The single
oral administration of a mixed
endothelin-A-and -B- (ETA/ETB) receptor antagonist,
J-104132 (L-753,037) decreased the blood pressure in conscious spontaneously hypertensive rats (SHR),
stroke-prone SHR (SHRSP) and Dahl
salt-sensitive hypertensive rats fed high-
salt diet (DS-H) at doses of 3 and 10 mg/kg, with a duration of approximately 24 h. The magnitude of the
antihypertensive effects was greater in DS-H than in SHR and SHRSP
Preproendothelin-1 mRNA expression in the kidney and aorta was greater (about twofold) in DS-H than that in nonnotensive Dahl salt-resistant rats fed high-
salt diet (DR-H), while there was no difference in
preproendothelin-1 mRNA expression between SHR and Wistar Kyoto rats (WKY). An AT1-receptor antagonist,
MK-954 (
Losartan), also attenuated
hypertension in SHR and SHRSP at oral doses of 3 and 10 mg/kg, but bad no effect in DS-H. The concomitant treatment with
MK-954 and
J-104132 showed additive
antihypertensive effects in SHR and SHRSP. In DS-H,
MK-954 potentiated the
antihypertensive effects of
J-104132. From these results, we suggest that: (1) the contribution of
endothelin (ET) to the maintenance of
hypertension is greater in
salt-sensitive hypertensive models than in SHR and SHRSP; (2) the
antihypertensive efficacy of ETA/ETB blockade is augmented by AT1-receptor blockade; (3) ET blockers alone or in combination with AT1 antagonists could be useful in the treatment of
hypertension for patients who do not respond adequately to renin-angiotensin system inhibitors alone.