Cerebrovascular effects of endothelin-3: Modulation of contraction by nitric oxide is independent of endothelin B receptor activation

In cerebral arteries, endothelin (ET)-3 induces relaxation in a low concentration range by activating ET(B) receptors located on the endothelium and, at higher concentrations, contraction by activating ET(A) receptors located on smooth muscle cells. The interaction of these receptors has been investigated in the present study by measuring isometric force in ring segments of basilar arteries obtained from male normotensive rats. In precontracted arteries, the ET(A) receptor antagonist BQ-123 markedly enhanced the relaxant effect of ET-3, while the ET(B) receptor antagonist BQ-788 appeared to exert a competitive antagonism. Under resting tension, the contractile action of ET-3 was enhanced following nitric oxide synthase inhibition and endothelium denudation but not in the presence of ET(B) receptor antagonists. These results suggest i. the relaxant effect of ET-3 is decreased by ET(A) receptor activation, ii. a functionally intact endothelium shifts the contractile action of ET-3 towards higher concentrations, and iii. the inhibitory effect of the endothelium on ET-3 induced contraction is independent of ET(B) receptor activation. The main action of ET-3 in the cerebral circulation thus appears to be relaxant, and blockade of this effect may not be desirable in pathological conditions in which the release of ET-3 is increased.