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1 Preclinical Cardiology,
The role of
endothelin (ET)-1 in blood pressure homeostasis and the interaction
with the renin-angiotensin system (RAS) was investigated in
normotensive conscious dogs. ETA
receptors were blocked by LU-135252 (1-30 mg/kg); trandolapril (2 mg/kg) or losartan (10 mg/kg) was used to inhibit the RAS. LU-135252 in
oral doses of 3-30 mg/kg significantly reduced mean arterial
pressure (MAP) by ~10 mmHg maximally, whereas trandolapril or
losartan were without any effect. MAP reduction was more pronounced
when LU-135252 was combined with either losartan (
15.5 ± 3.2 mmHg; 2 h postadministration; P < 0.05) or trandolapril
(30.9 ± 3.6 mmHg; P < 0.05). When endogenous nitric oxide (NO) generation was blocked but NO
concomitantly infused, this synergistic effect on MAP was prevented.
The data show that ET-1 contributes to the maintenance of blood
pressure via ETA receptors.
Furthermore, ET-1 and ANG II play a prominent role in the control of
blood pressure by opposing the effects of NO. The pronounced blood
pressure fall after combined blockade of
ETA receptors and the RAS may be
mediated by an enhanced release of NO.
angiotensin II receptor blockade; endothelin receptor blockade; angiotensin-converting enzyme inhibition; nitric oxide
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