Mechanisms of altered sensitivity to endothelin-1 between aortic smooth muscles of spontaneously hypertensive and Wistar-Kyoto rats.

Endothelin-1 (ET-1) caused a dose-dependent vasoconstriction in rat aortic strips in vitro. The sensitivity to ET-1 was significantly higher in 12-week-old spontaneously hypertensive rats (SHR) than in age-matched Wistar-Kyoto (WKY) rats. In contrast, the sensitivity was not different between SHR and WKY rats at 6 weeks of age, which was close to that of 12-week-old SHR. Receptor binding study in microsomal preparations of the aortas with [125I]ET-1 showed that maximum binding value for ET-1 receptor in 12-week-old SHR was only 1.5-fold greater than that in WKY rats and that there was no significant difference in the Kd values. K(+)-depolarization induced vasoconstrictive responses that were also augmented in 12-week-old SHR. Resting membrane potential of the aorta was significantly depolarized in tissues from 12-week-old SHR compared with age-matched WKY rats. The resting membrane potentials were similar in the aorta from 6-week-old SHR and WKY rats, and were between those of 12-week-old SHR and WKY rats. When the aortic strips from 12-week-old WKY rats were partially depolarized in high K(+)-solution or in the presence of ouabain (0.1 mM), the vasoconstrictor effect of ET-1 became similar to that on the strips from SHR in a normal solution. These results suggest that, although age-dependent changes appear to be complicated, the lower resting membrane potential may account considerably for the larger sensitivity to ET-1 in the aorta from 12-week-old SHR than that from age-matched WKY rats.