Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cascade testing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,045 records · Page 58Linked to original sources
PubMed2001

[Type I neurofibromatosis. A model for the study of molecular principles of cognition].

Cognitive impairment in neurofibromatosis type I (NF1) has only recently attracted interest. In addition to previous studies in children, our own investigation of 20 patients confirms the slightly lowered psychometric test scores also for adults with NF1. Molecular manipulation of the neurofibromin gene leads to learning disorders in the mouse model ("cognitive neurogenetics"). It is not just faulty brain development that underlies these findings: neurofibromin plays a role in signal transduction cascades that are active during learning and memory throughout the life span. Thus, it appears possible to cure the cognitive defects at least in the mouse ("cognitive enhancement"). In man, an early diagnosis of NF1 is presently essential in order to provide specific remedial education for children affected by the learning disorder of neurofibromatosis type I.

Adult↗
PubMed1997

Eight years of "Prostate Cancer Awareness Week": lessons in screening and early detection. Prostate Cancer Education Council.

BACKGROUND: Prostate Cancer Awareness Week began in 1989 to raise public awareness of the disease and impact on its clinical dynamics. Prior to 1990, prostate carcinoma was usually diagnosed in symptomatic men as advanced and ipso facto incurable. METHODS: A 5-year longitudinal study of screening and early detection was initiated in 1992, involving 250 centers that tested over 50,000 men annually. The study analyzed the following: 1) the efficacy of digital rectal examination and prostate specific antigen (PSA) tests for the early detection of prostate carcinoma, 2) the impact of serial screening on stage of disease at diagnosis and cancer detection, 3) age and race specific reference ranges for PSA, 4) prostate carcinoma risk factors, and 5) psychosocial variables that influence the appropriateness and acceptability of both screening and treatment. RESULTS: Community-based screening for prostate carcinoma is as effective as programs conducted at academic centers, but annual testing may not be necessary for all men. Participants in community screening programs may require more prescreening information and education regarding the potential risks and benefits of screening, and also regarding the cascade of diagnostic and treatment decisions that follow an abnormal digital rectal examination or an elevated PSA finding. CONCLUSIONS: Community-based prostate carcinoma screening programs have contributed to the shift in the diagnosis of prostate carcinoma at an earlier stage. They provide data that are useful in studying the natural course of prostate carcinoma and in designing studies of the effect that prostate carcinoma screening has on mortality from the disease.

Community Medicine↗
PubMed2006

Apoptosis promoted by up-regulation of TFPT (TCF3 fusion partner) appears p53 independent, cell type restricted and cell density influenced.

The TFPT/FB1 gene was identified because of its involvement in childhood pre-B acute lymphoblastic leukaemia (ALL). Although its specific function is still unclear, Tfpt has been implicated in cell proliferation and induction of programmed cell death (PCD). Given the critical role of PCD in leukemogenesis, we have investigated the responsiveness of different cell lines to TFPT over expression and the consequent induction of PCD by proliferation kinetic analysis, immunolocalization and TUNEL assay. We have also tested the involvement of factors implicated in cell cycle progression and apoptosis, i.e. caspases, p53, Cdc2. Our results indicate that over expression of TFPT promotes caspase 9-dependent apoptosis, nevertheless the apoptotic cascade is engaged only in culture conditions sustaining cell proliferation and different cell lines display differential responsiveness to TFPT induced apoptosis Although p53 is a main regulator of apoptosis in mammalian cells, the Tfpt induced apoptosis appears p53-independent. These results are discussed relatively to the role played by TFPT in leukemogenesis.

Animals↗
PubMed2005

LEF1 is a critical epithelial survival factor during tooth morphogenesis.

LEF1 is a cell-type-specific transcription factor and mediates Wnt signaling pathway by association with its co-activator beta-catenin. Wnt signaling is known to be critical for the specification of cranial neural crest (CNC) cells and may regulate the fate diversity of the CNC during craniofacial morphogenesis. Loss of Lef1 results in arrested tooth development at the late bud stage and LEF1 is required for a relay of a Wnt signaling to a cascade of FGF signaling activities to mediate the epithelial-mesenchymal interaction during tooth morphogenesis. It remains unclear, however, what is the cellular mechanism of LEF1 signaling in regulating tooth morphogenesis. To test the hypothesis that LEF1 signaling regulates the fate of the dental epithelial and the CNC-derived mesenchymal cells during tooth morphogenesis, we investigated and compared the cellular migration, proliferation, and apoptotic activity within the tooth germ between the wild-type and Lef1 null mutant mice. Using the Wnt1-Cre/R26R transgenic system for indelibly marking the progenies of CNC cells, we show that there is no CNC migration defect in the Lef1 null mutant mice, indicating that the arrest in tooth development is not the result of shortage of the CNC contribution into the first branchial arch in the Lef1 mutant. Furthermore, there is no alteration in cell proliferation or condensation of the CNC-derived dental mesenchyme in the Lef1 null mutant, suggesting that LEF1 may not affect the cell cycle progression of the multipotential CNC cells during tooth morphogenesis. Importantly, apoptotic activity is significantly increased within the dental epithelium in the Lef1 null mutant mice. As the result of this increased cell death, the bud stage tooth germ fails to advance to the cap stage in the absence of Lef1. Inhibition of apoptotic activity by FGF4 rescues the tooth development in the Lef1 null mutant. Our studies suggest that LEF1 is a critical survival factor for the dental epithelial cells during tooth morphogenesis.

Animals↗
PubMed2006

Phylogeographic incongruence of codistributed amphibian species based on small differences in geographic distribution.

Codistributed species may display either congruent phylogeographic patterns, indicating similar responses to a series of shared climatic and geologic events, or discordant patterns, indicating independent responses. This study compares the phylogeographic patterns of two similarly distributed salamander species within the Pacific Northwest of the United States: Cope's giant salamander (Dicamptodon copei) and Van Dyke's salamander (Plethodon vandykei). Previous studies of P. vandykei support two reciprocally monophyletic lineages corresponding to coastal populations, located from the Olympic Mountains to the mouth of the Columbia River, and inland populations within the Cascade Mountains. We hypothesized that D. copei would have a congruent phylogeographic pattern to P. vandykei due to similarity in distribution and dependence upon similar stream and stream-side habitats. We test this hypothesis by estimating the phylogeny of D. copei using approximately 1800bp of mitochondrial DNA and comparing it to that of P. vandykei. Sympatric populations of D. copei and of P. vandykei display an identical phylogeographic pattern, suggesting similar responses within their shared distribution. Populations of D. copei occurring outside the range of P. vandykei displayed high levels of genetic divergence from those sympatric to P. vandykei. Overall, phylogeographic patterns between the two species were ultimately incongruent due to the high divergence of these allopatric populations. These results provide an example of codistributed species displaying overall incongruent phylogeographic patterns while simultaneously displaying congruent patterns within portions of their shared geographic distribution. This pattern demonstrates that a simple dichotomy of congruent and incongruent phylogeographic patterns of codistributed species may be too simplistic and that more complex intermediate patterns can result even from minor differences in species' ranges.

Animals↗
PubMed1995

Extensive bone marrow necrosis associated with antiphospholipid antibodies.

Bone marrow necrosis (BMN), defined morphologically by destruction of hematopoietic tissue, including the stroma, with preservation of the bone, is a rare syndrome. The conditions in which it is seen include sickle cell disease, acute leukemia, metastatic neoplasia, and bacterial infection, particularly when hypovolemia and septic shock are present. BMN is also associated with disseminated intravascular coagulation (DIC) following irradiation and antineoplastic therapy. The antiphospolipid syndrome (APS) is characterized by antibodies directed against the antiphospolipid substrate. Because this substrate is prominently involved in the coagulation cascade and widely distributed on cell walls, patients present with venous or arterial thromboses, recurrent abortion, thrombocytopenia, and Coombs' positive hemolytic anemia, typically with raised anticardiolipin antibodies or a diagnostic lupus anticoagulant test. BMN does not appear to have been previously recognized in this context. We report what we believe to be the first such case and suggest that the high titers of antibodies present may have played a central role in its pathogenesis.

Adult↗
PubMed1998

Heparinless cardiopulmonary bypass with active-site blocked factor IXa: a preliminary study on the dog.

OBJECTIVE: Cardiopulmonary bypass is a potent stimulus for activation of procoagulant pathways. Heparin, the traditional antithrombotic agent, however, is often associated with increased perioperative blood loss because of its multiple sites of action in the coagulation cascade and its antiplatelet and profibrinolytic effects. Furthermore, heparin-mediated immunologic reactions (that is, heparin-induced thrombocytopenia) may contraindicate its use. Cardiopulmonary bypass with a selective factor IXa inhibitor was tested to see whether it could effectively limit bypass circuit/intravascular space thrombosis while decreasing extravascular bleeding, thereby providing an alternative anticoagulant strategy when heparin may not be safely administered. METHODS: Active site-blocked factor IXa, a competitive inhibitor of the assembly of factor IXa into the factor X activation complex, was prepared by modification of the enzyme's active site by the use of dansyl glutamic acid-glycine-arginine-chlormethylketone. Twenty mongrel dogs (five were given standard heparin/protamine; 15 were given activated site-blocked factor IXa doses ranging from 300 to 600 microg/kg) underwent 1 hour of hypothermic cardiopulmonary bypass, and blood loss was monitored for 3 hours after the procedure. RESULTS: Use of activated site-blocked factor IXa as an anticoagulant in cardiopulmonary bypass limited fibrin deposition within the extracorporeal circuit as assessed by scanning electron microscopy, comparable with the antithrombotic effect seen with heparin. In contrast to heparin, effective antithrombotic doses of activated site-blocked factor IXa significantly diminished blood loss in the thoracic cavity and in an abdominal incisional bleeding model. CONCLUSION: These initial studies on the dog suggest that administration of activated site-blocked factor IXa may be an effective alternative anticoagulant strategy in cardiopulmonary bypass when heparin is contraindicated, affording inhibition of intravascular/extracorporeal circuit thrombosis with enhanced hemostasis in the surgical wound.

Animals↗
PubMed1997

Gene activating and proapoptotic potential are independent properties of different CD4 epitopes.

CD4 engagement triggers an early signaling cascade which initiates late events such as transcription factor activation. The outcome of CD4 engagement is T-cell commitment to alternative, dramatically different fates, such as activation and apoptosis. We have tested a panel of anti-CD4 mAbs specific for different CD4 epitopes, as well as HIV-1 gp120, for the capacity to activate crucial early events such as enhancement of p56(lck) kinase activity and Shc phosphorylation. The same CD4 epitopes were characterized for their capacity both to deliver a gene activating signal and to program T-cells to activation dependent death. No correlation could be found between capacity of specific CD4 epitopes to deliver a gene activating signal and capacity to prime T-cells to apoptosis, suggesting that gene activating and proapoptotic potential are independent functions of CD4 epitopes. Furthermore, while triggering of the calcium pathway appears critical in NF-AT activation, optimal p56(lck) activation and Shc phosphorylation might be required for initiation of the apoptotic pathway.

Antibodies, Monoclonal↗
PubMed1998

Fluoride potentiates the osteogenic effects of IGF-I in aged ovariectomized rats.

The molecular mechanisms whereby fluoride stimulates osteogenic cell proliferation are not clearly established. However, fluoride has been shown to enhance the protein tyrosine phosphorylation of various constituents of intracellular signaling cascades in osteoblastic cells following stimulation of growth factor receptors such as the insulin-like growth factor-I (IGF-I) receptor. Such in vitro findings provided the rationale for testing whether the administration of fluoride could enhance IGF-I effects on bone mass in vivo. Adult ovariectomized osteopenic rats were treated with sodium fluoride at a dose of 6 mg/kg per day in drinking water for 8 weeks in association with IGF-I either at a dose of 2 mg/kg per day, which is capable of increasing bone mass, or at a lower dose without detectable skeletal effects. Bone mineral density (BMD) and content (BMC) were evaluated by dual-energy X-ray absorptiometry at the levels of the lumbar spine and proximal, midshaft, and total tibia before and after 8 weeks of treatment. During this period, fluoride alone did not significantly influence BMD/BMC at any skeletal site. However, it potentiated the effect of the higher dose of IGF-I on bone mass at the level of the proximal tibia. When administered in combination with the lower dose of IGF-I, which per se did not modify bone mass, it appeared to sensitize tibial bone to the effects of IGF-I. These changes were associated with a concomitant increase in osteocalcin, taken as a reflection of bone formation. These results indicate that fluoride could potentiate the osteogenic effects of IGF-I on bone in adult ovariectomized rats.

Absorptiometry, Photon↗
PubMed2001

Targeting complement in therapy.

With increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases, strategies that interfere with its deleterious action have become a major focus in pharmacological research. Endogenous soluble complement inhibitors (C1 inhibitor, recombinant soluble complement receptor 1, antibodies) blocking key proteins of the cascade reaction, neutralizing the action of the complement-derived anaphylatoxin C5a, or interfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium have successfully been tested in various animal models over the past years. Promising results consequently led to clinical trials. Furthermore, incorporation of membrane-bound complement regulators (decay-accelerating factor (CD55), membrane co-factor protein (CD46), CD59) in transgenic animals has provided a major step forward in protecting xenografts from hyperacute rejection. At the same time, the poor contribution of complement to the antitumor response, which is caused by multiple resistance mechanisms that hamper the efficacy of antibody-based tumor therapy, is increasingly recognized and requires pharmacologic intervention. First attempts have now been made to interfere with the resistance mechanisms, thereby improving complement-mediated tumor cell destruction.

Anaphylatoxins↗
PubMed1995

Different phenotypes for mice deficient in either activins or activin receptor type II.

Activins are believed to initiate a signal transduction cascade by binding to serine/threonine kinase receptors types I and II. Activins bind to several different receptors in vitro, but the significance of this interaction in vivo has not been confirmed. To test the function of the type II activin receptor (ActRcII) in mammalian development and reproduction, we generated a null mutation in the ActRcII gene in mice using embryonic stem cell technology. We expected ActRcII-deficient mice to phenocopy activin-deficient mice. A few ActRcII-deficient mice had skeletal and facial abnormalities reminiscent of the Pierre-Robin syndrome in humans, but most lacked these defects and developed into adults; their follicle-stimulating hormone was suppressed, and their reproductive performance was defective. These findings confirm a role of ActRcII in activin signalling in pituitary gonadotrophs. The striking lack of overlap between phenotypes of ActRcII-deficient and activin-deficient mice suggests that the ligands that signal through ActRcII during embryonic development are not activins.

Activin Receptors↗
PubMed2005

Calmodulin kinase II inhibition protects against structural heart disease.

Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling.

Adrenergic beta-Antagonists↗
PubMed2001

Genetic susceptibility to macrovascular complications of type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus have a threefold increased risk of developing macrovascular disease such that 75% of such patients will die of cardiovascular complications. This increased risk is, however, not completely explained by traditional risk factors such as smoking, hypercholesterolaemia, hypertension and glycaemic control. Moreover, the fact that not all patients with type 2 diabetes develop these complications, together with evidence of family clustering (a heritability of 50%), suggests that a proportion of the susceptibility to ischaemic heart disease in type 2 diabetes may be genetic. Unravelling the polygenic susceptibility factors for the complications of a disease that itself has multifactorial inheritance has proved difficult and has focused largely on the candidate gene approach. A review of some of the studies testing candidate genes specifically in patients with both type 2 diabetes and ischaemic heart disease is presented. These studies focus largely on four main areas: lipoprotein metabolism, glycation and oxidation pathways, haemostatic cascade, and other candidate genes.

Diabetes Mellitus, Type 2↗
PubMed1993

Gö 6976, a selective inhibitor of protein kinase C, is a potent antagonist of human immunodeficiency virus 1 induction from latent/low-level-producing reservoir cells in vitro.

Human immunodeficiency virus (HIV-1) infection is followed by a period of latency or a low-level-persistent (LLP) state that results in an asymptomatic infection of the host. Productive viral expression may be triggered by a variety of activators including mitogens, antigens, and cytokines. Protein kinase C (PKC) has been shown to be important in the intracellular cascade of signals induced by such activators. With U1 and ACH-2 cell lines representative of an HIV-1 postintegration state, the effect of Gö 6976, a synthetic inhibitor of PKC was tested. Gö 6976 is a nonglycosidic indolocarbazole found to potently inhibit HIV-1 induction by Bryostatin 1, tumor necrosis factor alpha, and interleukin 6. Gö 6976 effectively blocks viral transcription induced by Bryostatin 1 or tumor necrosis factor alpha that leads to the inhibition of intracellular viral protein synthesis and viral shedding. Gö 6976 also blocks interleukin 6-mediated posttranscriptional induction of viral proteins. The IC50 of Gö 6976 shows a 12- to 60-fold more potent effect than for H-7, another PKC inhibitor with a similar mechanism. The inhibitory effect is reduced when Gö 6976 is not added before or within 1 hr of induction by the potent PKC activator Bryostatin 1. However, U1 cells can be grown for long periods in a nontoxic concentration of Gö 6976 (300 nM), which confers virtual inhibition of HIV-1 induction without the development of resistance. Results indicate that inhibition of HIV-1 proviral induction from latent/low-level-producing infectious states with potent PKC inhibitors like Gö 6976 may represent an additional and promising antiviral approach.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Lateral geniculate neurons in behaving primates. III. Response predictions of a channel model with multiple spatial-to-temporal filters.

1. For the experiments reported in these papers, we recorded the responses of lateral geniculate (LGN) neurons to a large set of two-dimensional, black and white patterns based on Walsh functions and to a set of test stimuli. In the first two papers we reported that these neurons encode stimulus-related information in both the strength and the shape of the response waveforms and that there are more than two independent components in the response. These results cannot be explained by existing models. This paper provides a model of LGN neurons that not only accounts for the foregoing observations, but also yields predictions confirmed by direct tests. 2. The model represents a neuron as a set of three parallel channels. The input to each channel is an array of pixel luminances. Each channel consists of an input nonlinearity cascaded into a linear spatial-to-temporal filter. The output of each channel is a basic waveform, a principal component. The response of the neuron is the sum of the outputs of the three channels. 3. The model accounted for much of the variance in the coefficients of the first three principal components of the neuronal responses to the set of Walsh stimuli. Using parameters derived from the responses of neurons to the Walsh stimuli only, the model also predicted the responses to "center-surround" annuli of different contrasts and mean luminances, as well as to superpositions of pairs of Walsh patterns. The model made statistically significant predictions of the coefficients of two of the principal components of these responses. 4. After the parameters of the model had been fit to reproduce the responses of neurons to the Walsh stimuli, we found that the input nonlinearity of the model was compressed at both the high and low luminance levels. This compression produced response saturation that closely resembled the response saturation of neurons reported in the first paper in this series. Although not absolutely smooth, the spatial filter for the first channel had a dominant excitatory or inhibitory center and an antagonistic surround. Thus this spatial filter accounted for both the center and the surround structures of previous models of LGN receptive fields. There was greater variety in the structures of the spatial filters for the second and third channels, but none had a center-surround organization. Many of the spatial filters for these higher channels contained oriented ridges or valleys. Other spatial filters were dominated by a bipolar pair of pixels. 5. The model of LGN neurons that we present in this paper represents an extension over previous models in four ways. First, the model is capable of explaining the responses of neurons to a wider range of luminances than previous models. Second, the model is capable of explaining the shapes of the response waveforms as well as their magnitudes. Third, the concept of a single receptive field is extended to a series of spatial-to-temporal filters. Fourth, the model suggests that LGN neurons provide a description of both the brightness and the form of a stimulus in their response waveforms.

Animals↗
PubMed1993

Raynaud's syndrome, an enigma after 130 years.

The recent literature concerning Raynaud's syndrome is reviewed. Raynaud's syndrome is as common as hypertension and diabetes. In spite of its generally benign character, it causes a lot of discomfort to individuals and sickness absenteeism to society, especially in the colder regions of the world. The etiology remains an enigma 130 years after its first description, perhaps even more so than ever before, the many new theories proposed in the literature. Clearly, in a condition where seventy different etiologic theories are advocated, the culprit lesion is obviously missing, or there is not a culprit lesion but an accumulation of conditions having nothing in common but a few symptoms. Moreover a Raynaud attack may result, not from a single event, but from a cascade of events, just as, for example, hemostasis does. Controversy about diagnosis exists all over. For example, how does one make a diagnosis? Patient history has been considered unreliable. A standardized cold test, though highly reproducible in the authors' hands, is far from common property. Raynaud's syndrome is a condition for which thirty-eight therapies have been advocated in the last three years, but the curative answer is still to come.

Clinical Trials as Topic↗
PubMed2000

The mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl-leucyl-phenylalanine-induced p47phox phosphorylation in human neutrophils.

Phosphorylation of p47 phagocyte oxidase, (p47(phox)), one of the NADPH oxidase components, is essential for the activation of this enzyme and for superoxide production. p47(phox) is phosphorylated on multiple serine residues, but the kinases involved in this process in vivo remain to be characterized. We examined the role of extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinase in p47(phox) phosphorylation. Inhibition of ERK1/2 activation by PD98059, a specific inhibitor of ERK kinase 1/2, inhibited the fMLP-induced phosphorylation of p47(phox). However, PD98059 weakly affected PMA-induced p47(phox) phosphorylation, even though ERK1/2 activation was abrogated. This effect was confirmed using U0126, a second ERK kinase inhibitor. Unlike PD98059 and U0126, the p38 mitogen-activated protein kinase inhibitor SB203580 did not inhibit the phosphorylation of p47(phox) induced either by fMLP or by PMA. Two-dimensional phosphopeptide mapping analysis showed that, in fMLP-induced p47(phox) phosphorylation, PD98059 affected the phosphorylation of all the major phosphopeptides, suggesting that ERK1/2 may regulate p47(phox) phosphorylation either directly or indirectly via other kinases. In PMA-induced p47(phox) phosphorylation, GF109203X, a protein kinase C inhibitor, strongly inhibits p47(phox) phosphorylation. However, in fMLP-induced p47(phox) phosphorylation, PD98059 and GF109203X partially inhibited the phosphorylation of p47(phox) when tested alone, and exerted additive inhibitory effects on p47(phox) phosphorylation when tested together. These results show for the first time that the ERK1/2 pathway participates in the phosphorylation of p47(phox). Furthermore, they strongly suggest that p47(phox) is targeted by several kinase cascades in intact neutrophils activated by fMLP and is therefore a converging point for ERK1/2 and protein kinase C.

Butadienes↗
PubMed2002

Preconditioning modulates susceptibility to ischemia-induced arrhythmias in the rat heart: the role of alpha-adrenergic stimulation and K(ATP) channels.

A new concept of cardioprotection based on the exploitation of endogenous mechanisms is known as ischemic preconditioning (IPC). It has been hypothesized that substances released during brief ischemic stress (e.g. catecholamines) stimulate the receptors and trigger multiple cell signaling cascades. Opening of ATP-sensitive K+ channels [K(ATP)] has been suggested as a possible final step in the mechanisms of protection. In this study, the role of adrenergic activation was tested in Langendorff-perfused rat hearts subjected to test ischemia (TI; 30 min occlusion of LAD coronary artery) by: 1) mimicking IPC (5 min ischemia, 10 min reperfusion) with short-term (5 min) administration of norepinephrine (NE, 1 microM), 15 min prior to TI; 2) blockade with beta- or alpha1-receptor antagonists, propranolol (10 microM) and prazosin (2 microM), respectively, applied 15 min prior to TI during IPC. The role of K(ATP) opening was examined by perfusion with a K(ATP) blocker glibenclamide (10 microM) during IPC. Both IPC and NE-induced PC effectively reduced the incidence of ventricular tachycardia (VT) to 33% and 37%, respectively, vs 100% in the non-PC controls, whereby ventricular fibrillation (VF) was totally abolished by IPC and markedly suppressed by PC with NE (0% and 10%, respectively, vs 70% in the non-PC hearts; P < 0.05). The severity of arrhythmias (arrhythmia score, AS) was also markedly attenuated by both interventions (IPC: AS 1.7 +/- 0.4; NE-PC: AS 1.8 +/- 0.3 vs AS 4.1 +/- 0.2 in the controls; P < 0.05). Protection was not suppressed by propranolol (VT 28%; VF 14%; AS 2.2 +/- 0.6), whereas prazosin reversed the protective effect of PC (VT 83%; VF 67%; AS 4.0 +/- 0.8). Antiarrhythmic protection afforded by NE-PC was abolished by pretreatment of rats with pertussis toxin (25 microg/kg, i.p.) given 48 h prior to the experiments. Glibenclamide did not suppress the IPC-induced protection. In conclusion, the sensitivity of the rat heart to ischemic arrhythmias can be modulated by IPC. Protection is mediated via stimulation of alpha1-adrenergic receptors coupled with Gi-proteins but glibenclamide-sensitive K(ATP) channels do not appear to be involved in the mechanisms of antiarrhythmic protection in this model.

Adenosine Triphosphate↗