CHARACTERISTICS OF ENDOTHELIN RECEPTORS IN THE CENTRAL-NERVOUS-SYSTEM OF SPONTANEOUSLY HYPERTENSIVE RATS

The binding of [I-125]sarafotoxin 6b (SRT 6b) and [I-125]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. [I-125]SRT 6b and [I-125]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 [I-125]SRT 6b were found to be similar to binding of [I-125]ET-1 in all the regions. The concentration-dependent inhibition of binding of [I-125]ET-1 by unlabeled ET-1, in spinal cord membranes showed an IC50 value of 2.48 +/- 0.72 nM and a K(i) value of 2.35 +/- 0.68 nM in WKY rats and an IC50 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 [I-125]SRT 6b by unlabeled ET-1, in spinal cord membranes showed an IC50 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 IC50 value of 10.30 +/- 3.26 pM and a K(i) value of 7.46 +/- 2.36 pM. The binding of [I-125]SRT 6b and [I-125]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 [I-125]SRT 6b and [I-125]ET-1 were decreased in SHR, as compared to WKY rats. The decreased binding of [I-125]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 [I-125]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.