Distribution of Endothelin Receptor Subtypes in the Rat Kidney Renal and Haemodynamic Effects of the Mixed (A/B) Endothelin Receptor Antagonist Bosentan

Hocher, Berthold; Rohmeiss, Peter; Diekmann, Fritz; Zart, Rüdiger; Vogt, Volker; Schiller, Sigrid; Bauer, Christian; Koppenhagen, K; Distler, A.; Gretz, Norbert

doi:10.1515/cclm.1995.33.8.463

Cited by 17 publications

(20 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Blocking the ETA receptors might direct ET-1 toward the ETB receptor. The ETB receptor is especially localized on renal tubular cells (26,27 (20,21). HIF might exert further proliferationstimulating effects on the already proliferating tubular cells in ADPKD rats.…”

Section: Discussionmentioning

confidence: 99%

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Hocher¹,

Kalk²,

Slowinski³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Abstract. Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 Ϯ 119 [cysts/kidney section Ϯ SD]; LU 135252-treated APKD rats, 1084 Ϯ 314; P Ͻ 0.001), cyst surface area (ADPKD rats, 7.97 Ϯ 2.04 [% of total section surface Ϯ SD]; LU 135252-treated ADPKD rats, 33.83 Ϯ 10.03; P Ͻ 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 Ϯ 17.3 [BrdUpositive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 Ϯ 286.9; P Ͻ 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Hocher¹,

Kalk²,

Slowinski³

et al. 2003

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The single-shot clearance was evaluated by displaying a twocompartment model with resolution of the plasma inulin concentrations into two monoexponential functions. The Nambi et al (1990) and Hocher et al (1995) with minor modifications. Approximately 0.3 g of the kidney was homogenized at 4°C in 20 ml of 20 mmol I' NaHCO3 with a motordriven pestle homogenizer.…”

Section: Light Microscopymentioning

confidence: 99%

“…The [1251I]-ET-I tracer concentration was kept constant at 40,000 c.p.m./tube, while the concentration of unlabelled ET-1 was increased from 0 to 25 nM (competition studies with 'cold saturation'). Samples from crude plasma membranes were used at a concentration of 0.53 mg protein ml-' according to Hocher et al (1992bHocher et al ( , 1995. Binding studies were performed at room temperature for 120 min.…”

Section: Light Microscopymentioning

confidence: 99%

“…Provided that natriuretic peptides also increase the expression of ETB in renal inner medullary collecting duct cells, the increased plasma levels of natriuretic peptides in rats with liver cirrhosis (Gines et al, 1988;Laffi et al, 1989) may contribute to the ETB overexpression. (iii) An upregulation of ETB in the renal medulla was observed in rats with acute renal failure after administration of hypertonic glycerol leading to tissue hypoxia (Roubert et al, 1993a (Hocher et al, 1995) and dogs (Teerlink et al, 1995) thus allowing an independent analysis of tubular functions, whereas ET-l and ETB agonists like sarafotoxin 6c (Warner et al, 1993) markedly decreased renal blood flow thus not allowing an independent analysis of tubular functions. Bosentan differs in its in vivo potency in blocking ETA-and ETBmediated effects.…”

Section: Plasma Et-] Concentrations In Liver Cirrhosismentioning

confidence: 99%

“…Bosentan differs in its in vivo potency in blocking ETA-and ETBmediated effects. Blockade ofET-l-induced EA-mediated effects requires higher dosages of bosentan compared to the blockade of the ET-1-induced ETB-mediated effects (Clozel et al, 1994;Hocher et al, 1995 ET-1 (Hocher et al, 1995). Based on these pharmacological characteristics of bosentan, we demonstrated in our study using both dosages of bosentan that the low bosentan dosage reduced water excretion in cirrhotic rats to an extent similar to that achieved with the higher one, suggesting that the bosentan effect on water excretion is ETB-mediated.…”

Section: Plasma Et-] Concentrations In Liver Cirrhosismentioning

confidence: 99%

See 2 more Smart Citations

Paracrine renal endothelin system in rats with liver cirrhosis

Hocher

Zart

Diekmann

et al. 1996

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Endothelin-induced inositol phosphate formation in rat kidney. Studies on receptor subtypes, G-proteins and regulation during ontogenesis

Becker

Erdbrügger

Heinroth-Hoffmann

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

The aim of this study was to characterize the properties of endothelin (ET)-receptor subtypes mediating inositol phosphate (IP)-formation in rat kidney and their regulation during ontogenesis. In renal cortical slices of adult rats (12-16 weeks old) ET's concentration-dependently increased IP-formation with an order of potency ET-1 >> ET-3. While the non-selective ET-receptor antagonist bosentan (10 microM) completely suppressed ET-induced IP-formation, the ETA-receptor antagonist BQ-123 (10 microM) inhibited it only by 70%, the ETB-receptor antagonist IRL 1038 (1 microM) by 25%; combined application of BQ-123 + IRL 1038 caused complete inhibition of ET-1-induced IP-formation. Pretreatment of isolated renal cells with pertussis toxin (PTX, 500 ng/ml) overnight did not attenuate but significantly increased ET-1-induced IP-formation. Ontogenetic studies in renal sites from neonatal, 1, 2, 3, 6, 12 and 24 weeks old rats revealed that ET-1-induced IP-formation maturation-dependently declined being highest in neonatal rats (increase: 169% over basal) and lowest in 24 weeks old rats (increase: 47% over basal). This decline in ET-induced IP-formation was accompanied by a decrease in renal ET-receptor number and the amount of immunodetectable Gq/11 (assessed by Western-blotting using the QL-antiserum). Moreover, ET-receptor subtypes changed during the maturation process: from neonates to 12 weeks old rats number and functional responsiveness of ETA-receptors declined, while that of ETB-receptors increased. We conclude that in adult rat renal cortex ET-induced IP-formation is mediated by activation of both ETA- and ETB-receptors and does not involve a PTX-sensitive G-protein. ET-induced IP-formation declines during the maturation process; this is associated with a decrease in ET-receptor number and the immunodetectable amount of Gq/11.

show abstract

Distribution of Endothelin Receptor Subtypes in the Rat Kidney Renal and Haemodynamic Effects of the Mixed (A/B) Endothelin Receptor Antagonist Bosentan

Cited by 17 publications

References 27 publications

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Paracrine renal endothelin system in rats with liver cirrhosis

Endothelin-induced inositol phosphate formation in rat kidney. Studies on receptor subtypes, G-proteins and regulation during ontogenesis

Contact Info

Product

Resources

About