Inhibition of overexpression of endothelin-1 by an RNA synthesis inhibitor, doxorubicin, in the rat vasospasm model

There are three isoforms of endothelin (ET) such as ET-1, ET-2, and ET-3, and the vascular endothelium expresses only ET-1 binding to ET receptor type A of adjacent vascular smooth muscle cells of the vessel wall and causes a potent and sustained contraction [1, 5, 7, 8]. Cerebral vasospasm. after subarachnoid hemorrhage (SAH) remains one of the major decisive factors in the clinical course of SAH patients and ET-1 has been identified as one of the causative substances [5, 8]. It has been reported that a non-specific RNA synthesis inhibitor, dactinomycin (actinomycin-D), aimed to suppress de novo synthesis of peptides including ET-1, almost completely prevented cerebral vasospasm in the dog two-hemorrhage model [6], and that ET receptor antagonists and ET-converting-enzyme blockers attenuated cerebral vasospasm in various animal SAH models [8]. However, the spasm-preventive effect of dactinomycin [6] seems to be much more potent than that of ET receptor antagonists or ET-converting-enzyme blockers so far tested. Considering the possibility of clinical use of RNA synthesis inhibitors, which have been used as anti-cancer drugs for long time, we previously examined the therapeutic dose and timing of administration of dactinomycin and other RNA synthesis inhibitors and found that doxorubicin (DOX) is more effective than dactinomycin [2]. In the present study, by a method of reverse transcription polymerase chain reaction (RT-PCR), we investigated whether mRNA of ET-1 is effectively inhibited by DOX.