Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory-motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation (P = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.

The present study indicates that long-term blockade of the activated endothelin system in the clipped kidney of rats with renovascular hypertension using an ETA receptor antagonist led to a fibrotic atrophy of the clipped kidney.

Polycystic kidney disease (PKD) is characterized by structural alterations such as thickening of the tubule basement membrane, interstitial fibrosis, and formation of cysts. Han:SPRD rats are a well-known rat model of human PKD. Interestingly, interstitial fibrosis, glomerulosclerosis, and cyst formation were also seen in human endothelin-1 (ET-1) transgenic mice. We therefore analyzed the tissue concentrations of ET-1 and the expression of ET receptor subtypes in the kidneys of young homozygous (cy/cy), heterozygous (cy/+) 6 week-old male Han:SPRD, and corresponding control rats. The kidneys of affected rats showed significantly elevated tissue levels of ET-1 compared to age-matched controls. Scatchard analysis, on the other hand, revealed markedly decreased ETA and ETB receptor density in all groups of affected rats. The binding affinity of both ET receptor subtypes was slightly decreased in Han:SPRD rats. These data show that the renal paracrine ET system is activated in PKD and might contribute to renal cyst formation and development of end-stage kidney disease.

The paracrine renal endothelin system has been implicated in acute and chronic kidney diseases. However, there are only few data about the expression of endothelin receptor subtypes and their impact on renal function in the normal rat kidney. Therefore, we analyzed the age-dependent expression of endothelin receptors (endothelin receptor A and B) using Scatchard analysis, in vitro and in vivo receptor autoradiography. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan on haemodynamic and renal function in conscious chronically instrumented rats. The renal endothelin receptor A and endothelin receptor B expression is age-dependent. The relative amount of endothelin receptor A significantly decreased with age, whereas the endothelin receptor B significantly increased with age. Compared to the other renal structures, a high endothelin receptor density (endothelin receptor B » endothelin receptor A) was seen in the renal tubules and even more in the glomeruli. Bosentan blocks both the pressor and depressor response of endothelin. Blocking of both endothelin receptor subtypes using bosentan without application of endothelin, on the other hand, did not alter blood pressure, heart rate, renal blood flow, water excretion or glomerular filtration rate, but significantly decreased sodium excretion.

Our data demonstrated a correlation between the overexpression of vascular ETA receptors and the pronounced upregulation of glomerular ETB receptors in the kidneys of SHR and their impact on the regulation of renal blood flow, glomerular filtration rate and blood pressure in these animals.

1 Liver cirrhosis was induced in rats by CCL1 administration. We analysed the expression of endothelin receptor subtypes in the renal cortex and medulla using Scatchard analysis and receptor autoradiography, and measured plasma as well as renal-tissue endothelin-1 concentrations using a specific radioimmunoassay. Furthermore, we analysed the effects of the non-selective (A/B) endothelin receptor antagonist, bosentan (6 and 100 mg kg-' day-') on mean arterial blood pressure, water and sodium excretion and glomerular filtration rate. 2 Our study revealed an overexpression of the endothelin B receptor (ETB) in the renal medulla of rats with liver cirrhosis (Cir: 2775+299 fmol mg'-; Con:1695+255 fmol mg'-; n= 8; means+s.d., P<0.01), whereas the density of ETB in the cortex and the endothelin A receptor (ETA) in the cortex and medulla were similar in both cirrhotic and control rats. Receptor autoradiography showed that the upregulation of medullary ETB in cirrhotic rats was due to an upregulation of ETB in the inner medullary collecting duct cells. 3 The tissue endothelin-1 concentrations were increased in the renal medulla of cirrhotic rats (Cir:271+68 pg g-'wet wt.; Con: 153+36 pg g-' wet wt., n=8; means+s.d., P<0.01). 4 The glomerular filtration rate was slightly decreased in cirrhotic rats but not altered after bosentan treatment in either cirrhotic or control rats. Bosentan decreased sodium excretion to a similar extent in both cirrhotic and control rats, whereas water excretion was significantly reduced by both dosages of bosentan in cirrhotic rats only (Cir + vehicle: 12.5 + 0.62 ml day-', Cir + 6 mg kg-day'-bosentan: 8.6+1.0 ml day'-; Cir+ 100 mg kg'-day'-bosentan:7.4+0.6 ml day'-; n= 10; means+s.e.mean). 5 We therefore suggest that the upregulation of the medullary ETB in cirrhotic rats is involved in the regulation of water excretion in rats with CCL-induced liver cirrhosis.

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