endothelin-1 and Necrosis

Myocardial ischemia results in myocardial dysfunction. Recovery may be delayed ("stunning"), or persistent if perfusion remains reduced ("hibernation") and ischemia may go on to necrosis, thus, contributing to chronic heart failure. In addition, myocardium not directly affected by ischemia may undergo adaptive processes like hypertrophy and dilatation, which may result in chronic left heart failure. This process is characterized by hemodynamic, neurohumoral, and progressive morphologic changes of the heart which are closely interrelated. Hemodynamic changes basically consist of an increase in left ventricular filling pressure and a decrease in global ejection fraction, and, in most cases years after myocardial infarction, in an increase in systemic vascular resistance and right atrial pressure. Neurohumoral changes consist of an increase in plasma catecholamines, atrial natriuretic factor and vasopressin, and in an activation of the renin-angiotensin-system. Plasma endothelin-1 was recently reported to be increased in patients with heart failure, and prognosis was related to endothelin levels. Diminished response of vessels to endothelium (EDRF/NO) dependent vasodilatation suggests impairment of vascular endothelium in heart failure. Local changes of cardiac neurohumoral systems could contribute to structural changes of the heart, e.g., systemic activation to hemodynamic changes. Structural changes of the heart are characterized by an increase in volume and thickness of surviving myocardium and an expansion of ischemic and necrotic myocardium. Molecular control of these processes which include various cell types, such as cardiomyocytes and cardiofibroblasts, are currently an issue of intense research and could result in specific therapeutic importance.

Topics: Chronic Disease; Endothelin-1; Endothelium, Vascular; Heart Failure; Hemodynamics; Humans; Myocardial Ischemia; Myocardial Stunning; Myocardium; Necrosis; Nitric Oxide

Endothelin-1, the most potent endothelium-derived vasoconstrictor peptide identified so far, exerts multiple biologic effects that are potentially relevant for the pathogenesis of coronary atherosclerosis and ischemic heart disease. Since the discovery of the peptide, a good deal of experimental and clinical data have been accumulated to support an important role of endothelin-1 in ischemic heart disease. In experimental animals, exogenous endothelin-1 was found to cause coronary vasoconstriction and, at higher doses, ventricular fibrillation and death. Endothelin receptor subtypes have been demonstrated and pharmacologically characterized in the coronary vascular bed. The plasma levels of immunoreactive endothelin-1 were found to be increased in patients with coronary atherosclerosis, acute myocardial infarction, and angina. Given its growth-promoting and mitogenic action, endothelin-1 has also been suspected to participate in the mechanism of restenosis after PTCA. The purpose of this study was to critically review the experimental and clinical data supporting the involvement of endothelin-1 in ischemic heart disease and the results of more recent studies on the effects of endothelin-1 blockade on experimental myocardial necrosis and restenosis after PTCA.

Topics: Angioplasty, Balloon, Coronary; Animals; Coronary Vessels; Endothelin-1; Heart; Hemodynamics; Humans; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Necrosis; Platelet Aggregation; Receptors, Endothelin

The primary forms of cell death seen in ischemic stroke are of two major types: a necrotic/necroptotic form, and an apoptotic form that is frequently seen in penumbral regions of injury. Typically apoptotic versus necroptotic programmed cell death is described as competitive in nature, where necroptosis is often described as playing a backup role to apoptosis. In the present study, we examined the relationship between these two forms of cell death in a murine endothelin-1 model of ischemia-reperfusion injury in wildtype and caspase-3 null mice with and without addition of the pharmacologic RIPK1 phosphorylation inhibitor necrostatin-1. Analyses of ischemic brain injury were performed via both cellular and volumetric assessments, electron microscopy, TUNEL staining, activated caspase-3 and caspase-7 staining, as well as CD11b and F4/80 staining. Inhibition of caspase-3 or RIPK1 phosphorylation demonstrates significant neural protective effects which are non-additive and exhibit significant overlap in protected regions. Interestingly, morphologic analysis of the cortex demonstrates reduced apoptosis following RIPK1 inhibition. Consistent with this, RIPK1 inhibition reduces the levels of both caspase-3 and caspase-7 activation. Additionally, this protection appears independent of secondary inflammatory mediators. Together, these observations demonstrate that the necroptotic protein RIPK1 modifies caspase-3/-7 activity, ultimately resulting in decreased neuronal apoptosis. These findings thus modify the traditional exclusionary view of apoptotic/necroptotic signaling, revealing a new form of interaction between these dominant forms of cell death.

Topics: Animals; Apoptosis; Brain Ischemia; Endothelin-1; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases

The sole FDA-approved drug treatment for ischemic stroke is tissue-type plasminogen activator (tPA). However, upregulation of JNK mitogen-activated protein kinase (MAPK) and endothelin 1 (ET-1) by tPA after stroke contributes to impaired cerebrovascular autoregulation. Wild-type (wt) tPA can bind to the lipoprotein-related receptor (LRP), which mediates vasodilation, or NMDA receptors (NMDA-Rs), exacerbating vasoconstriction. Elevations in IL-6, a marker of inflammation that accompanies stroke, are reported to be an adverse prognostic factor. We hypothesized that IL-6 released into CSF after stroke by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK contribute to impairment of cerebrovascular autoregulation and increased histopathology. Results show that IL-6 was increased post stroke in pigs, which was increased further by wt-tPA. Co-administration of the IL-6 antagonist LMT-28 with wt-tPA prevented impairment of cerebrovascular autoregulation and necrosis of hippocampal cells. wt-tPA co-administered with the JNK inhibitor SP 600125 and the ET-1 antagonist BQ 123 blocked stroke-induced elevation of IL-6. Co-administration of LMT-28 with wt-tPA blocked the augmentation of JNK and ET-1 post stroke. In conclusion, IL-6 released after stroke, which is enhanced by wt-tPA through activation of NMDA-Rs and upregulation of ET-1 and JNK, impairs cerebrovascular autoregulation and increases histopathology. Strategies that promote fibrinolysis while limiting activation of NMDA-Rs and upregulation of IL-6 may improve the benefit/risk ratio compared to wt-tPA in treatment of stroke.

Topics: Animals; Anthracenes; Cerebral Cortex; Disease Models, Animal; Endothelin-1; Hippocampus; Homeostasis; Interleukin-6; Necrosis; Oxazolidinones; Random Allocation; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Stroke; Swine; Tissue Plasminogen Activator; Up-Regulation

Traumatic brain injury (TBI) is an important contributor to morbidity and mortality. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Extracellular signal-related kinase (ERK) mitogen activated protein kinase (MAPK) and ET-1 are upregulated and contribute to impairment of cerebral autoregulation and histopathology after porcine fluid percussion brain injury (FPI). Recent studies show that inhaled nitric oxide (iNO) prevents impairment of cerebral autoregulation and histopathology after FPI in pigs. Unrelated studies indicated an association between ERK and increased IL-6 after FPI. However, the role of IL-6 in central nervous system (CNS) pathology is not well understood. We investigated whether iNO protects autoregulation and limits histopathology after FPI in pigs due to modulation of brain injury associated upregulation of ET-1, ERK MAPK, and IL-6.. Lateral FPI was produced in anesthetized pigs equipped with a closed cranial window and iNO administered at 30 min or 2 h post injury.. CSF ET-1, ERK MAPK, and IL-6 were increased by FPI, but release was blocked by iNO administered at 30 min or 2 h after TBI. The IL-6 antagonist LMT-28 prevented impairment of cerebral autoregulation and hippocampal CA1 and CA3 neuronal necrosis after FPI. Papaverine induced dilation was unchanged by FPI and LMT-28. Protection lasted for at least 2 h after iNO administration was stopped.. These data indicate that iNO protects cerebral autoregulation and reduces hippocampal necrosis after traumatic brain injury through inhibition of ET-1, ERK MAPK, and IL-6 upregulation in pigs.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Brain Injuries, Traumatic; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Female; Hippocampus; Homeostasis; Interleukin-6; Male; Necrosis; Nitric Oxide; Oxazolidinones; Papaverine; Protein Synthesis Inhibitors; Signal Transduction; Swine; Up-Regulation; Vasodilator Agents

Tissue-type plasminogen activator (tPA) is neurotoxic and exacerbates uncoupling of cerebral blood flow (CBF) and metabolism after stroke, yet it remains the sole FDA-approved drug for treatment of ischemic stroke. Upregulation of c-Jun-terminal kinase (JNK) after stroke contributes to tPA-mediated impairment of autoregulation, but the role of endothelin-1 (ET-1) is unknown. Based on the Glasgow Coma Scale, impaired autoregulation is linked to adverse outcomes after TBI, but correlation with hippocampal histopathology after stroke has not been established. We propose that given after stroke, tPA activates N-Methyl-D-Aspartate receptors (NMDA-Rs) and upregulates ET-1 in a JNK dependent manner, imparing autoregulation and leading to histopathology. After stroke, CBF was reduced in the hippocampus and reduced further during hypotension, which did not occur in hypotensive sham pigs, indicating impairment of autoregulation. Autoregulation and necrosis of hippocampal CA1 and CA3 neurons were further impaired by tPA, but were preserved by the ET-1 antagonist BQ 123 and tPA-A,

Topics: Animals; Cerebrovascular Circulation; Endothelin-1; Female; Hippocampus; Homeostasis; Male; Necrosis; Neurons; Stroke; Swine; Tissue Plasminogen Activator; Up-Regulation

To aid in development of chronic stage treatments for sensorimotor deficits induced by ischemic stroke, we investigated the effects of GABA antagonism on brain structure and fine skilled reaching in a rat model of focal ischemia induced via cortical microinjections of endothelin-1 (ET-1). Beginning 7 days after stroke, animals were administered a gamma-aminobutyric acid (GABAA) inverse agonist, L-655,708, at a dose low enough to afford α5-GABAA receptor specificity. A week after stroke, the ischemic lesion comprised a small hypointense necrotic core (6±1 mm(3)) surrounded by a large (62±11 mm(3)) hyperintense perilesional region; the skilled reaching ability on the Montoya staircase test was decreased to 34%±2% of the animals' prestroke performance level. On L-655,708 treatment, animals showed a progressive decrease in total stroke volume (13±4 mm(3) per week), with no change in animals receiving placebo. Concomitantly, treated animals' skilled reaching progressively improved by 9%±1% per week, so that after 2 weeks of treatment, these animals performed at 65%±6% of their baseline ability, which was 25%±11% better than animals given placebo. These data indicate beneficial effects of delayed, sustained low-dose GABAA antagonism on neuroanatomic injury and skilled reaching in the chronic stage of stroke recovery in an ET-1 rat model of focal ischemia.

Topics: Animals; Behavior, Animal; Brain Ischemia; Endothelin-1; GABA Antagonists; Heart Rate; Imidazoles; Male; Motor Skills; Necrosis; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Recovery of Function; Respiratory Rate; Stroke; Stroke Volume

Recently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET-1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways.. Following SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection.. These findings suggest that ET-1 may be one of the upstream effectors for programmed neuronal necrosis through abnormal LIMK2 over-expression by ROCK1.

Topics: Amides; Animals; Apoptosis; Blood-Brain Barrier; Caveolin 1; Endothelin-1; Hippocampus; Lim Kinases; Male; Mitochondrial Dynamics; Models, Biological; Necrosis; Neurons; Nitric Oxide Synthase Type I; Oligopeptides; Peptides; Piperidines; Pyridines; Rats, Sprague-Dawley; Receptors, Endothelin; rho-Associated Kinases; RNA, Messenger; Status Epilepticus

Severe acute pancreatitis (SAP) is a commonly seen acute abdominal syndrome characterized by sudden onset, rapid progression and high mortality rate. The damage in peripheral organs may be more severe than that in the pancreas, and can even lead to multiple organ dysfunction. It is critical to recognize early pathological changes in multiple organs. This study aimed to assess the early pathological features of damaged organs in a rat model of SAP.. Thirty clean grade healthy male Sprague-Dawley rats weighing 250-300 g were randomly divided into a model control group (n=15) and a sham-operated group (n=15). The SAP rat model was induced by sodium taurocholate. Samples of blood and from multiple organs were collected 3 hours after operation. We assessed the levels of IL-6, TNF-alpha, PLA2, NO, ET-1, MDA, amylases and endotoxin in blood and observed the early pathological changes in multiple damaged organs.. Levels of IL-6, TNF-alpha, PLA2, NO, ET-1 and MDA in serum and of amylase and endotoxin in plasma of the model control group rats were significantly higher than those of the sham-operated group (P<0.01). Different degrees of pathological change were observed in multiple damaged organs.. Multiple organ injury may occur at the early stage of SAP in rats.

Topics: Acute Disease; Animals; Cytokines; Disease Models, Animal; Edema; Endothelin-1; Hemorrhage; Kidney; Liver; Lung; Male; Malondialdehyde; Necrosis; Nitric Oxide; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley

We investigated the role of angiotensin II and endothelin-1 using the angiotensin AT1 receptor antagonist losartan and the endothelin ETA receptor antagonist atrasentan, in malignant hypertension and renal failure and damage induced by nitric oxide (NO) synthase inhibition in Harlan Sprague-Dawley (SD) rats. We also evaluated whether the protective effects of losartan go beyond the blood pressure reduction. Within only 3 weeks of treatment with the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME), Harlan SD rats developed malignant hypertension with renal failure and injuries. The latter were comprised of fibrinoid necrosis of small arteries and glomerular and tubular necrosis. Although both losartan and atrasentan attenuated the development of hypertension and renal failure, losartan only prevented the renal damage. In contrast to antrasentan, the vasodilator hydralazine reduced blood pressure and prevented the renal injuries similar to losartan. However, when these treatments were prolonged to 5 weeks, losartan, but not hydralazine, was still effective in reducing renal failure and damage, despite a marked increase in blood pressure. Our results indicate that angiotensin II and endothelin-1 play a differential role in the pathogenesis of malignant hypertension and in vascular and renal damage induced by L-NAME in Harlan SD rats. Although the protective effects of atrasentan may depend on the reduction of blood pressure, which was shown to retard the development of renal injury using hydralazine, those of losartan go beyond the blood pressure reduction. Hence, tissue protective effects of angiotensin AT1 receptor blockade may be pivotal for long-term vascular and renal protection.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Atrasentan; Blood Pressure; Endothelin-1; Hydralazine; Hypertension, Malignant; Losartan; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renal Insufficiency

The endothelin axis consists of endothelin-1 (ET-1) and its two receptors, ET(A)- and ET(B)-receptor (ET(A)-R and ET(B)-R). In several tumor entities, the ET(A)-R plays a significant role as a drug target. In our study, we investigated whether inhibition of ET(A)-R with atrasentan leads to an antitumor effect in urinary bladder carcinoma as well.. Twenty nude mice with thymic aplasia were subcutaneously administered 2 x 10(6) KU-19-19 bladder cancer cells in the right flank. Starting on the 22nd day after the injection, ten animals were treated with atrasentan (2.5 mg/kg BW intraperitoneally), and another ten animals were treated with placebo. During treatment, absolute tumor growth and relative growth rate over time were determined. After the end of treatment, the mitosis and necrosis rates, microvessel density, and receptor density in the tumor tissue were analyzed by immunohistochemistry. In addition, the expression intensities of ET-1, ET(A)-R, and ET(B)-R were evaluated semiquantitatively and compared between the groups.. No significant differences between the active-treatment and placebo groups were detected, either with respect to absolute tumor growth (P = 0.333) or mitosis rate (P = 0.217). In the analysis of the necrosis rate and receptor density for ET(A)-R, a trend toward higher values in the active-treatment group (mean necrosis rate = 63.67%, receptor density: 1.417) than in the placebo group (mean necrosis rate = 46.25%, receptor density: 1.270) was found; however, neither difference was statistically significant (P = 0.08 and 0.219, respectively).. ET(A)-R blockade with atrasentan in a bladder cancer xenograft model shows no significant antitumor effect.

Topics: Animals; Atrasentan; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Female; Humans; Immunoenzyme Techniques; Mice; Mice, Nude; Mitosis; Necrosis; Pyrrolidines; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thymus Gland; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Nephrotoxicity is the main side effect of antibiotics such as gentamicin. Preconditioning has been reported to protect against injuries as ischemia/reperfusion. The objective of the present study was to determine the effect of preconditioning with gentamicin on LLC-PK1 cells. Preconditioning was induced in LLC-PK1 cells by 24-h exposure to 2.0 mM gentamicin (G/IU). After 4 or 15 days of preconditioning, cells were again exposed to gentamicin (2.0 mM) and compared to untreated control or G/IU cells. Necrosis and apoptosis were assessed by acridine orange and HOESCHT 33346. Nitric oxide (NO) and endothelin-1 were assessed by the Griess method and available kit. Heat shock proteins were analyzed by Western blotting. After 15 days of preconditioning, LLC-PK1 cells exhibited a significant decrease in necrosis (23.5 +/- 4.3 to 6.5 +/- 0.3%) and apoptosis (23.5 +/- 4.3 to 6.5 +/- 2.1%) and an increase in cell proliferation compared to G/IU. NO (0.177 +/- 0.05 to 0.368 +/- 0.073 microg/mg protein) and endothelin-1 (1.88 +/- 0.47 to 2.75 +/- 0.53 pg/mL) production significantly increased after 15 days of preconditioning compared to G/IU. No difference in inducible HSP 70, constitutive HSC 70 or HSP 90 synthesis in tubular cells was observed after preconditioning with gentamicin. The present data suggest that preconditioning with gentamicin has protective effects on proximal tubular cells, that involved NO synthesis but not reduction of endothelin-1 or production of HSP 70, HSC 70, or HSP 90. We conclude that preconditioning could be a useful tool to prevent the nephrotoxicity induced by gentamicin.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Blotting, Western; Cell Proliferation; Endothelin-1; Gentamicins; Heat-Shock Proteins; Kidney Tubules, Proximal; LLC-PK1 Cells; Necrosis; Nitric Oxide; Swine

Necrotizing enterocolitis (NEC) has high morbidity in premature infants. Hypoxia-ischemia, infection, and enteral feeding are risk factors associated with NEC, whereas feeding human milk is protective. Vasoactive and inflammatory mediators in NEC remain elusive. Gangliosides are found in human milk and enterocyte membranes. An infant bowel model of NEC was developed to test the hypothesis that gangliosides modulate the inflammatory response to infection and hypoxia.. Viable, noninflamed bowel was obtained from 9 infants between 26 and 40 weeks' gestational age. Infant bowel was treated in culture with Escherichia coli lipopolysaccharide (LPS) and hypoxia in the presence or absence of preexposure to gangliosides. Bowel necrosis and production of nitric oxide, endothelin-1, serotonin, eicosanoids, hydrogen peroxide, and proinflammatory cytokines were measured.. Ganglioside preexposure reduced bowel necrosis and endothelin-1 production in response to LPS. Gangliosides suppressed infant bowel production of nitric oxide, leukotriene B4, prostaglandin E2, hydrogen peroxide, interleukin-1beta, interleukin-6, and interleukin-8 in response to LPS exposure and hypoxia.. A bowel protective effect of gangliosides is indicated by modulation of vasoactive mediators and proinflammatory signal suppression.

Topics: Animals; Anti-Inflammatory Agents; Colon; Endothelin-1; Enterocolitis, Necrotizing; Escherichia coli; Gangliosides; Humans; Hypoxia; In Vitro Techniques; Infant, Newborn; Inflammation; Inflammation Mediators; Lipopolysaccharides; Milk; Necrosis

We tested the hypothesis that unloading the left ventricle with intra-aortic balloon counter-pulsation just prior to reperfusion provides infarct salvage compared with left ventricular (LV) unloading postreperfusion or reperfusion alone.. Previous reports demonstrated infarct salvage with complete LV unloading with an LVAD prior to reperfusion; however, partial LV unloading using intra-aortic balloon pumps (IABPs) has not been evaluated.. Twenty-eight Yorkshire pigs were subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion. An IABP was inserted and activated just prior to reperfusion (IABP-Pre), or 15 min after reperfusion (IABP-Post), or not at all (control).. At baseline, the hemodynamic data were similar in the three groups. Myocardial infarct size expressed a percentage of zone at risk in control animals was 44.9% +/- 4.8%, IAPB-Pre group 20.9% +/- 5.1% (P < 0.05 compared to control), and IABP-Post group 33.2 +/- 6.1% (P = 0.16 vs. control group). There was a correlation between transcardiac endothelin-1 release at 15 min postreperfusion and infarct size (r = 0.59).. LV unloading with an IABP prior to reperfusion reduces the extent of myocardial necrosis in hearts subjected to 1 hr of left anterior descending artery occlusion and 4 hr of reperfusion compared with either reperfusion alone or LV unloading after reperfusion. Inhibition of myocardial ET-1 release by LV unloading may be a significant mechanism of myocardial protection. These data suggest that in high-risk STEMI patients, IABP unloading prior to reperfusion might be more beneficial than IABP placement postreperfusion.

Topics: Angioplasty, Balloon, Coronary; Animals; Coronary Circulation; Disease Models, Animal; Endothelin-1; Heart-Assist Devices; Hemodynamics; Intra-Aortic Balloon Pumping; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Necrosis; Swine; Time Factors; Ventricular Function, Left

Maternal endothelial activation in pre-eclampsia is attributed to the release of unknown factors from a hypoperfused placenta. To further characterize these factors, we have used a serum-free placental villous explant culture model and investigated the effect of the liberated soluble factors produced on human endothelial cell cultures. Term placental villous explants from uncomplicated pregnancies were cultured for 4 days in 20, 6 or 1% O2 to mimic placental hyperoxia, normoxia and hypoxia. Medium collected from viable explants was applied to cultured human uterine microvascular endothelial cells. Medium conditioned by hypoxic explants caused a significant decrease in endothelial cell ATP levels and mitochondrial dehydrogenase activity, suggestive of a reduced metabolic rate. An additional reduction in mitochondrial membrane potential and increased endothelial cell death occurred as the oxygen concentration to which explants had been exposed decreased. Effects of the hypoxic explant medium were also seen ex vivo in a wire myography model of myometrial artery function, with increased vasoconstriction and attenuated vasodilation following exposure to hypoxic explant medium. These results suggest that hypoxia (1% O2) may stimulate the release of soluble factors from the placenta, which have an adverse effect on endothelial cell metabolism and mitochondrial integrity in vitro. These potentially pathogenic factors are now being characterized.

Topics: Apoptosis; Arginine Vasopressin; Benzimidazoles; Bradykinin; Carbocyanines; Cells, Cultured; Chorionic Villi; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Epoprostenol; Female; Formazans; Humans; Hyperoxia; Hypoxia; Membrane Potentials; Mitochondria; Myometrium; Necrosis; Neovascularization, Physiologic; Oxygen; Placenta; Pregnancy; Tetrazolium Salts; Vasodilator Agents

Oxidative stress has been implicated in cell death in range of disease states including ischemia/reperfusion injury of the heart and heart failure. Here we have investigated the mechanisms of cell death following chronic exposure of cardiac myocytes to oxidative stress initiated by hydrogen peroxide. This exposure induced a delayed form of cell death with ultrastructural changes typical of necrosis, and that was accompanied by the release of lactate dehydrogenase and increased lipid peroxidation. However, this delayed death was not accompanied by the loss of mitochondrial membrane potential or caspase-3 activation. Furthermore, we could demonstrate that this delayed necrosis was at least partially prevented by pre-treatment with the hypertrophic stimuli endothelin-1 or leukemic inhibitory factor. Our results suggest that this delayed form necrosis may also comprise an ordered series of events involving pathways amenable to therapeutic modulation.

Topics: Animals; Antioxidants; Calpain; Caspase 3; Cathepsins; Cells, Cultured; Doxorubicin; Endothelin-1; Hydrogen Peroxide; L-Lactate Dehydrogenase; Leukemia Inhibitory Factor; Lipid Peroxidation; Microscopy, Electron, Transmission; Mitochondria; Myocytes, Cardiac; Necrosis; Oxidative Stress; Rats; Rats, Sprague-Dawley

Two different theories of migraine aura exist: In the vascular theory of Wolff, intracerebral vasoconstriction causes migraine aura via energy deficiency, whereas in the neuronal theory of Leão and Morison, spreading depression (SD) initiates the aura. Recently, it has been shown that the cerebrovascular constrictor endothelin-1 (ET-1) elicits SD when applied to the cortical surface, a finding that could provide a bridge between the vascular and the neuronal theories of migraine aura. Several arguments support the notion that ET-1-induced SD results from local vasoconstriction, but definite proof is missing. If ET-1 induces SD via vasoconstriction/ischemia, then neuronal damage is likely to occur, contrasting with the fact that SD in the otherwise normal cortex is not associated with any lesion. To test this hypothesis, we have performed a comprehensive histologic study of the effects of ET-1 when applied topically to the cerebral cortex of halothane-anesthetized rats. Our assessment included histologic stainings and immunohistochemistry for glial fibrillary acidic protein, heat shock protein 70, and transferase dUTP nick-end labeling assay. During ET-1 application, we recorded (i) subarachnoid direct current (DC) electroencephalogram, (ii) local cerebral blood flow by laser-Doppler flowmetry, and (iii) changes of oxyhemoglobin and deoxyhemoglobin by spectroscopy. At an ET-1 concentration of 1 muM, at which only 6 of 12 animals generated SD, a microarea with selective neuronal death was found only in those animals demonstrating SD. In another five selected animals, which had not shown SD in response to ET-1, SD was triggered at a second cranial window by KCl and propagated from there to the window exposed to ET-1. This treatment also resulted in a microarea of neuronal damage. In contrast, SD invading from outside did not induce neuronal damage in the absence of ET-1 (n = 4) or in the presence of ET-1 if ET-1 was coapplied with BQ-123, an ET(A) receptor antagonist (n = 4). In conclusion, SD in presence of ET-1 induced a microarea of selective neuronal necrosis no matter where the SD originated. This effect of ET-1 appears to be mediated by the ET(A) receptor.

Topics: Animals; Depression; Endothelin-1; Hemoglobins; Immunohistochemistry; Male; Necrosis; Neurons; Rats; Rats, Wistar

In this study stereotaxic injections of the vasoconstrictive peptide endothelin-1 (ET-1) were used to create infarcts in the white matter of the internal capsule underlying sensorimotor cortex in rats. Resulting deficits were assessed using established sensorimotor tests conducted on each rat before and after the ET-1-induced infarct. After a 14-day survival period, histological examination revealed tissue necrosis and demyelination in the infarcted white matter of ET-1-injected rats, but not saline-injected control rats. Infarcts resulted in measurable sensorimotor deficits in rats that received ET-1 injections. The same sensorimotor tests showed no deficits in surgical-control rats. The present model of white matter infarct should be valuable in examining the underlying mechanisms of subcortical ischemic stroke and to evaluate potential therapeutic interventions.

Topics: Animals; Behavior, Animal; Brain Infarction; Demyelinating Diseases; Disease Models, Animal; Endothelin-1; Forelimb; Internal Capsule; Male; Necrosis; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Vibrissae

The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA).. Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections.. Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

Topics: Aged; Case-Control Studies; Cell Proliferation; Coronary Artery Disease; Endothelin-1; Female; Fibrosis; Humans; Macrophages; Male; Mammary Arteries; Middle Aged; Muscle, Smooth, Vascular; Necrosis; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin

Ischemic preconditioning (IP) and intermittent inflow occlusion (IO) have provided beneficial outcomes in hepatic resection. However, comparison of these two procedures against warm hepatic ischemia-reperfusion injury has not been studied enough.. Pigs that had undergone 65% hepatectomy were subjected to Control (120 min continuous ischemia, n = 6), IP (10 min ischemia and 10 min reperfusion, followed by 120 min continuous ischemia, n = 6), and IO (120 min ischemia in the form of eight successive periods of 15 min ischemia and 5 min reperfusion, n = 6). We evaluated hepatocyte injury by aspartate aminotransferase, lactate dehydrogenase and hepaplastin test, hepatic microcirculation by hepatic tissue blood flow (HTBF) and endothelin (ET)-1, inflammatory response by tumor necrosis factor-alpha (TNF-alpha), and histopathology after reperfusion.. IP prevented hepatocyte injury, HTBF disturbance, and hepatocyte necrosis in histopathology as well as IO. These two groups showed significantly better outcomes than Control. IP produced significantly less ET-1 and TNF-alpha than IO.. IP ameliorated hepatic warm ischemia-reperfusion injury. Furthermore, IP gained more advantages in preventing chemokine production such as ET-1 and inflammatory response over IO. IP could take the place of IO for hepatectomy.

Topics: Animals; Aspartate Aminotransferases; Blood Flow Velocity; Endothelin-1; Hepatectomy; Inflammation; Ischemic Preconditioning; L-Lactate Dehydrogenase; Liver; Male; Microcirculation; Necrosis; Postoperative Complications; Reperfusion Injury; Specific Pathogen-Free Organisms; Swine; Time Factors; Tumor Necrosis Factor-alpha

Sepsis involves a heterogeneous class of syndromes, and septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs. The present study examined the time-dependent alterations of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) levels in liver tissue in a septic rat model. Healthy male Wistar rats aged 15 weeks received 15 mg/kg lipopolysaccharide (LPS) and were sacrificed at different time points (1, 3, 6, and 10 hrs after treatment). Rats that did not receive LPS were considered to be controls. A 28-fold increase in the ET-1 level was observed in liver tissue 10 hrs after LPS administration. VEGF was also altered in hepatic tissue in a time-dependent manner. A gradual increase of VEGF expression in liver tissue after LPS administration was observed. Expression of Flt-1, the vascular permeability receptor of VEGF, was also increased in liver tissue after LPS administration. ET-1 is a potent vasoconstrictor and, therefore, may play a role in the regulation of hepatic perfusion in a sepsis model. On the other hand, VEGF may be involved in capillary leakage in liver tissue after LPS administration. The present findings suggest that there might be a loss of balance between the ET-1 and VEGF levels in the septic liver at different time points, which could contribute to the pathogenesis of acute liver injury in endotoxemia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Endothelin-1; Lipopolysaccharides; Liver; Male; Necrosis; Neutrophil Infiltration; Rats; Rats, Wistar; Time Factors; Vascular Endothelial Growth Factor A

In vivo studies have shown that chronic alcohol consumption sensitizes the liver to endotoxemic shock, leading to liver microcirculation disruption. In the present study, we investigated the molecular mechanisms involved, focusing on endothelial nitric oxide synthase (eNOS) activity and regulation, which represents one of the major vasodilatory pathways. Male Sprague-Dawley rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks. Priming effects of ethanol were studied in a model with or without a 24-h LPS treatment (1 mg/kg body weight). At the end of the diet, liver tissue was harvested for western blot, reverse transcriptase-PCR, histological analysis, and immunostaining and blood for serum alanine aminotransferase analysis. Chronic ethanol and LPS alone induced a mild hepatitis and infiltration, respectively. Combined, LPS and chronic ethanol feeding showed a synergistic effect on the liver, leading to extensive steatohepatitis with extensive focal necrosis associated with significantly higher levels of serum ALT. Chronic ethanol and LPS significantly inhibited eNOS activity, but exerted their effects through different mechanisms. Caveolin-1, an eNOS inhibitory protein, was upregulated after LPS and chronic alcohol consumption. Additionally, chronic alcohol consumption down-regulated endothelin B receptor, eNOS protein levels, and eNOS phosphorylation. In conclusion, chronic ethanol consumption and LPS share a similar pathophysiology and both lead to the impairment of eNOS activity, but through distinct molecular mechanisms. The presence of focal necrosis in a mild stress model could provide a good animal study to investigate the advanced stages of alcoholic liver diseases.

Topics: Alanine Transaminase; Alcohol Drinking; Animals; Blotting, Western; Body Weight; Down-Regulation; Drug Synergism; Endothelin-1; Endotoxins; Ethanol; Gene Expression Regulation, Enzymologic; Hepatitis; Immunohistochemistry; Lipopolysaccharides; Liver; Male; Necrosis; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phosphorylation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger

Hypertension is frequently associated with the development of renal vascular and glomerular fibrosis. The purpose of the present study was to investigate whether epidermal growth factor receptor (EGFR) activation participates in the development of renal fibrosis and to test if blockade of EGFR activation would have therapeutic effects. Experiments were performed during nitric oxide (NO) deficiency-induced hypertension in rats (L-NAME model). After 4 weeks of L-NAME treatment, animals developed hypertension associated to deterioration of renal structure and function. Over the same period, EGFR was activated twofold within glomeruli. This activation was accompanied by increased activity of the mitogen-activated protein kinase (MAPK) p42/p44 pathway and exaggerated collagen I expression. Gefitinib, an EGFR-tyrosine kinase inhibitor, given concomitantly with L-NAME, normalized MAPK activation and collagen I expression and prevented the decline of renal function and the development of fibrosis. Since endothelin mediates the L-NAME-induced fibrogenesis, the endothelin-EGFR interaction was tested in transgenic mice expressing luciferase under the control of collagen I-alpha2 promoter: In renal cortex of these animals, the endothelin-induced collagen I gene activity was inhibited by an EGFR-phosphorylation inhibitor. These results provide the first evidence that EGFR activation plays an important role in the progression of renal vascular and glomerular fibrosis.

Topics: Animals; Capillaries; Collagen; Collagen Type I; Creatinine; Endothelin-1; ErbB Receptors; Fibrosis; Gefitinib; Gene Expression Regulation; Genes, Reporter; Glomerulosclerosis, Focal Segmental; Hypertension; Ischemia; Kidney; Kidney Cortex; Kidney Diseases; Kidney Glomerulus; Male; MAP Kinase Signaling System; Mice; Mice, Transgenic; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphorylation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Proteinuria; Quinazolines; Rats; Rats, Sprague-Dawley

Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Mesenteric vasoconstriction is one of the most probable types of pathogenesis of these complications.. To investigate the involvement of endothelin-1 (ET-1), a potent vasoconstrictor.. Plasma ET-1 concentrations were extremely high in patients with pancreatic and/or diffuse intestinal necrosis. ET-1 mRNA was demonstrated in the rat pancreas, and the production of ET-1 protein by human umbilical vein endothelial cells was enhanced by tumor necrosis factor-alpha, thrombin, and protease-activated receptor-2-activating peptide. Administration of ET-1 in vivo induced mesenteric arterial spasm and decreased pancreatic and intestinal blood flow.. These results suggest the following: ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; in the inflammatory setting, cytokines, activated thrombin and trypsin, may stimulate ET-1 production in a paracrine fashion; produced ET-1 may exaggerate the splanchnic microcirculation; and progressive ischemia may lead to necrosis of the pancreas and intestine.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Endothelin-1; Female; Humans; Intestines; Ischemia; Male; Mesenteric Arteries; Middle Aged; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Wistar; RNA, Messenger; Vasoconstriction

The combining of molecular biology and physiology is essential for the further development of cardiovascular medicine, and DNA microarray is a useful tool for assessing multiple gene expressions. A canine DNA microarray has been designed and tested. Approximately 60 cardiovascular-related genes were cloned from newly developed canine cDNA libraries and spotted on slides. Using the arrays, the gene expression profiles of canine myocardium in were analyzed 2 protocols: (1). ischemic myocardium by 50% reduction of the coronary blood flow, and (2). necrotic myocardium caused by coronary artery ligation. Three hours after 50% flow reduction, cardiovascular-related genes, including ecto-5'-nucleotidase, endothelin-1, PAI-1, and AT receptors, exhibited rapid alteration and there were many more altered genes than with the complete coronary occlusion. Irreversible ischemic damage without necrosis more strongly affected gene expressions in surviving myocardium than in fatally damaged myocardium. The canine DNA microarray is a useful tool for assessing the precise molecular events following changes in the pathophysiological conditions of the heart.

Topics: 5'-Nucleotidase; Animals; Coronary Circulation; Dogs; Endothelin-1; Gene Expression Profiling; Myocardial Ischemia; Necrosis; Oligonucleotide Array Sequence Analysis; Plasminogen Activator Inhibitor 1; Receptors, Angiotensin

Endothelin-1 (ET-1) induces severe pathologic conditions such as coronary spasm followed by vasospastic angina pectoris and acute myocardial infarction. The related pathophysiologic mechanisms have remained obscure. Endothelin-1 receptor (ET(A) and ET(B)) is reported to couple with several types of G protein-involved pathways that participate in phospholipase C activation and atrial myofibrils organization into sarcomeric units. Here we demonstrate that ET-1 induces histologic and pathologic dysfunction in the rabbit myocardium and that such pathologic events are prevented by the Rho-kinase inhibitor fasudil. Although the bolus injection of ET-1 (1.4 nmol/kg) via the auricular vein of the rabbit induced only transient T-wave elevation, irreversible, severe histologic changes were observed in papillary muscles of the ventricle, and multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the left ventricle occurred. Oral administration of fasudil (10 mg/kg) significantly reduced the occurrence of myocardial injury determinants, whereas conventional Ca2+ channel blockers (nifedipine, diltiazem) and a K+ channel opener (nicorandil; 10 mg/kg, p.o. each) showed a lesser or no effect on such determinants. These results suggest that ET-1 induces severe myocardial dysfunction based not only on the occurrence of vasospastic ischemia but also on its direct effects on the myocardium.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cell Movement; Diltiazem; Electrocardiography; Endothelin-1; Enzyme Inhibitors; Heart Ventricles; Macrophages; Male; Microscopy; Myocardial Ischemia; Necrosis; Neutrophils; Nicorandil; Nifedipine; Papillary Muscles; Rabbits; Random Allocation; Vasodilator Agents

The objectives of this study were to characterize the effects of endothelin (ET)-1 on intestinal mucosal parameters and to assess the contribution of polymorphonuclear leukocytes (PMNs), intercellular adhesion molecule-1 (ICAM-1), and a platelet-activating factor (PAF) to the mucosal dysfunction induced by ET-1. Different concentrations of ET-1 (100, 200, and 400 pmol/kg) were infused into the superior mesenteric artery for 10 min, and tissue samples were obtained 30 min after terminating the infusion. ET-1 administration significantly elevated tissue myeloperoxidase activity, plasma carbonyl content, and tissue chemiluminescence intensity, indicating that ET-1 produces PMN infiltration and oxidant stress. Blood-to-lumen clearance of (51)Cr-EDTA significantly increased after ET-1 infusion (400 pmol/kg). Monoclonal antibodies against ICAM-1 (1A29, 2 mg/kg), antineutrophil serum, and PAF antagonist (WEB-2086, 10 mg/kg) attenuated the mucosal barrier dysfunction induced by ET-1. Overall, our data indicate that ET-1 causes PMN accumulation, oxidant stress, and mucosal dysfunction in the rat small intestine and that ET-1-induced mucosal dysfunction involves a mechanism that includes a role for PMNs, ICAM-1, and PAF.

Topics: Animals; Antibodies, Monoclonal; Azepines; Cell Movement; Endothelin-1; Female; Injections, Intra-Arterial; Intercellular Adhesion Molecule-1; Intestinal Mucosa; Intestine, Small; Luminescent Measurements; Male; Necrosis; Neutrophils; Oxidative Stress; Peroxidase; Platelet Activating Factor; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Triazoles

In this study we investigated kinetic changes in the ratio of endothelin-1 (ET-1) and eicosanoids (6-keto-PG-F1 alpha TX-B2) in 20 x 60 mm random pattern flaps from rats. The ET-1 content of regions A (20 mm from the peripheral end) and B (20-40 mm) 6 h after surgery tended to decrease slightly compared to the ET-1 content immediately after surgery. The ET-1 content of region C (20 mm from the flap base) 6 h postoperatively increased significantly compared to that immediately after surgery. The ET-1 content of region C 6 h after surgery was significantly higher compared to that of regions A and B, which were obtained simultaneously. The ratios of eicosanoids in the three regions 6 h after surgery were significantly lower than those immediately after operation. However, the ratio in region A was higher than that in region C, showing that there was a difference in distribution in the flap between ET-1 and eicosanoids. The administration of an ETA receptor antagonist, FR-139317, extended the survival length of the flap. These results suggest that ET-1 can regulate the microcirculation in a flap directly and/or indirectly.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Eicosanoids; Endothelin Receptor Antagonists; Endothelin-1; Indoles; Male; Necrosis; Rats; Rats, Wistar; Receptor, Endothelin A; Skin; Thromboxane B2

Endothelin 1 is considered to be an important regulator of sinusoidal blood flow and increases during endotoxemia. The purpose of this study was to investigate the role of endothelin 1 in hepatic microcirculation, oxygen transport, and liver injury during endotoxemia.. Male Sprague-Dawley rats were continuously infused with 2.5 mL/h of saline, 0.8 mg . kg-1 . h-1 of lipopolysaccharide (LPS), 3 mg . kg-1 . h-1 of BQ-485, an endothelin A-receptor antagonist, or LPS plus BQ-485 for 7 hours.. BQ-485 infusion had no significant effect on hepatic microcirculation and liver injury. LPS increased the plasma levels of aspartate aminotransferase (AST) and total bilirubin and decreased the hepatic adenosine triphosphate (ATP) level and bile flow rate. LPS + BQ-485 infusion further increased the plasma levels of AST and total bilirubin and decreased the bile flow rate and the hepatic ATP level. Dual-spot microspectroscopy revealed mild decreases in sinusoidal erythrocyte velocity and oxygen transport in the LPS group and profound decreases in these parameters in the LPS + BQ-485 group. Histological examinations revealed massive necrotic changes in the pericentral regions of the LPS + BQ-485 group.. These results suggest that blockade of endothelin A receptors disturbs hepatic microcirculation and oxygen transport and aggravates the necrotic injury induced by endotoxin.

Topics: Adenosine Triphosphate; Animals; Arteries; Bile; Blood; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Endotoxins; Gases; Liver; Liver Circulation; Male; Microcirculation; Necrosis; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A

Among our cases of IgA glomerulonephritis (IgAGN), 10% show necrotizing/extracapillary lesions involving a small percentage of glomeruli and associated with a certain degree of inflammation in absence of glomerular and interstitial scarring. In our experience, also in repeat biopsies, these cases of IgAGN have a worse prognosis probably because necrotizing/extracapillary lesions can repeat and accumulate, leading to the progression of damage. As it is well known that transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) are key-factors in the progression of glomerulonephritis, aim of the study was to examine their expression in renal biopsies of primary IgAGN with necrotizing/crescentic lesions in complete absence of interstitial fibrosis. To obtain information about the mitogenic effect of ET-1, the expression of c-fos, whose upregulation by ET-1 has been established in culture, was also studied.. Eighteen renal biopsies of patients with necrotizing/crescentic IgAGN were examined by immunohistochemistry with antibodies against TGF-beta, ET-1 and c-fos. The results were compared with those obtained on 22 cases of IgAGN characterized only by pure mesangial proliferation and 25 IgAGN biopsies with advanced, not active, glomerulointerstitial lesions.. In necrotizing/crescentic IgAGN glomerular TGF-beta appeared more positive than in cases characterized only by pure mesangial proliferation and was especially expressed on cellular crescents. In the interstitium, TGF-beta, ET-1 and c-fos were expressed by infiltrating leukocytes, tubules, and small vessels. This positivity, although similar as localization, was less diffuse than in biopsies with advanced interstitial damage, but significantly greater than in cases with pure mesangial proliferation.. Positivity of TGF-beta on cellular crescents is similar to that observed from other authors in different types of necrotizing/crescentic human glomerulonephritis and supports our hypothesis that this is a peculiar type of IgAGN. Moreover, interstitial expression of TGF-beta, ET-1 and c-fos in biopsies with glomerular active lesions but complete absence of interstitial fibrosis may potentially represent a signal of activation of mechanisms that induce and amplify the damage leading to further progression of the disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Endothelin-1; Female; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunohistochemistry; Kidney Glomerulus; Male; Middle Aged; Necrosis; Proto-Oncogene Proteins c-fos; Transforming Growth Factor beta

Portal hypertension predisposes gastric mucosa to increased injury by various noxious factors. Because endothelin-1 (ET-1) is a potent vasoconstrictor that enhances gastric mucosal injury, we examined ET-1 expression in the portal hypertensive (PHT) gastric mucosa and its possible role in increased mucosal susceptibility to damage.. In gastric specimens of PHT or sham-operated rats, ET-1 mRNA expression was studied by S1-nuclease protection assay and ET-1 protein by enzyme immunoassay and immunostaining. We also determined the extent of ethanol-induced gastric mucosal necrosis in PHT and sham-operated rats after administering either a placebo or FR 139317, a selective ETA receptor antagonist.. In PHT stomachs ET-1 mRNA expression and protein concentration were significantly increased compared with sham-operated controls: mRNA expression (ET-1/glyceraldehyde-3-phosphate-dehydrogenase ratio), 0.54 +/- 0.18 versus 0.30 +/- 0.08; protein concentration, 7.36 +/- 2.21 pg/mg versus 3.93 +/- 0.40 pg/mg, respectively; both p < 0.01. Immunofluorescence signal of ET-1 protein was predominantly localized to endothelia of gastric mucosal and submucosal vessels. In PHT stomachs FR 139317 significantly reduced mucosal necrosis (percentage of necrotic area, from 24.9 +/- 5.9% to 10.8 +/- 4.0%; p < 0.01), although it had no effect on sham-operated controls.. Portal hypertension activates the ET-1 gene with overexpression of ET-1 protein in the gastric mucosa. Protection of PHT gastric mucosa by ETA receptor antagonist against damage indicates that overexpression of ET-1 plays an important role in increased susceptibility of PHT gastric mucosa to injury.

Topics: Animals; Azepines; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Ethanol; Gastric Mucosa; Glyceraldehyde-3-Phosphate Dehydrogenases; Hemodynamics; Hypertension, Portal; Indoles; Necrosis; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Transcription, Genetic; Veins; Venules

Widespread digital ischemic changes and gangrene of the hands and feet is an uncommon but dramatic presentation in patients with human immunodeficiency virus (HIV) infection. We describe a patient in whom these clinical findings were associated with elevated serum endothelin levels. Because endothelin may affect the fibrinolytic system, we elected to treat with tissue plasminogen activator (tPA), which resulted in salvage of tissue of the fingers and toes. Patients with HIV infection with widespread ischemic necrosis and gangrene may require treatment with corticosteroids (in the event of possible vasculitis), thrombolytic agents (for the thrombotic component), or both, unless there are contraindications to either.

Topics: Acquired Immunodeficiency Syndrome; Adult; Endothelin-1; Fingers; Gangrene; Humans; Ischemia; Male; Necrosis; Recombinant Proteins; Tissue Plasminogen Activator; Toes