Blood pressure and vascular effects of endothelin blockade in chronic nitric oxide-deficient hypertension.
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(omega)-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.
Moreau
P
P
University Hospital, Bern, Switzerland.
Takase
H
H
Küng
C F
CF
Shaw
S
S
Lüscher
T F
TF
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D009569:Nitric Oxide; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester