Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats
Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats
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DOI：
10.1038/sj.ijir.3901612
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发表时间：
2008-03-01
影响因子：
2.6
通讯作者：
Gonzalez-Cadavid, N.
中科院分区：
文献类型：
--
作者：
Kovanecz, I.;Rambhatla, A.;Gonzalez-Cadavid, N.
最近在大鼠中报道，以连续长期方式给予伐地那非可成功预防双侧海绵体神经切除术（BCNR）后发生的阴茎海绵体平滑肌纤维化和海绵体静脉闭塞功能障碍（CVOD），BCNR是根治性阴茎切除术后人类勃起功能障碍的模型。为了扩展这一发现，并确定这种作用是否与其他PDE 5抑制剂相同，以及是否部分通过刺激诱导型一氧化氮合酶的自发诱导而发生（iNOS，也称为NOS 2），雄性Fischer 344大鼠（N = 10/组）接受BCNR或单侧海绵体神经切除术（UCNR），并接受西地那非治疗（20 mg kg（-1）天（-1）），每天饮用水，持续45天。其他BCNR组接受L-NIL（6.7 mg/kg，第-1天）作为iNOS活性抑制剂，同时给予或不给予西地那非。经测定，西地那非与伐地那非一样，（1）防止平滑肌细胞/胶原蛋白比率降低30%，细胞凋亡增加3-4倍，细胞增殖减少，并部分抵消胶原蛋白增加，观察到UCNR和BCNR;（2）使BCNR和UCNR诱导的CVOD正常化（通过动态输注海绵体测量法测量）。iNOS活性的长期抑制加重了BCNR大鼠的躯体纤维化和CVOD，但西地那非的功能效应不受L-NIL的影响。这些数据表明，阴茎海绵体神经切除术后，持续的长期PDE 5抑制剂对勃起功能的有益影响涉及其防止海绵体神经损伤诱导的身体组织学改变的能力，在一个过程中，明显独立于内源性iNOS诱导。
It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal veno-occlusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N = 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg(-1) day(-1)) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7mg kg(-1) day(-1)) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.