氟哌啶醇对雄性大鼠阴茎勃起功能和一氧化氮合酶基因表达及其活性的影响

The effects of haloperidol on erectile function and gene expression and activity of nitric oxide synthase in rats

目的探讨氟哌啶醇对雄性大鼠阴茎勃起功能和一氧化氮合酶(NOS)基因表达及其活性的影响。方法将40只3月龄雄性Sprague-Dawley大鼠随机均分为氟哌啶醇组(20只)和蒸馏水对照组(20只,以下简称对照组)。对两组鼠均每日连续灌胃给药,氟哌啶醇组鼠为氟哌啶醇2mg/kg体质量,对照组鼠为与氟哌啶醇组同等容积的蒸馏水。分别在给药第3,6周时每组各随机取10只大鼠与发情期雌鼠进行交配实验,并判断阴茎勃起功能。以逆转录-聚合酶链反应法测定雄鼠阴茎海绵体组织神经型(nNOS)、内皮型(eNOS)、诱导型(iNOS)NOS的mRNA表达情况,并以NOS活性试剂盒测定总NOS活性(tNOS)以及结构型NOS(cNOS,包括nNOS、eNOS)和iNOS的活性。结果氟哌啶醇组鼠给药第3,6周时雄鼠骑跨次数(U均=6.5,P均<0.001)、阴茎插入次数(第3周U=8.0,P=0.001;第6周U=10.0,P=0.02)低于对照组鼠,差异有统计学意义;两者比率(插入命中率)在给药第6周时亦低于对照组鼠,差异有统计学意义(U=19,P=0.019)。给药第3周时氟哌啶醇组鼠阴茎海绵体组织eNOS mRNA表达低于对照组鼠,差异有统计学意义(t=-3.379,P=0.003);给药第6周时eNOS及nNOS mRNA表达均低于对照组鼠,差异有统计学意义(eNOSt=-3.846,P=0.001;nNOSt=-5.773,P<0.001);iNOS mRNA表达在给药第3,6周均未见有明显影响。氟哌啶醇组鼠给药第3,6周阴茎海绵体组织tNOS、cNOS活性低于对照组鼠,差异有统计学意义(t=-2.173～-4.184;P=0.001～0.048),iNOS活性的差异无统计学意义。结论结构型NOS基因表达以及NOS活性降低,可能是氟哌啶醇长期应用后阴茎勃起障碍的发生机制之一。

Objectives To assess the effect of haloperidol on erectile function and gene expression and activity of nitric oxide synthase （NOS） in the penile cavernous tissue of male rats. Methods Two groups of Sprague Dawley rats （ n = 20 each） were orally treated by gavage with haloperidol （2 mg/kg） or vehicle （distilled water） respectively for three or six weeks. Their penile erectile behaviors were evaluated on the third or the sixth weekend with copulatory behavior test. The mRNA expressions of three subtypes NOS in the penile cavernous tissue were analyzed by reverse transcription-polymerase chain reaction. And NOS activity of the penile cavernous tissue was also examined. Results Compared with the control group, mount frequency （both weeks 3 and 6 ： U = 6. 5, P 〈 0. 001 ） and intromission frequency （ weeks 3 ： U = 8.0, P = 0. 001 ; weeks 6 ： U = 10. 0, P = 0. 02） in haloperidol group were significantly decreased after both three and six weeks. Hit ratio （HR） in haloperidol group was also significantly decreased after six weeks （U= 19,P =0. 019）. At the third weekend, the expression of eNOS mRNA was significantly reduced in penile cavernous tissues of haloperidol group （t = - 3. 379, P = 0. 003 ）. At the sixth weekend, the mRNA products of eNOS and nNOS were both lowly expressed in haloperidol group （ eNOS： t = - 3. 846, P = 0. 001 ; nNOS： t = - 5. 773, P 〈 0. 001 ）. The activity of tNOS and constitutive NOS （ cNOS, including eNOS and nNOS） in haloperidol group were all significantly lower than that in the control group at both the third and sixth weekend （t = - 2. 173 - - 4. 184, P= 0. 001 - 0. 048 ）. Haloperidol had no effect on gene expression and activity of iNOS in the penile cavernous tissue. Conclusion The gene expression and activity of cNOS are suppressed by long-term treatment of haloperidol, which suggests that NOS impairment play a role in erectile dysfunction induced by antipsychotics.