Rho-kinase (ROCK) is a serine/threonine kinase that has two isoenzymes, ROCK-1 and ROCK-2. ROCK promotes the assembly of actin stress fibers and focal adhesions and regulates cell contraction and motility. ROCK inhibitor is a derivative of azainolde that inhibits the ROCK-1 and ROCK-2 isoenzymes with IC50 values of 0.6 nM and 1.1 nM in an ATP competitive manner. ROCK inhibitor also inhibits TRK and FLT3 with IC50 values of 252 nM and 303 nM, respectively. In addition, ROCK inhibitor inhibits only moderately the L-type calcium channel and the sodium channel with IC50 values of 6.7 μM and 6.8 μM, respectively. In vitro, ROCK inhibitor concentration-dependently inhibited the phenylephrine-induced contraction of rabbit saphenous artery with an IC50 value of 65 nM. In the rat heart langendorff preparation, administration of 10 nM, 100 nM, 1000 nM of ROCK inhibitor resulted in a reduction of the maximal perfusion pressure of 50%, 60% and 65%, respectively. In vivo, intravenous administration of ROCK inhibitor at dose range from 0.03-0.3 mg/kg lowered blood pressure dose-dependently in anaesthetized normotensive rats. Treatment of the conscious normotensive and spontaneously hypertensive rats with ROCK inhibitor at dose range from 1-10 mg/kg via oral administration induced a dose-dependent reduction of blood pressure, without inducing a significant reflex increase in heart rate. In addition, intravenous administration of ROCK inhibitor at dose of 0.1 and 0.3 mg/kg decreased mean arterial blood pressure in anaesthetized dog[1].
作用机制
ROCK inhibitor interacts with the ATP-binding site of ROCK and interferes with ATP binding in a competitive manner[1].
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