一氧化氮生物系统及其药理学作用.ppt

阴茎勃起生理 大脑或阴茎局部接受性刺激→下丘脑/骶髓低级中枢发出冲动→传至阴茎海绵体→副交感神经末梢及VEC合成释放NO↑→进入SMC→激活鸟苷酸环化酶→cGMP↑→激活PKG→作用于钙离子通道→胞内〔Ca2＋〕↓→平滑肌细胞舒张 一氧化氮：里程碑式的奇迹——勃起功能障碍和一氧化氮（一） 　　大多数患者阳痿的原因是器质性的而不是心理性的——病因常常是血管问题。　 * 一氧化氮：里程碑式的奇迹——勃起功能障碍和一氧化氮（二） 多么令人振奋！ 　　“我是一名34岁男性，患有轻度勃起功能障碍。为了预防心脏病，我开始一氧化氮疗法。不久，我发现我的性生活改善了。在促一氧化氮治疗后3周，我的勃起功能明显改善，4个月后已经完全正常。在预防心脏病的同时还出现了这么惊人的结果，真令人惊奇！” Jerry, 34, Atlantic City * * 阴茎海绵体平滑肌内的cGMP由5型磷酸二酯酶(phosphodiesterase type5, PDE5)降解，而此作用可被药物西地那非（万艾可）特异性地抑制，从而防止NO引发的细胞内cGMP信号快速消失，维持海绵体平滑肌细胞舒张、增加血流量。 * cGMP的合成和降解 GTP GC cGMP PDE5 Ca2+ /Mg2+ 5′- GMP PPi H2O 　PDE 5 主要分布在海绵体组织及血小板中,以cGMP 为特异性底物。 * - * 西地那非 (Sildenafil) * 由于Ignarro教授与Furchgott教授在长期的研究中积累了大量宝贵的经验，同时由于他们具有敏锐的洞察力， * Solid and dashed arrows stand for stimulation and inhibition, respectively. Ang II, via the AT1 receptor coupled to G protein, activates PLC and in turn produces IP3, followed by stimulation of Ca2 mobilization from the IP3 receptor. MLCK is activated by Ca2, and activation of MLCK leads to phosphorylation of MLC and smooth muscle contraction. In addition, Ang II induces Ca2 sensitization of the contractile apparatus through activation of RhoA/Rho kinase and in turn inactivation of MLCP. NO, through activation of sGC, stimulates cGMP production and in turn activates PKG. PKG could reduce Ca2 levels by different mechanisms, including downregulating IP3 production by inhibiting PLC activity, decreasing Ca2 mobilization through the IP3 receptor by phosphorylation of the IP3 receptor and IRAG, promoting Ca2 sequestration by regulating SR Ca2- ATPase activity via phosphorylation of Plb, reducing Ca2 influx by blocking VDCCs, and increasing Ca2 efflux by stimulating cell membrane Ca2-ATPase. In addition, PKG is able to inactivate the RhoA/Rho kinase signaling pathway to inhibit RhoA-induced Ca2 sensitization. Ang II indicates angiotensin II; AT1R, Ang II type 1 receptor; Ca2-ATPase, Ca2-pumping ATPase; Gq, heterotrimeric G protein; IP3, inositol 1,4,5,-triphosphate; IP3R, IP3 receptor; IRAG, IP3