Effects of endothelin-1 on norepinephrine-induced vasoconstriction in deoxycorticosterone acetate-salt hypertensive...

We investigated the effects of endothelin-1 on pressor responses to norepinephrine in perfused mesenteric arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The response to norepinephrine (10(-6) M) was significantly increased in DOCA-salt rats compared with that in uninephrectomized control rats. Perfusion of the arteries with subpressor dose of endothelin-1 (3 x 10(-10) M) for 15 min markedly enhanced the pressor responses to norepinephrine (10(-6) and 3 x 10(-6) M) in control rats and this effect was significantly prevented by BQ788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1-methoxycarbonyl-tryptophanyl-D-norleucine] (10(-6) M), but not by FR139317 ((R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-+ ++methylpentanoyl]amino-3-[3-(1-methyl-1H-indoyl)]propionyl]ami no-3-(2-pyridyl)propionic acid) (10(-6) M). In DOCA-salt hypertensive rats, increased pressor response to norepinephrine was declined to the level of control rats by BQ788, but not by FR139317. In contrast to the case seen with control rat, exogenous endothelin-1 had little effect on pressor responses to norepinephrine in the arteries of DOCA-salt hypertensive rats. Total immunoreactive endothelin content in the arteries of DOCA-salt hypertensive rats was significantly higher than that of uninephrectomized control rats. These results suggest that endothelin-1 enhances contractile responses to norepinephrine through endothelin ETB receptor. Moreover, this phenomenon is stimulated tonically by endogenous endothelin-1 in DOCA-salt hypertensive rats and may contribute to the maintenance of hypertension in DOCA-salt rats.