Characteristics of endothelin receptors in the central nervous system of spontaneously hypertensive rats

Abstract

The binding of [ 125I]sarafotoxin 6b (SRT 6b) and [ 125I]endothelin-1 (ET-1) to endothelin (ET) receptors of neuronal membranes prepared, from regions of the brain and spinal cord of 8 week-old, spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. Spontaneously hypertensive rats had significantly higher blood pressure as compared to WKY rats. Heart rate was similar in SHR and WKY rats. [ 125I]SRT 6b and 125I]ET-1 bound to the membranes of the cerebral cortex, hypothalamus, ventrolateral medulla, dorsomedial medulla and spinal cord at a single, high affinity site. The K d and B max values of the binding of [ 125I]SRT 6b were found to be similar to binding of [ 125I]ET-1 in all the regions. The concentration-dependent inhibition of binding of [ 125I]ET-1 by unlabeled ET-1, in spinal cord membranes showed an IC 50 value of 2.48 ± 0.72 nM and a K i , value of 2.35 ± 0.68 nM in WKY rats and an IC 50 value of 1.77 ± 0.49 nM and a K i value of 1.68 ± 0.46 nM in SHR rats. On the other hand, the concentration-dependent inhibition of the binding of [ 125I]SRT 6b by unlabeled ET-1, in spinal cord membranes showed an IC 50 value of 12.86 ± 3.09 pM and a K i value of 9.54 ± 2.18 pM in WKY rats, while SHR rats showed an IC 50 value of 10.30 ± 3.26 pM and a K i value of 7.46 ± 2.36 pM. The binding of [ 125I]SRT 6b and [ 125I]ET-1 in the cerebral cortex, dorsomedial medulla and spinal cord membranes was found to be similar in SHR and WKY rats. In the hypothalamus and ventrolateral medulla, the binding of both [ 125I]SRT 6b and [ 125I]ET-1 were decreased in SHR, as compared to WKY rats. The decreased binding of [ 125I]SRT 6b was due to 27.1% and 39.2% decreases in the B max values in hypothalamus and ventrolateral medulla, respectively. The decreased binding of [ 125I]ET-1 was due to 49.8% and 47.5% decreases in the B max values in hypothalamus and ventrolateral medulla, respectively. The K d values were similar in SHR and WKY rats. The endothelin receptors in the hypothalamus and ventrolateral medulla of SHR rats were down-regulated as compared to WKY rats and may be contributing to the regulation of blood pressure.