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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 myosin light chain 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 endothelin-1 (ET-1) 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 myosin light chain. In the permeabilized preparation, hydroxyfasudil inhibited the contraction induced by ET-1, guanosine 5'-O-(3-thiotriphosphate), or the catalytic subunit of rho-associated kinase, but it did not inhibit Ca2+-induced contraction under the condition of inhibited myosin light chain phosphatase. 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 myosin light chain phosphatase through the inhibition of rho-associated kinase and that this effect depends on the intracellular ATP concentration.

Hydroxyfasudil, an Active Metabolite of Fasudil Hydrochloride, Relaxes the Rabbit Basilar Artery by Disinhibition of Myosin Light Chain Phosphatase