Significance of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats : renal and hemodynamic effects of endothelin receptor antagonists

The renal endothelin (ET) system has been implicated in the maintenance of hypertension in spontaneously hypertensive rats (SHRs). However, little is known about the expression and cellular distribution of the ET receptor subtypes in the kidney of SHRs. We therefore analyzed the expression of ET receptor subtypes in the kidneys of 16-week-old SHRs. Wistar-Kyoto (WKY) rats served as controls. Furthermore, we investigated the effects of the ET A receptor antagonist BQ 123 and the mixed (ET A /ET B ) receptor antagonist bosentan on mean arterial blood pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) in conscious, chronically instrumented rats. In SHRs we found overexpression of the ET A in the glomeruli and smooth muscle cells of intrarenal arteries compared to age-matched WKY rats. Furthermore, our study revealed a pronounced upregulation of the ET B in the glomeruli of SHRs. Blockade of ET A and ET B receptors in SHR with bosentan as well as with BQ 123 led to a significant decrease in MAP and a significant increase in RBF, indicating that the ET A receptor plays a major role in the maintenance of high blood pressure and the regulation of RBF in SHRs. The blockade of both ET A and ET B receptors by bosentan has no further effect on MAP reduction or increase in RBF in SHRs compared to ET A blockade by BQ 123. In contrast, combined blockade of ET A and ET B receptors by bosentan significantly decreased GFR in SHRs, whereas no effect on GFR was observed in WKY rats, suggesting that the glomerular ET B overexpression in SHRs is of pathophysiologic relevance.