CN112603587A - 一种用于评价治疗血管性ed的药物的动物模型的构建方法 - Google Patents
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Abstract
本发明公开了一种用于评价治疗血管性ED的药物的动物模型的构建方法，该方法将阿扑吗啡注射到大鼠体内，利用热成像技术动态反馈血管性ED变化程度，形成稳定反馈阴茎勃起功能的系统。
Description
技术领域
本发明涉及一种用于评价治疗血管性ED的药物的动物模型的构建方法，属于动物实验模型构建领域。
背景技术
男性勃起功能障碍(ED)是指连续或重复阴茎勃起后硬度不够或维持时间不足不能满意的完成性交活动的症状，病程持续半年以上。大鼠是研究勃起功能障碍的最常用模型。目前，国际上检测大鼠勃起功能的公认手段是测量海绵体内压(ICP)。但是，这套检测系统需要解剖出性神经并对阴茎海绵体进行有创插管，因此海绵体内压的测量只能实施一次。ICP检测后由于阴茎海绵体完整性已经被破坏，只能获取大鼠一次的勃起数据，不能对大鼠进行长期动态研究；并且该方法手术操作精细程度高，极易失败，且不同的人可能测得不同的结果，实验重复性差。
无论是勃起功能障碍疾病进展还是药物发挥疗效，总是一个需要一段时间的动态变化过程。因为无法重复测量ICP，因此无法在同一只受试大鼠上进行动态测量阴茎勃起功能。过去虽让有人曾提出使用血氧检测的办法替代ICP检测，但是由于准确性差，受干扰因素多，一直未得到承认和推广。本发明主要解决该问题，尝试以近期发展的高灵敏度热成像仪为核心，建立一套无创、非接触、实时动态、稳定可靠、高精度的阴茎勃起功能检测系统。
凡是温度高于绝对零度的任何物体均可以向外发出各种波长的电磁波，其中波长在2.0-1000μm部分称为热红外线。随着温度的变化，红外辐射强度也会发生改变。热成像技术就是利用热成像仪接受人体或动物辐射的红外辐射能，将不可见的红外辐射转变为可见的图像，从而了解人体或动物温度的改变，了解其功能变化。早在1957年，热成像技术就开始应用乳腺癌检测方面，到现在热成像技术在检测乳腺癌方面的敏感和特异性高达90％。目前，热成像技术凭借着其低成本、高灵敏度(0.025℃)、快速、非接触、无创以及可长期动态监测的特点在临床应用方面越来越受欢迎。新的应用方面也越来越广泛，如诊断口腔鳞状细胞癌颈淋巴结转移、诊断皮肤肿瘤和检测亚健康状态等方面的研究。但是，经过多次查重查新，发现该技术在勃起功能障碍方面的研究为零。
发明内容
本发明克服了上述现有技术的不足，提供一种用于评价治疗血管性ED的药物的动物模型的构建方法，该方法将阿扑吗啡注射到大鼠体内，利用热成像技术动态反馈血管性ED变化程度，形成稳定反馈阴茎勃起功能的系统。
一种用于评价治疗血管性ED的药物的动物模型的构建方法，包括如下步骤：
1)将血管性ED大鼠和健康大鼠分别放置在恒温鼠台进行麻醉；
2)给血管性ED大鼠和健康大鼠分别注射阿扑吗啡；
3)使用热成像仪实时监控并记录健康大鼠和血管性ED大鼠阴茎从疲软到刺激勃起再到撤去刺激疲软的过程的图像，并将图像信息转变为数据信息，获得健康大鼠变化曲线图A和血管性ED大鼠变化曲线图B，即可形成用于评价治疗血管性ED的药物的动物模型。
进一步的，上述步骤1)中所述麻醉指使用吸入性麻醉装置给大鼠进行乙醚吸入麻醉。
进一步的，上述步骤2)中所述注射是使用显微注射装置进行。
进一步的，上述步骤2)中所述阿扑吗啡的注射量以大鼠体重为参照，按80-100μg/kg的比例注射。
给予使用上述方法构建的动物模型应用需评价的治疗药物，利用热成像仪检测大鼠阴茎从疲软到勃起时图像，并转化成变化曲线图，对比上述健康大鼠的变化曲线图A，即可获得该药物治疗效果。
有益效果：
(1)热成像技术依赖于现代相机技术的检测和量化。由于红外相机和计算机技术的巨大进步、新的图像处理算法以及红外传感器的进步，使红外探测器灵敏度、分辨率越来越高，甚至精确到0.025℃。该技术更加精密，更加稳定。
(2)热成像技术使用热照相机来记录皮肤发出的红外辐射，没有电离辐射，没有直接接触，避免了用ICP测量的损伤，可以连续、动态监测实验动物的阴茎勃起功能。
(3)用显微注射平台行腹腔注射阿扑吗啡的方法来刺激阴茎勃起取代了神经刺激，试验后大鼠并无其他生理状态改变，可以用来长期动态监测，这是ICP不能实现的。使用精密可控的恒定部位及恒定剂量注射阿扑吗啡，保证刺激的均质性。
附图说明
图1实验设备放置图。
图2健康大鼠阴茎变化过程图。
图3健康大鼠勃起过程中温度变化图。
图4血管性ED大鼠勃起过程稳定变化图。
图5ICP测得血管性ED大鼠勃起程度数据图像。
具体实施方式
为了使本技术领域人员更好地理解本申请中的技术方案，下面结合实施例对本发明作进一步说明，所描述的实施例仅是本申请一部分实施例，而不是全部，本发明不受下述实施例的限制。
实施例1
一、实验步骤
1)将显微注射装置、吸入性麻醉装置、直肠测温装置、恒温鼠台、热成像仪摆放连接，放置情况如图1所示。
2)分别将健康大鼠和血管性ED大鼠放置在恒温鼠台进行吸入性麻醉；
3)利用显微注射装置分别给健康大鼠和血管性ED大鼠注射100μg/kg(以大鼠体重为参照)阿扑吗啡。
4)使用热成像仪实时监控并记录健康大鼠和血管性ED大鼠阴茎从疲软到刺激勃起再到撤去刺激疲软的过程的图像，并将图像信息转变为数据信息，获得变化曲线图，即可形成动态反馈血管性ED情况的模型。
5)利用ICP技术分别对健康大鼠和血管性ED大鼠勃起情况进行检测。
二、实验结果
健康大鼠在经过腹腔注射阿扑吗啡100μg/kg，6min内即可观察到勃起现象，勃起的主要机制是一氧化氮和其他神经内分泌因子引起海绵状动脉和组织平滑肌的松弛，勃起开始，导致阴茎血流量增加。当海绵体充满血液时，引流海绵体的静脉会被压缩，从而保持阴茎的肿胀。血流同样能够给阴茎带来热量，能使阴茎热量带来变化，所以热量即可反应血流变化。如图2即为健康大鼠阴茎从疲软到刺激勃起再到撤去刺激疲软的过程，验证了温度实时监测对勃起过程的监测效力，也证实了该模型相较神经刺激模型对血管性ED的模拟优势。
热成像仪还能够将图像信息转变为数据信息，热成像技术可以通过温度变化检测勃起程度。经实验，我们发现正常大鼠与糖尿病型ED大鼠勃起的最高温度存在差异。图3为健康大鼠的温度变化图，图4为血管性ED大鼠的温度变化图，两种图像进行对照，利用我们构建的模型及热成像检测系统获得的数据可以验证不同药物对具有该疾病大鼠的应用效果。
图5是利用ICP测得血管性ED大鼠勃起程度数据图像，将热成像技术和ICP检测技术所测得的数据进行拟合，发现两者在图像上的变化一致，并且热成像技术测得数据密度为(25.6-24.2)/0.025＝56，ICP技术测得数据密度为(60-10)/20＝2.5，可以看出，热成像技术更加精确。
Claims (5)
1.一种用于评价治疗血管性ED的药物的动物模型的构建方法，其特征在于，包括如下步骤：
1)将血管性ED大鼠和健康大鼠分别放置在恒温鼠台进行麻醉；
2)给血管性ED大鼠和健康大鼠分别注射阿扑吗啡；
3)使用热成像仪实时监控并记录健康大鼠和血管性ED大鼠阴茎从疲软到刺激勃起再到撤去刺激疲软的过程的图像，并将图像信息转变为数据信息，获得健康大鼠变化曲线图A和血管性ED大鼠变化曲线图B，即可形成用于评价治疗血管性ED的药物的动物模型。
2.如权利要求1所述的用于评价治疗血管性ED的药物的动物模型的构建方法，其特征在于，步骤1)中所述麻醉指使用吸入性麻醉装置给大鼠进行乙醚吸入麻醉。
3.如权利要求1所述的用于评价治疗血管性ED的药物的动物模型的构建方法，其特征在于，步骤2)中所述注射是使用显微注射装置进行。
4.如权利要求1所述的用于评价治疗血管性ED的药物的动物模型的构建方法，其特征在于，步骤2)中所述阿扑吗啡的注射量以大鼠体重为参照，按80-100μg/kg的比例注射。
5.利用如权利要求1-4任一项所述的构建方法所构建的用于评价治疗血管性ED的药物的动物模型的应用方法，其特征在于，给予用于评价治疗血管性ED的药物的动物模型使用需评价的药物，利用热成像仪检测大鼠阴茎从疲软到勃起时图像，并转化成变化曲线图，对比健康大鼠的变化曲线，即可评价该药物情况。
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| WO2017100324A1 (en) * | 2015-12-10 | 2017-06-15 | Repros Therapeutics Inc. | Combination therapy for treating female hypoactive sexual desire disorders |
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| CN104306371A (zh) * | 2013-08-12 | 2015-01-28 | 成都百裕科技制药有限公司 | 银杏内酯类化合物的新用途 |
| WO2017100324A1 (en) * | 2015-12-10 | 2017-06-15 | Repros Therapeutics Inc. | Combination therapy for treating female hypoactive sexual desire disorders |
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| ALEXANDRIA HERTZ, ED. AL.: "THERMAL IMAGING AS A NON-INVASIVE METHOD FOR SSESSING ERECTILE FUNCTION", THE JOURNAL OF UROLOGY, vol. 199, no. 4, pages 1003, XP085374162, DOI: 10.1016/j.juro.2018.02.2393 * |
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