Bivalacqua T J, Usta M F, Champion H C, Leungwattanakij S, Dabisch P A, McNamara D B, Kadowitz P J, Hellstrom W J G
Department of Urology, Tulane University School of Medicine, New Orleans, Louisana 70112, USA.
Int J Impot Res. 2004 Feb;16(1):21-9. doi: 10.1038/sj.ijir.3901054.
Erectile dysfunction associated with diabetes mellitus is caused in part by disordered endothelial smooth muscle relaxation, neuropathy, and a decrease in cavernosal nitric oxide synthase (NOS) activity. The purpose of this study was to determine whether a combination of sildenafil and adenoviral gene transfer of endothelial NOS (eNOS) could enhance the erectile response in diabetic rats. Five groups of animals were utilized: (1) age-matched control rats, (2) streptozotocin (STZ)-induced diabetic rats (60 mg/kg i.p.), (3) STZ-rats + sildenafil (2 mg/kg i.v.), (4) STZ-rats transfected with AdCMVbetagal or AdCMVeNOS, and (5) STZ-rats transfected with AdCMVeNOS +sildenafil (2 mg/kg i.v.). At 2 months after i.p. injection of STZ, groups 4 and 5 were transfected with the adenoviruses and 1-2 days after transfection, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Cyclic 3',5'-guanosine monophosphate (cGMP) levels were assessed in the cavernosal tissue. STZ-diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve; AUC) after CNS when compared to control rats. STZ-diabetic rats+AdCMVeNOS had a peak ICP and AUC, which were similar to control animals. STZ-diabetic rats administered sildenafil demonstrated a significant increase in peak ICP at the 5 and 7.5 V settings, while the AUC was significantly increased at all voltage (V) settings. The increase in both ICP and AUC of STZ-diabetic rats transfected with AdCMVeNOS at all V settings was greater than STZ-diabetic rats transfected with AdCMVbetagal. STZ-diabetic rats transfected with AdCMVeNOS and administered sildenafil had a significant increase in total ICP that was greater than eNOS gene therapy alone. Cavernosal cGMP levels were significantly decreased in STZ-diabetic rats, but were increased after transfection with AdCMVeNOS to values greater than control animals. In conclusion, overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the peak ICP and total ICP to CNS in the STZ-diabetic rat, which was similar to the response observed in control rats. Moreover, the total erectile response was greater in STZ-diabetic rats receiving eNOS gene therapy plus sildenafil than STZ-rats receiving sildenafil or eNOS gene therapy alone.
糖尿病相关的勃起功能障碍部分是由内皮平滑肌舒张紊乱、神经病变以及海绵体一氧化氮合酶（NOS）活性降低所致。本研究的目的是确定西地那非与内皮型一氧化氮合酶（eNOS）腺病毒基因转移联合应用是否能增强糖尿病大鼠的勃起反应。使用了五组动物：（1）年龄匹配的对照大鼠，（2）链脲佐菌素（STZ）诱导的糖尿病大鼠（腹腔注射60mg/kg），（3）STZ大鼠 + 西地那非（静脉注射2mg/kg），（4）用AdCMVβgal或AdCMVeNOS转染的STZ大鼠，以及（5）用AdCMVeNOS + 西地那非（静脉注射2mg/kg）转染的STZ大鼠。腹腔注射STZ后2个月，第4组和第5组用腺病毒转染，转染后1 - 2天，所有动物均接受海绵体神经刺激（CNS）以评估勃起功能。测定海绵体组织中环磷酸鸟苷（cGMP）水平。与对照大鼠相比，STZ糖尿病大鼠经CNS刺激后，海绵体内压峰值（ICP）和总ICP（勃起曲线下面积；AUC）所确定的勃起功能显著降低。STZ糖尿病大鼠 + AdCMVeNOS的ICP峰值和AUC与对照动物相似。给予西地那非的STZ糖尿病大鼠在5V和7.5V刺激强度下ICP峰值显著增加，而在所有电压（V）刺激强度下AUC均显著增加。在所有V刺激强度下，用AdCMVeNOS转染的STZ糖尿病大鼠的ICP和AUC增加幅度均大于用AdCMVβgal转染的STZ糖尿病大鼠。用AdCMVeNOS转染并给予西地那非的STZ糖尿病大鼠的总ICP显著增加，且大于单独进行eNOS基因治疗的情况。STZ糖尿病大鼠海绵体cGMP水平显著降低，但用AdCMVeNOS转染后升高，且高于对照动物。总之，eNOS和cGMP的过表达与西地那非联合应用显著增加了STZ糖尿病大鼠对CNS刺激的ICP峰值和总ICP，这与对照大鼠中观察到的反应相似。此外，接受eNOS基因治疗加西地那非的STZ糖尿病大鼠的总勃起反应大于单独接受西地那非或eNOS基因治疗的STZ大鼠。
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