Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries |
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Authors: | J Petersson G C Hanson B F Lindberg E D Högestätt |
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Institution: | (1) Department of Neurology, University Hospital, Matmö, Sweden;(2) Department of Clinical Pharmacology, Institute of Laboratory Medicine, University Hospital, S-221 85 Lund, Sweden |
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Abstract: | The effect of big endothelin-1 (big ET-1) and its conversion to endothelin-1 (ET-1) in rabbit cerebral arteries were examined. Big ET-1 and ET-1 induced concentration-dependent contractions in the basilar artery; ET-1 was approximately 8 times more potent than big ET-1. The metalloprotease inhibitor phosphoramidon (30 ol/1) almost abolished the contractile response to big ET-1, whereas the ET-1-induced contraction 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 induced by big ET-1, ET-1 and ET-3 were all inhibited by the ETA receptor antagonist BQ 123 (3 mol/l). The ETB receptor antagonist IRL 1038 (3 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 contraction. Formation of ET-1 was demonstrated in membrane fractions of cerebral arteries incubated with big ET-1 as measured by high pressure liquid chromatography followed by radioimmunoassay. These results suggest that externally applied big ET-1 is converted to ET-1 by a phosphoramidon-sensitive endothelin converting enzyme present in the vascular smooth muscle cells. The ET-1 formed subsequently mediates the big ET-1-induced contraction by activation of mainly ETA receptors, although a small contribution of ETB receptors cannot be excluded. |
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Keywords: | Cerebral arteries Endothelin converting enzyme Endothelin receptors Endothelins Phosphoramidon Vascular endothelium |
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