Phosphoramidon inhibits the conversion of intracisternally administered big endothelin-1 to endothelin-1.
It is suggested that endothelin-1 (ET-1), a potent vasoconstrictor peptide, is involved in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). We examined the effects of intracisternal administration of big ET-1 on the cerebral arteries in the absence or presence of pretreatment with phosphoramidon, an inhibitor of ET converting enzyme, in anesthetized dogs. After intracisternal administration of big ET-1 (10 micrograms/dog), the caliber of the basilar artery on the angiogram was decreased to about 59% of the control. This was accompanied by a marked increase in immunoreactive ET in the cerebrospinal fluid. Systemic arterial pressure was markedly elevated following big ET-1 injection. All changes induced by big ET-1 were effectively prevented with phosphoramidon. These data suggest that intracisternally administered big ET-1 is converted to ET-1 and that the generated ET-1 produces cerebral vasospasm and hypertension. A phosphoramidon-sensitive metalloproteinase appears to contribute to this conversion.
Shinyama
H
H
Central Research Laboratory, Green Cross Corporation, Osaka, Japan.
Uchida
T
T
Kido
H
H
Hayashi
K
K
Watanabe
M
M
Matsumura
Y
Y
Ikegawa
R
R
Takaoka
M
M
Morimoto
S
S
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D019332:Endothelin-1; D016232:Endothelins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006020:Glycopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D011498:Protein Precursors / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D013238:Stereotaxic Techniques
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D008666:Metalloendopeptidases; C008890:phosphoramidon