In conclusion the present study shows

In conclusion, the present study shows that the endothelin system is of importance in the cardiopulmonary vascular pathophysiology of porcine endotoxin shock. In this model, combination of a selective endothelin ETA and a selective endothelin ETB receptor antagonist markedly improved pulmonary circulation, cardiac performance and the metabolic condition. In bright contrast, selective endothelin ETB receptor antagonist alone had detrimental effects resulting in cardiovascular collapse. A possible mechanism is increased endothelin ETA receptor-mediated events due to decreased clearance from endothelin ETB receptors. Previous results in an identical model using selective endothelin ETA receptor antagonism showed effects mainly limited to the pulmonary circulation. These results show the importance of the balance between the different endothelin receptor subtypes and that this has to be taken in consideration when discussing interference of the endothelin system as a treatment modality.
Acknowledgements
In long-term peritoneal dialysis, chronic scarring of the peritoneal membrane may result in treatment failure . The mechanisms involved in the initiation and progression of peritoneal fibrosis are not well understood. The dialysate is not a physiologic fluid and may play an important role. The high glucose concentrations may alter mesothelial cell function , , and trigger the release of profibrotic mediators , , . Alternatively, the high osmolarity could play a role , . Multiple exchanges must be performed throughout the day with stretching and distension of the mesothelial cells. Conceivably, mechanical forces could be involved. Such forces are important in regulating cell proliferation and differentiation in various Benazepril HCl including endothelial cells , , vascular smooth muscle cells , cardiac myocytes , and pulmonary mesothelial cells . We recently reported on the effects of dwell volume and osmolarity of peritoneal dialysate on peritoneal endothelin-1 (ET-1) release in stable peritoneal dialysis patients . We found that increasing dwell volumes from 1500mL to 2500mL per dwell led to a significant increase in peritoneal ET-1 release. Furthermore, changing the dialysate glucose concentration from 1.36% to 3.86% activated the peritoneal ET-system. Since endothelin is known to exert substantial profibrotic properties , , we reasoned that volume and osmolarity-induced ET-1 release might play a role in the process of fibrotic remodeling. To test this notion further, we have conducted a series of experiments in cultured HPMCs. METHODS
STATISTICS Statistical analysis was carried out with the SPSS System (Release 10.0). Only nonparametric tests were used for comparison. The Mann-Whitney U test was used for unpaired data, the Wilcoxon signed rank test was used for paired data. Results are expressed as mean ± SE. A P value <0.05 was regarded as significant.
RESULTS
DISCUSSION In good agreement with other studies 19., 20., 21., we could also demonstrate that high glucose concentrations induce synthesis of transforming growth factor-β (TGF-β) in HPMCs (data not shown). TGF-β is a well-known stimuli of endothelin [22]. Thus, the observed activation of the endothelin system might be, at least partially, secondary to the enhanced TGF-β release. ET-1 has shown to directly stimulate collagen I synthesis in vascular smooth muscle cells from coronary arteries and the aorta [17]. Furthermore, ET-1 stimulates fibrogenic activity in various organs by regulating production and turnover of matrix components [23]. ET-1 is implicated in fibrotic diseases such as systemic sclerosis 24., 25., pulmonary fibrosis [26], and hepatic fibrosis [27]. Moreover, ET-1 overexpression in transgenic mice [16] and ET-2 in transgenic rats [28] causes renal fibrosis. These observations would support a possible mechanistic role of ET-1 in peritoneal fibrosis. We recently observed that by increasing the dwell volume or the glucose-induced osmolarity of the peritoneal dialysis fluid, we could activate the peritoneal paracrine endothelin system [15]. Our present findings suggest glucose and fluid shear stress are the primary triggers. In addition, we present evidence that links the activated mesothelial endothelin system to the profibrotic process within the peritoneum. Glucose is known as a potent stimulant for the paracrine ET-system 16., 29., 30.. Furthermore, high glucose concentrations may enhance ET-1 promoter activity in primary mesangial cells [31]. In experimental animal models of diabetes, blocking the ET-system has shown to ameliorate glucose-induced end organ damage 32., 33., 34..