Cardiovascular effects of endothelin-1 and endothelin antagonists in conscious, hypertensive ((mRen-2)27) rats

1 SB 209670 is a potent antagonist of the vasoconstrictor (ETA- and ETB-rec eptor-mediated) and vasodilator (ETB-receptor-mediated) effects of endothel in, whereas SB 234551 is relatively selective for the constrictor (ETA-rece ptor-mediated) effects. Since we had previously found SB 209670 exerted ant ihypertensive, vasodilator effects in conscious, heterozygous, transgenic ( (mRen-2)27) (abbreviated to TG) rats, here we compared the two antagonists in that model, and assessed their chronic effects on responses to exogenous endothelin-1. We did this to test our global hypothesis, namely, that SB 2 09670, but not SB 234551, would cause inhibition of the depressor effects o f exogenous endothelin-1 in vivo, and that this differential effect would b e associated with a more marked antihypertensive action of SB 234551 in TG rats. 2 SB 209670 and SB 234551 (infused for 50 h) exerted similar, sustained, an tihypertensive effects in TG rats. 3 The antihypertensive effects of the antagonists occurred at times when th e presser effects of exogenous endothelin-1 were not significantly inhibite d. Furthermore, SB 234551 did not exert a greater antihypertensive effect t han SB 209670 at a time (i.e., 2-4 h) when the depressor effects of endothe lin-1 were abolished by the latter, but not by the former (although this di fferential action was lost after 24 h infusion). 4 The results caused us to reject the hypothesis that selective antagonism of the vasoconstrictor effects of endothelin-1 would result in SB 234551 ex erting a greater antihypertensive effect than SB 209670 in TG rats.