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 co ncentration range by activating ET(B) receptors located on the endothe lium and, at higher concentrations, contraction by activating ET(A) re ceptors located on smooth muscle cells. The interaction of these recep tors has been investigated in the present study by measuring isometric force in ring segments of basilar arteries obtained from male normote nsive rats. In precontracted arteries, the ET(A) receptor antagonist B Q-123 markedly enhanced the relaxant effect of ET-3, while the ET(B) r eceptor antagonist BQ-788 appeared to exert a competitive antagonism. Under resting tension, the contractile action of ET-3 was enhanced fol lowing nitric oxide synthase inhibition and endothelium denudation but not in the presence of ET(B) receptor antagonists. These results sugg est i. the relaxant effect of ET-3 is decreased by ET(A) receptor acti vation, ii. a functionally intact endothelium shifts the contractile a ction of ET-3 towards higher concentrations, and iii. the inhibitory e ffect of the endothelium on ET-3 induced contraction is independent of ET(B) receptor activation. The main action of ET-3 in the cerebral ci rculation thus appears to be relaxant, and blockade of this effect may not be desirable in pathological conditions in which the release of E T-3 is increased.