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(Hypertension. 1997;29:763-769.)
© 1997 American Heart Association, Inc.

Articles

Blood Pressure and Vascular Effects of Endothelin Blockade in Chronic Nitric Oxide–Deficient Hypertension

Pierre Moreau; Hiroyuki Takase; Christoph F. Kung; Sidney Shaw; Thomas F. Luscher

the Cardiology, Cardiovascular Research, and Hypertension Division (S.S.), University Hospital, Bern, Switzerland.

Because nitric oxide inhibits the synthesis and vasoconstrictor effect of endothelin-1, the effect of endothelin-1 may be enhanced under conditions of chronic inhibition of nitric oxide synthesis. We studied the effect of chronic therapy with bosentan, a combined endothelin-A/endothelin-B receptor antagonist, on blood pressure and vascular function and structure of small arteries as well as on the reactivity of the aorta in N-nitro-L-arginine methyl ester (L-NAME)–induced hypertension. Six-week-old Wistar-Kyoto rats were randomly treated for 6 weeks with placebo (control), L-NAME (70 mg/kg per day), or L-NAME plus bosentan (100 mg/kg per day). The treatments were stopped 2 to 3 days before the in vitro experiments so that only the long-term effects of the drugs could be observed. L-NAME increased systolic blood pressure; bosentan did not prevent this effect although the initial blood pressure rise was delayed (P=NS versus L-NAME group). Bosentan administration did not modify the structural alteration of the resistance vessels induced by L-NAME, nor did it improve endothelium-dependent relaxation of resistance vessels or the aorta. However, bosentan therapy markedly increased endothelium-dependent contraction to acetylcholine, which was slightly enhanced by L-NAME. In contrast, bosentan inhibited aortic endothelium-dependent contractions when applied acutely in vitro. This observation, together with the increased maximal vasoconstriction to the thromboxane A₂ receptor agonist U46619 after 2 weeks of bosentan administration, suggests that bosentan also interacts with the receptors mediating endothelium-dependent contractions. In conclusion, our experiments suggest a minor role of endothelin in chronic L-NAME–induced hypertension as well as in the concomitant alterations of vascular structure.

Key Words: endothelins • hypertension, experimental • blood vessels

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