. The distinct decrease of BRS in AWS and in long-term abstained subjects described here is of importance since similar alterations have been identified as independent prognostic factors for cardiac mortality in other diseases.

Acute Disease↗
PubMed2006

Influence of antipsychotic medication on pain perception in schizophrenia.

A number of clinical observations indicate that pain processing might be disturbed in psychotic disorders such as schizophrenia. Only a few studies have investigated pain perception in schizophrenia. The main objective of this study was the investigation of thresholds of warmth perception (WP), thermal pain onset (TPO) and thermal pain tolerance (TPT) in acute schizophrenic patients and the influence of antipsychotic medication on the patients' responses. We investigated 23 schizophrenic subjects who had been not received antipsychotic treatment for 8 weeks, and we then reassessed them 3 days later after the introduction of neuroleptics. Acute symptoms of schizophrenia were measured using the Scales for the Assessment of Positive and Negative Symptoms. Thresholds were determined by a contact thermode on both volar wrists. Schizophrenic patients showed significantly increased thresholds of WP and TPO relative to healthy controls. Antipsychotics did not alter pain thresholds. We found no correlation between pain perception and psychometric scales. Our findings demonstrate altered warmth and heat pain perception in acute schizophrenia. We believe that our findings can be attributed to information-processing abnormalities of the disorder and that they are not specific to pain processing, per se, since both WP and TPO were significantly different. Future studies should evaluate attentional deficits in schizophrenia in relation to pain perception.

Adult↗
PubMed2006

Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation.

Growing stem cells are subjected to mechanical forces, which may initiate differentiation programs. Mechanical strain stimulated cardiovascular differentiation of mouse embryonic stem (ES) cells as evaluated by quantification of contracting cardiac foci and capillary areas, respectively. Mechanical strain rapidly elevated intracellular reactive oxygen species (ROS). After 24 h up-regulation of NADPH oxidase subunits p22-phox, p47-phox, p67-phox, and Nox-4 as well as Nox-1 and Nox-4 mRNA was observed. In parallel, mechanical strain increased hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) mRNA and protein as well as MEF2C and GATA-4 mRNA, which are involved in cardiovascular development. Furthermore, phosphorylation of extracellular-regulated kinase 1,2 (ERK1,2), p38, and c-jun N-terminal kinase (c-Jun NH2-terminal kinase (JNK)) was observed. Stimulation of cardiovascular commitment, HIF-1alpha, VEGF, and MEF2C expression as well as MAPK activation were abolished by free radical scavengers, whereas GATA-4 expression was increased. Cardiomyogenesis was inhibited by the p38 inhibitor SB203580, the ERK1,2 inhibitor UO126, and the JNK inhibitor SP600125. Vasculogenesis/angiogenesis was blunted following inhibition of ERK1,2 and JNK, whereas p38 inhibition was ineffective. Our data outline a role of ROS as mechanotransducing molecules in mechanical strain-stimulated cardiovascular differentiation of ES cells, and point toward a microenvironment of elevated ROS required for signaling cascades initiating cardiovascular differentiation programs.

Animals↗
PubMed2006

Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation.

OBJECTIVE: Reactive oxygen species (ROS) produced by NAD(P)H oxidases (Nox) play a significant role in the pathophysiology of cardiovascular diseases. Expression and activity of NAD(P)H oxidases are regulated by growth factors such as angiotensin II and platelet-derived growth factor (PDGF). We characterized the effects of the novel Nox inhibitor VAS2870 on PDGF-dependent ROS liberation and cellular events in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: PDGF-BB increased NAD(P)H oxidase activity (lucigenin-enhanced chemiluminescence) and intracellular ROS levels (detected by confocal laserscanning microscopy using 2,7-DCF) to 229+/-9% and 362+/-54% at 1 and 2 h, respectively. Preincubation with VAS2870 (10 and 20 microM) completely abolished PDGF-mediated NAD(P)H oxidase activation and ROS production. Since ROS are involved in various growth factor-induced cellular functions, the influence of VAS2870 on PDGF-induced DNA synthesis and chemotaxis was determined. PDGF promoted a 4.2+/-0.2-fold increase of VSMC migration (modified Boyden chamber, p<0.01) and increased DNA synthesis by maximally 3.2+/-0.4-fold (BrdU incorporation, p<0.01) in a concentration-dependent manner. Preincubation with VAS2870 (0.1-20 microM) did not affect PDGF-induced cell cycle progression. However, it abolished PDGF-dependent chemotaxis of VSMC in a concentration-dependent manner (100% inhibition at 10 microM). These findings were related to PDGF-dependent signaling events. Western blot analyses using phospho-specific antibodies revealed that the downstream signaling molecules Akt, Erk, and Src were activated by PDGF. However, VAS2870 blocked PDGF-dependent activation of Src, but not of Akt and Erk, in a concentration-dependent manner. CONCLUSIONS: VAS2870 effectively suppresses growth factor-mediated ROS liberation in VSMC. Furthermore, it completely inhibits PDGF-dependent VSMC migration, whereas it does not affect DNA synthesis. These divergent effects reflect the critical role of Src activity, which-in contrast to Akt and Erk-appears to be redox-sensitive and is absolutely required for PDGF-induced chemotaxis, but not cell cycle progression.

Animals↗
PubMed2006

Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1alpha and intracellular reactive oxygen species.

Cardiomyogenesis in differentiating mouse embryonic stem (ES) cells is promoted by cardiotrophin-1 (CT-1), a member of the IL-6 interleukin superfamily that acts through the tall gp130 cytokine receptor. We show that prooxidants (menadione, hydrogen peroxide) as well as chemical (CoCl2) and physiological (1% O2) hypoxia increased CT-1 as well as HIF-1alpha protein and mRNA expression in embryoid bodies, indicating that CT-1 expression is regulated by reactive oxygen species (ROS) and hypoxia. Treatment with either prooxidants or chemical hypoxia increased gp130 phosphorylation and protein expression of NADPH oxidase subunits p22-phox, p47-phox, p67-phox, as well as Nox1 and Nox4 mRNA. Consequently, inhibition of NADPH oxidase activity by diphenylen iodonium chloride (DPI) and apocynin abolished prooxidant- and chemical hypoxia-induced upregulation of CT-1. Prooxidants and chemical hypoxia activated ERK1,2, JNK and p38 as well as PI3-kinase. The proxidant- and CoCl2-mediated upregulation of CT-1 was significantly inhibited in the presence of the ERK1,2 antagonist UO126, the JNK antagonist SP600125, the p38 antagonist SKF86002, the PI3-kinase antagonist LY294002, the Jak-2 antagonist AG490 as well as in the presence of free radical scavengers. Moreover, developing embryoid bodies derived from HIF-1alpha-/- ES cells lack cardiomyogenesis, and prooxidants as well as chemical hypoxia failed to upregulate CT-1 expression. Our results demonstrate that CT-1 expression in ES cells is regulated by ROS and HIF-1alpha and imply a crucial role of CT-1 in the survival and proliferation of ES-cell-derived cardiac cells.

Animals↗
PubMed2006

Cortical inefficiency in patients with unipolar depression: an event-related FMRI study with the Stroop task.

BACKGROUND: The present study is aimed to examine the neuronal correlates of Stroop interference in medication-free patients with major depressive disorder. METHODS: Sixteen patients fulfilling Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for unipolar depression and 16 healthy control subjects matched for age, gender, and education were included. All subjects underwent an event-related functional magnetic resonance imaging (fMRI) design with an adapted version of the Stroop task including congruent and incongruent task conditions. The fMRI experiment was conducted on a 1.5 T magnetic resonance (MR) scanner, and item responses were given manually by the subjects. RESULTS: With regard to behavioral performance, patients revealed no differences in both reaction time and accuracy relative to control subjects. With regard to brain activations, direct comparison of patients with control subjects in the interference condition revealed hyperactivity in rostral anterior cingulate gyrus (rACG) and left dorsolateral prefrontal cortex (DLPFC) in depressive patients, which correlated strongly with the Stroop interference. CONCLUSIONS: The study provides new evidence for the functioning and dissociation of the anterior cingulate in depressed patients. The greater prefrontal activation may reflect a cortical inefficiency due to hyperactivity in rACG enhancing the cognitive interferences from the emotional state.

Adult↗
PubMed2006

Changes of pain perception, autonomic function, and endocrine parameters during treatment of anorectic adolescents.

OBJECTIVES: The underlying mechanisms of reduced pain perception in anorexia nervosa (AN) are unknown. To gain more insight into the pathology, the authors investigated pain perception, autonomic function, and endocrine parameters before and during successful treatment of adolescent AN patients. METHOD: Heat pain perception was assessed in 15 female adolescent AN patients and matched controls. Results were correlated with autonomic and endocrine parameters (free triiodothyronine, free cortisol). Autonomic function was studied using heart rate variability and pupillary light reflex assessment. To investigate the influence of therapy on these parameters, data were obtained at three different time points. RESULTS: Heat pain thresholds were significantly increased in the acute state and decreased after weight had been regained for 6 months. Similarly, an increased parasympathetic tone was present in the acute state only. The relative amplitude of the pupillary light reflex showed a positive correlation to pain thresholds over time and predicted disease progression. In addition, the authors found a negative correlation between increased pain thresholds and low free cortisol. CONCLUSION: Increased pain thresholds are associated with increased parasympathetic tone and a hypothyroid state in AN. This may either indicate common central mechanisms or suggest a causative interaction.

Adolescent↗
PubMed2006

Heart rate variability and sympathetic skin response in male patients suffering from acute alcohol withdrawal syndrome.

BACKGROUND: Many symptoms of alcohol withdrawal (AW) such as tachycardia or elevated blood pressure might be explained by increased peripheral and central adrenergic activity. In contrast to many neurochemical studies of sympathetic activation during AW, only very few studies investigated autonomic balance using neurophysiological methods. METHODS: We investigated heart rate variability (HRV) and sympathetic skin response (SSR) in male patients suffering from mild AW syndrome (n = 20, no treatment required) and in patients with moderate to severe AW syndrome (n = 20, clomethiazole treatment) in the acute stage. Sympathovagal influence was quantified using measures of time and frequency domain of HRV as well as modern nonlinear parameters (compression entropy). Furthermore, we obtained latencies and amplitudes of SSR to quantify isolated sympathetic influence. Measures were obtained during the climax of withdrawal symptomatology before treatment, 1 day after climax, and shortly before discharge from hospital. Alcohol withdrawal scores were obtained and correlated to autonomic measures. RESULTS: Ambulatory blood pressure and AW scores revealed characteristic withdrawal symptoms in both patient groups. Apart from the nonlinear parameter compression entropy, Hc, measures of HRV revealed no sign of autonomic dysfunction in contrast to the significantly increased heart rates at the time of admission. Latencies and amplitudes of SSR did not indicate any increase of sympathetic activity. A negative correlation was found between Hc and mental withdrawal symptoms. CONCLUSIONS: We show here that classical measures for autonomic nervous system activity such as HRV and SSR are not suitable for describing the autonomic changes seen in acute AW, although a major role for the sympathetic nervous system has been proposed. This might be due to multiple dysregulation of metabolites in AWS or to subtle alcohol-induced damage to neuronal structures, issues that should be addressed in future studies.

Adult↗
PubMed2006

Confrontation cultures of embryonic stem cells with multicellular tumor spheroids to study tumor-induced angiogenesis.

Human embryonic stem cells efficiently differentiate blood vessels, which allows using this in vitro model to study the interaction of blood vessels with adjacent tissues. Herein, we introduce confrontation cultures of human embryonic stem cells with multicellular tumor spheroids to investigate molecular mechanisms of tumor-induced angiogenesis. Vascularization of tumor tissue by the host is a prerequisite for tumor growth, which has led to the development of antiangiogenic therapy. This promising anti-cancer therapy intends to reduce, halt, or even regress tumor growth by deprivation from blood, oxygen, and nutrient supply. Confrontation cultures of human embryonic stem cells with multicellular tumor spheroids allow the investigation of the time course of endothelial cell invasion into the tumor tissue, the concomitant analysis of changes in angiogenesis-related gene expression, and analysis of the cellular microenvironment (i.e., pericellular oxygen pressure, tissue pH, and levels of tissue reactive oxygen species). The in vitro model of confrontation cultures is suitable for routine screening of antiangiogenic agents in pre-clinical trials and may be used to replace animal experiments applied in antiangiogenesis research.

Animal Use Alternatives↗
PubMed2005

Feed forward cycle of hypotonic stress-induced ATP release, purinergic receptor activation, and growth stimulation of prostate cancer cells.

ATP is released in many cell types upon mechanical strain, the physiological function of extracellular ATP is largely unknown, however. Here we report that ATP released upon hypotonic stress stimulated prostate cancer cell proliferation, activated purinergic receptors, increased intracellular [Ca(2+)](i), and initiated downstream signaling cascades that involved MAPKs ERK1/2 and p38 as well as phosphatidylinositol 3-kinase (PI3K). MAPK activation, the calcium response as well as induction of cell proliferation upon hypotonic stress were inhibited by preincubation with the ATP scavenger apyrase, indicating that hypotonic stress-induced signaling pathways are elicited by released ATP. Hypotonic stress increased prostaglandin E(2) (PGE(2)) synthesis. Consequently, ATP release was inhibited by antagonists of PI3K (LY294002 and wortmannin), phospholipase A(2) (methyl arachidonyl fluorophosphonate (MAFP)), cyclooxygenase-2 (COX-2) (indomethacin, etodolac, NS398) and 5,8,11,14-eicosatetraynoic acid (ETYA), which are involved in arachidonic acid metabolism. Furthermore, ATP release was abolished in the presence of the adenylate cyclase (AC) inhibitor MDL-12,330A, indicating regulation of ATP-release by cAMP. The hypotonic stress-induced ATP release was significantly blunted when the ATP-mediated signal transduction cascade was inhibited on different levels, i.e. purinergic receptors were blocked by suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), the Ca(2+) response was inhibited upon chelation of intracellular Ca(2+) by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), and ERK1,2 as well as p38 were inhibited by UO126 and SB203580, respectively. In summary our data demonstrate that hypotonic stress initiates a feed forward cycle of ATP release and purinergic receptor signaling resulting in proliferation of prostate cancer cells.

Adenosine Triphosphate↗