Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz.
Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz.
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发表时间：
1998-05
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通讯作者：
M. Nakatsuka;K. Nakatsuka;Y. Osawa
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作者：
M. Nakatsuka;K. Nakatsuka;Y. Osawa
胍那苄（Wytensin）在体外和体内显示出降低一氧化氮合酶（NOS）活性。在使用阴茎组织胞质组分的体外研究中，发现灭活取决于NADPH、时间和胍那苄浓度。精氨酸的L-异构体（而非D-异构体）可保护细胞免于失活，表明活性位点定向事件。失活的动力学可以描述为初始可逆复合物（Ki）和伪一级失活常数（kinact）分别为38.5 μ M和0.179 min-1的表观解离常数。在体内研究中，胍那苄以剂量和时间依赖性方式抑制阴茎胞质NOS活性。用胍那苄（5 mg/kg/天）治疗大鼠4天，导致阴茎胞质组分的NOS活性降低约一半，同时免疫可检测NOS蛋白量减少。治疗4天，剂量为0。5 mg/kg/天剂量组显示出类似的活动减少，而0.05 mg/kg/天剂量组显示无影响。由于NO调节的过程众多，NOS的失活是与药物相关的各种生物学效应中要考虑的潜在机制。
Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase (NOS) activity in vitro and in vivo. In in vitro studies with the use of a cytosolic fraction from penile tissue, the inactivation was found to depend on NADPH, time, and the concentration of guanabenz. The L-, but not the D-, isomer of arginine could protect from the inactivation, suggesting an active site-directed event. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (kinact) of 38.5 microM and 0.179 min-1, respectively. In in vivo studies, guanabenz was shown to inhibit penile cytosolic NOS activity in a dose- and time-dependent manner. Treatment of rats with guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately one-half in the NOS activity of the penile cytosolic fraction with a concomitant loss in the amount of immunodetectable NOS protein. Treatment for 4 days at a dose of 0. 5 mg/kg/day showed a similar decrease in activity, whereas a dose of 0.05 mg/kg/day showed no effects. Due to the multitude of processes that are regulated by NO, the inactivation of NOS is a potential mechanism to be considered in a variety of biological effects associated with drugs.