Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Elevation of circulating big endothelin-1: an independent prognostic factor for tumor recurrence and survival in patients with esophageal squamous cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Endothelin(ET) axis plays a key role in many tumor progression and metastasis via various mechanisms such as angiogenesis, mediating extracellular matrix degradation and inhibition of apoptosis. However, there is limited information regarding the clinical significance of plasma big ET-1 levels in esophageal cancer patients. Circulating plasma big ET-1 levels were measured in patients with esophageal squamous cell carcinoma(ESCC) to evaluate the value of ET-1 as a biomarker for predicting tumor recurrence and patients survival.</p> <p>Methods</p> <p>Preoperative plasma big ET-1 concentrations were measured by an enzyme linked immunosorbent assay(ELISA) in 108 ESCC patients before surgery, and then again at 1,2,3,10 and 30 days after curative radical resection for ESCC. The association between preoperative plasma big ET-1 levels and clinicopathological features, tumor recurrence and patient survival, and their changes following surgery were evaluated.</p> <p>Results</p> <p>The preoperative plasma big ET-1 levels in ESCC patients were significantly higher than those in controls. And there was a significant association between plasma big ET-1 levels and disease stage, as well as invasion depth of the tumor and lymph node status. Furthermore, plasma big ET-1 levels decreased significantly after radical resection of the primary tumor and patients with postoperative recurrence had significantly higher plasma big ET-1 levels than that of patients without recurrence. Finally, the survival rate of patients with higher plasma big ET-1 concentrations (>4.3 pg/ml) was significantly lower than that of patients with lower level (≤ 4.3 pg/ml). Multivariate regression analysis showed that plasma big ET-1 level is an independent prognostic factor for survival in patients with ESCC.</p> <p>Conclusion</p> <p>Plasma big ET-1 level in ESCC patients may reflect malignancy and predict tumor recurrence and patient survival. Therefore, the preoperative plasma big ET-1 levels may be a clinically useful biomarker for choice of multimodality therapy in ESCC patients.</p

Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1

The effect of endothelin receptor blockade on the development of the Sephadex-induced inflammation in the rat lung

The non-peptide ET-receptor antagonist Bosentan was used to investigate the role of endogenous endothelin-1 (ET-1) in the development of the Sephadex-induced lung inflammation in the rat. Intratracheal instillation of Sephadex caused a 60-fold rise in endothelin-1-like-immunoreactivity (ET-1-LI) in bronchoalveolar lavage fluid (BALF) concomitant with development of lung oedema, an influx of inflammatory cells into the airways and a rise in the protein content in BALF. The ET-1-LI level in lung homogenate was not significantly affected. Pre-treatment with Bosentan reduced ET-1-LI content in the lung parenchyma but increased ET-1-LI levels in BALF, possibly indicating an effective displacement of ET-1 from its receptors. In Bosentan-treated animals there was an enhancement of the lung oedema formation following Sephadex instillation, but no significant change in the number of leucocytes or protein concentration in BALF. The present data thus do not support the hypothesis that endogenous ET-1 mediates oedema formation or leucocyte influx in this model. If anything, Bosentan enhanced the oedema formation in parallel with increased ET-1-LI in BALF

Aktueller Stand der chirurgischen Expertise bei plastischrekonstruktiven Verfahren im Rahmen tumorchirurgischer Interventionen in den Deutschen Hals-Nasen-Ohrenkliniken

Die ektodermalen Karzinome der Kopf-Hals-Region liegen derzeit an sechster Stelle aller neu diagnostizierten Malignome. In Deutschland wurden im Jahr 2007 annähernd 17.000 Neuerkrankungen diagnostiziert. Die aktuelle Therapie basiert nach wie vor auf den drei Säulen Chirurgie, Strahlentherapie und Chemotherapie, wobei mittlerweile auch die Bedeutung der monoklonalen Antikörper zunimmt. Derzeit zeichnet sich, insbesondere bei den Neoplasien des Pharynx, ein deutlicher Trend hin zu den primär radio-chemotherapeutischen Konzepten ab. In Abhängigkeit von Ausdehnung und Größe der Primärtumore besteht andererseits häufig die Indikation zu primär chirurgischen Maßnahmen, um insbesondere funktionellen und ästhetischen Aspekten Rechnung zu tragen. Darüber hinaus wird die sogenannte Rettungschirurgie in den kommenden Jahren eine zunehmend wichtige Bedeutung im Rahmen der Therapie von Kopf- Hals-Karzinomen erlangen. Hierbei müssen teilweise ausgedehnte Defekte nach ablativen Maßnahmen verschlossen werden. Hierzu eignen sich zahlreiche seit den 1980er Jahren zunehmend populäre gewordene mikrovaskuläre und gefäßgestielte Gewebetransplantate. Durch den Einsatz des genannten Gewebetransfers können mittlerweile umfassende Rekonstruktionen sowohl im Bereich des oberen Aero- Digestivtraktes als auch der Haut mit optimalen funktionellen und ästhetischen Ergebnissen erreicht werden. Aus diesem Grund birgt diese Art der rekonstruktiven Chirurgie eine hohe Attraktivität für Institutionen, in denen onkologische Kopf-Hals-Chirurgie betrieben wird. Die führenden Zentren auf dem Gebiet der insbesondere mikrovaskulär-rekonstruktiven Chirurgie im Kopf-Hals-Bereich befinden sich derzeit unzweifelhaft in Ostasien (Taiwan und China) und Nordamerika. In diesem Zusammenhang stellt sich die Frage nach der aktuellen Expertise in den Deutschen HNO-Kliniken. Ziel der vorliegenden Arbeit ist die Evaluation des hierzulande gegenwärtigen Spektrums der eingesetzten mikrovaskulären und gestielten Transplantate. Bezugszeitraum war das Jahr 2010. Hierzu erfolgte eine retrospektive Fragebogenanalyse. Die Rücklaufquote lag bei 60,4%.Im Beobachtungszeitraum wurde von 12472 neu diagnostizierten Tumoren berichtet. Im gleichen Zeitraum wurden insgesamt 2141 Transplantate durchgeführt, wobei gestielte und mikrovaskuläre Transplantate zu etwa gleichen Teilen eingesetzt wurden. Allerdings muss hierbei berücksichtigt werden, dass Transplantate nicht nur im Rahmen einer primären chirurgischen Therapie sondern insbeondere auch in der Rezidiv- oder Salvage-Situation eingesetzt werden. Der hohe Anteil plastisch-rekonstruktiver Verfahren unterstreicht die Bedeutung des Gewebetransfers im Rahmen der Tumorchirurgie. Während an den Universitätskliniken überwiegend freie Transplantate zum Einsatz kamen (2010: 693 freie versus 499 gestielte Transplantate), ist das Verhältnis in den Hauptabteilungen umgekehrt (2010: 358 freie versus 591 gestielte Transplantate). Durchschnittlich führte somit jede Klinik 22 rekonstruktive Operationen mit mikrovaskulären oder gestielten Transplantaten durch (Universitäts-Klinik: 41, Hauptabteilung: 14). In Abhängigkeit von Art und Größe der Institution sowie der Anzahl der neu diagnostizierten Tumore bestehen signifikante Unterschiede im Hinblick auf die Anzahl der durchgeführten Transplantate. Tendenziell zeichnet sich hier auch ein größerer Anteil plastisch-rekonstruktiver Verfahren im Verhältnis zur Anzahl neu diagnostizierter Tumore ab. Gleiches gilt für den Anteil mikrovaskulär-anastomosierter Lappen an allen Transplantaten. Eine qualitative Aussage über die durchgeführten Operationen lässt sich anhand der vorliegenden Analyse nicht ableiten. Es ist jedoch wahrscheinlich, dass das Outcome der genannten Verfahren mit großer Wahrscheinlichkeit proportional an die Frequenz der jeweiligen Intervention gekoppelt ist. Schlussfolgernd scheint die höchste Expertise bei der Durchführung plastisch-rekonstruktiver Verfahren an den Kliniken vorzuliegen, die mehr als 200 neu diagnostizierte Tumore behandeln und / oder den Universitätsstatus genießen. Gleiches gilt für den hohen Schwierigkeitsgrad bei mikrovaskulären Techniken, die einen hohen Qualitätsstandard erfordern

Release of endothelin-1 into rat airways following Sephadex-induced inflammation; modulation by enzyme inhibitors and budesonide

The intratracheal (i.t.) instillation of Sephadex beads into rat induced inflammation and a 30-fold increase in the endothelin-1-like immunoreactivity (ET-1-LI) of broncho-alveolar lavage fluid. The levels were highest 24 h after the instillation and had declined significantly after 48 h. At a dose of 1 mg kg-1 i.t., the glucocorticosteroid budesonide almost abolished this response. Phosphoramidon, which inhibits neutral endopeptidase, an enzyme reported to degrade ET-1 and also to inhibit the endothelin-converting enzyme, potentiated the Sephadex-induced rise in ET-1-LI. Chymostatin and heparin, which are reported to reduce the formation of ET-1, did not affect the increase in ET-1-LI. The present model represents a very reactive system for analyzing the changes in ET-1 levels during inflammation

Regulatory effects of aerosolized budesonide and adrenalectomy on the lung content of endothelin-1 in the rat

This study was designed to investigate the effect of inflammation and glucocorticosteroids (GCS) on the content of endothelin-1-like immunoreactivity (ET-LI) in the rat lung. Following intratracheal instillation of Sephadex beads, which induces a long-lasting inflammation in the lung, there was an increase in the lung content of ET-LI measured by RIA. This increase was abolished by locally administered aerosolized budesonide at doses that had only minor systemic effects (measured as a reduction in body weight). In a second series of experiments, rats were subjected to surgical adrenalectomy in order to reduce the levels of endogenous GCS. This procedure elevated the ET-LI levels in the lungs. In contrast, neither adrenalectomy nor high doses of budesonide administered systemically affected the concentration of ET-LI in the kidney. It is concluded that the lung ET levels are elevated in inflammatory conditions and that this increase is highly sensitive to locally administered GCS. Endogenous GCS may, directly or indirectly, play a role in the regulation of lung ET content but there seems to be no general GCS effect on basal tissue levels of ET