Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats.
OBJECTIVE
The renal endothelin system has been implicated in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). However, little is known about the function and cellular distribution of endothelin receptor subtypes in the kidneys of SHR.


METHODS
We analyzed the expression of endothelin receptor subtypes in the kidneys of 16-week-old SHR using Scatchard analysis, receptor autoradiography, Northern blot analysis and in situ hybridization. Wistar-Kyoto rats (WKY) served as controls. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan and the ETA receptor antagonist BQ 123 on mean arterial blood pressure (MAP), renal blood flow (RBF) and glomerular filtration rate (GFR) in conscious chronically instrumented rats.


RESULTS
In SHR, we found by receptor autoradiography an overexpression of the endothelin A receptor (ETA) in the glomeruli (2.2 +/- 0.4-fold; P < 0.05) and smooth muscle cells of intrarenal arteries (1.9 +/- 0.2-fold; P < 0.05) compared to age-matched WKY. In addition, our study revealed a pronounced upregulation of endothelin B receptor (ETB) in the glomeruli of SHR (5.6 +/- 0.8-fold; P < 0.01). Blockade of endothelin receptors in SHR with bosentan (A and B receptor blockade) as well as with BQ 123 (A receptor blockade) led to a significant decrease in MAP (-18.6 +/- 2.1 and -19 +/- 1.3 mmHg, respectively; P < 0.05 in both cases) and a significant increase in RBF (+2.8 +/- 0.5 and +3.1 +/- 0.37 ml/min, respectively; P < 0.05 in both cases). The blockade of both ETA and ETB by bosentan had no further effect on MAP reduction or RBF increase in SHR compared to the ETA blockade by BQ 123. The ETA antagonist BQ 123 had no effect on GFR either in SHR or in WKY, whereas the combined blockade of ETA and ETB by bosentan significantly decreased GFR in SHR by about 50% but not in WKY.


CONCLUSIONS
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.
Hocher
B
B
Department of Nephrology, Universitätsklinikum Charité der Humboldt Universität zu Berlin, City, Germany.
Rohmeiss
P
P
Zart
R
R
Diekmann
F
F
Vogt
V
V
Metz
D
D
Fakhury
M
M
Gretz
N
N
Bauer
C
C
Koppenhagen
K
K
Neumayer
H H
HH
Distler
A
A
D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism*; D017403:In Situ Hybridization; D007668:Kidney / Q000737:chemistry / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000737:chemistry; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000737:chemistry; D010456:Peptides, Cyclic / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)