
<ArticleTitle>Hydroxyfasudil, an active metabolite of fasudil hydrochloride, relaxes the rabbit basilar artery by disinhibition of <prot><prot>myosin light chain</prot> phosphatase</prot>.</ArticleTitle>
<AbstractText>Fasudil hydrochloride (AT877, hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, identical to HA1077) inhibits cerebral vasospasm after subarachnoid hemorrhage in experimental animals and humans. In the current study, the vasorelaxing mechanism of hydroxyfasudil, a hydroxylated metabolite of fasudil hydrochloride, was determined in the rabbit basilar artery. The effects of hydroxyfasudil on tension, intracellular Ca2+ concentration ([Ca2+]i), and phosphorylation of the <prot>myosin light chain</prot> were examined using the isolated and intact or permeabilized rabbit basilar artery without endothelium in vitro. In the intact rabbit basilar artery, hydroxyfasudil elicited a concentration-dependent relaxation of the artery precontracted with 1 nmol/L <prot>endothelin-1</prot> (<prot>ET-1</prot>) plus 20 mmol/L KCl without any significant decrease in [Ca2+]i as determined by fura-2 microfluorometry (IC50: 5.1 +/- 4.6 micromol/L). The relaxation induced by hydroxyfasudil was accompanied with dephosphorylation of the <prot>myosin light chain</prot>. In the permeabilized preparation, hydroxyfasudil inhibited the contraction induced by <prot>ET-1</prot>, guanosine 5'-O-(3-thiotriphosphate), or the catalytic subunit of <prot><prot>rho</prot>-associated kinase</prot>, but it did not inhibit Ca2+-induced contraction under the condition of inhibited <prot><prot>myosin light chain</prot> phosphatase</prot>. Hydroxyfasudil showed a greater relaxant effect under decreased adenosine triphosphate (ATP) levels. The present study indicated that hydroxyfasudil relaxes the rabbit basilar artery mainly by disinhibiting <prot><prot>myosin light chain</prot> phosphatase</prot> through the inhibition of <prot><prot>rho</prot>-associated kinase</prot> and that this effect depends on the intracellular ATP concentration.</AbstractText>
