Inhibition of vascular contraction by intracisternal administration of preproendothelin-1 mRNA antisense oligoDNA in a rat experimental vasospasm model.
To clarify the role of endothelin-1 (ET-1) in the etiology of hemolysate-induced contraction of vessels, the authors introduced antisense oligoDNA for preproendothelin-1 (ppET-1) messenger RNA in a rat model of vasospasm. Phosphorothioate antisense oligoDNAs for ppET-1 were injected into the cisterna magna. Fluorescein isothiocyanate-labeled phosphorothioate antisense oligoDNAs were proven by fluorescence chasing to be incorporated into the vascular wall. Striking inhibitory effects of experimental vasospasm were observed in the basilar artery (BA) in which the oligoDNAs were injected. The vascular contraction was significantly inhibited by oligoDNAs after 20 minutes of hemolysate exposure, which suggested that ET synthesis started approximately 20 minutes after hemolysate stimulation. Expression of ppET-1 in the BA in which the spasm was inhibited was markedly suppressed at the transcription level. The results indicate that ET-1 may play an important role in hemolysate-induced vasoconstriction in rats. In addition, the antisense approach in the cerebrospinal fluid might be a useful tool for preventing cerebral vasospasm.
Department of Neurological Surgery, Okayama University Medical School, Japan.
K
K
Onoda
S
S
Ono
K
K
Ogihara
T
T
Shiota
S
S
Asari
T
T
Ohmoto
Y
Y
Ninomiya
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D016232:Endothelins; D016376:Oligonucleotides, Antisense; D011498:Protein Precursors