Potential for endothelin-1-mediated impairment of contractile activity in hypertension

The present study examined the potential for reduced exercise capacity observed in hypertensive patients as a result of elevated levels of endothelin (ET)-1. We have previously reported that ET-1 exerts low-dose stimulatory or high-dose inhibitory effects on the metabolism of the rat isolated perfused hindlimb from its vasoconstrictor activity. Herein, we determined whether there are similar effects on tension development by the rat isolated constant-flow hindlimb during ET-1-mediated vasoconstriction. The dose-dependent vasoconstrictor effects of ET-1 on metabolism in contracting muscle were the same as those observed previously in resting muscle. Highest concentrations of ET-1 gave rise to a transient stimulation followed by a marked inhibition of tension development, consistent with a decrease in aerobic capacity of the muscle. The vasoconstriction due to the higher doses of ET-1 was not dilated by electrical stimulation. In conclusion, the biphasic nature of the actions of ET-1 suggests that although lower concentrations of ET-1 do not affect exercise capacity, higher concentrations that may occur in hypertension are inhibitory to metabolism and aerobic capacity of muscle. The inhibitory effects of ET-1 appear to result from enhanced functional shunting