Down-regulation of ETA receptors in ETB receptor-deficient mice

Autoradiographical images of whole body sections from control mice (29 +/- 3 days old) revealed high ETA densities within the cardiovascular system, with ETB receptors predominating in the kidney. A similar distribution of ETA receptors was found in ETB-deficient mice (25 +/- 2 days old) but the density was reduced in peripheral tissues including the heart and vessels. ETB receptors were not detected in any animal, confirming gene deletion. In the central nervous system, ETA receptors localized to the cerebral vasculature of controls, with lower levels in brain regions including the molecular layer of the cerebellum. The highest ETB densities were also in the cerebellum, but to the granular layer. A similar pattern of ETA binding was detected in brain regions from knockout animals but the density was reduced. BQ3020 competed biphasically for [I]-endothelin-1 binding to control brains: KDETB = 9.3 +/- 5.4 nM, Bmax = 48.7 +/- 5.8 fmol/mg protein; KDETA = 2.1 +/- 0.8 microM, Bmax = 32.7 +/- 6.3. In knockout mice, only ETA receptors could be detected (KDETA = 1.9 +/- 0.7 microM) and the receptor density (18.2 +/- 1.9 fmol/mg protein) was significantly reduced by 45%. These results reveal deletion of the ETB subtype is associated with a reduction in both central and peripheral ETA number, and may reflect an unsuspected role for ETB receptors in regulating development or expression of the ETA subtype.