CONTRACTILE EFFECT OF BIG ENDOTHELIN-1 AND ITS CONVERSION TO ENDOTHELIN-1 IN RABBIT CEREBRAL-ARTERIES

The effect of big endothelin-1 (big ET-1) and its conversion to endoth elin-1 (ET-1) in rabbit cerebral arteries were examined. Big ET-1 and ET-1 induced concentration-dependent contractions in the basilar arter y; ET-1 was approximately 8 times more potent than big ET-1. The metal loprotease inhibitor phosphoramidon (30 mu mol/l) almost abolished the contractile response to big ET-1, whereas the ET-1-induced contractio n was unaffected. Removal of the endothelium did not attenuate the big ET-1-induced contraction. ET-1 was approximately 14 times more potent than endothelin-3 (ET-3) to elicit contraction. The contractions indu ced by big ET-1, ET-1 and ET-3 were all inhibited by the ET(A) recepto r antagonist BQ 123 (3 mu mol/l). The ET(B) receptor antagonist IRL 10 38 (3 mu mol/l) had no effect on the contractile responses to big ET-1 and ET-1, but produced a small inhibition of the ET-3-induced contrac tion. Formation of ET-1 was demonstrated in membrane fractions of cere bral arteries incubated with big ET-1 as measured by high pressure liq uid chromatography followed by radioimmunoassay. These results suggest that externally applied big ET-1 is converted to ET-1 by a phosphoram idon-sensitive ''endothelin converting enzyme'' present in the vascula r smooth muscle cells. The ET-1 formed subsequently mediates the big E T-1-induced contraction by activation of mainly ET(A) receptors, altho ugh a small contribution of ET(B) receptors cannot be excluded.