Gangula Pandu R R, Maner William L, Micci Maria-Adelaide, Garfield Robert E, Pasricha Pankaj Jay
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Mar;292(3):G725-33. doi: 10.1152/ajpgi.00406.2006.
Diabetic gastroparesis is a disorder that predominantly affects women. However, the biological basis of this sex bias remains completely unknown. In this study we tested the hypothesis that a component of this effect may be mediated by the nitrergic inhibitory system of the enteric nervous system. Age-matched male and female Sprague-Dawley rats were studied 8 or 12 wk after streptozotocin (55 mg/kg body wt ip)-induced sustained hyperglycemia and compared with controls. Solid gastric emptying (GE) studies were performed in all the groups. Changes in gastric antrum neuronal nitric oxide synthase (nNOS) mRNA and protein levels were analyzed by real-time PCR and Western immunoblotting, respectively. nNOS dimerization studies were performed using low-temperature SDS-PAGE. In vitro nitrergic relaxation (area under curve/mg tissue wt) was studied after the application of electric field stimulation in an organ bath. Changes in intragastric pressure (mmHg.s) in freely moving rats in the presence or absence of N(G)-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) were examined by an ambulatory telemetric method. After diabetes induction, GE is delayed in both male and female rats. However, diabetic females exhibited significant delayed GE than in diabetic males. Compared with male controls, gastric nNOS expression and nitrergic relaxation were substantially elevated in healthy female control rats, accompanied by significantly reduced intragastric pressure. The active dimeric form and dimer-to-monomer ratio of nNOSalpha were also higher in healthy females compared with male rats (P < 0.05). Diabetic females, but not males, showed significant (P < 0.05) impairment in both gastric nNOSalpha dimerization and nitrergic relaxation, accompanied by an increase in intragastric pressure. Our data provide evidence that females may have a greater dependency on the nitrergic mechanisms in health. Furthermore, diabetes seems to affect the nitrergic system to a greater extent in females than in males. Together, these changes may account for the greater vulnerability of females to diabetic gastric dysfunction.
糖尿病性胃轻瘫是一种主要影响女性的疾病。然而，这种性别差异的生物学基础仍然完全未知。在本研究中，我们检验了这样一种假设，即这种效应的一个组成部分可能由肠神经系统的一氧化氮能抑制系统介导。对链脲佐菌素（55mg/kg体重，腹腔注射）诱导的持续高血糖8周或12周后的年龄匹配的雄性和雌性Sprague-Dawley大鼠进行研究，并与对照组进行比较。对所有组进行固体胃排空（GE）研究。分别通过实时PCR和Western免疫印迹分析胃窦神经元型一氧化氮合酶（nNOS）mRNA和蛋白水平的变化。使用低温SDS-PAGE进行nNOS二聚化研究。在器官浴中施加电场刺激后，研究体外一氧化氮能舒张（曲线下面积/毫克组织重量）。通过动态遥测法检查在存在或不存在N（G）-硝基-L-精氨酸甲酯（一氧化氮合酶抑制剂）的情况下自由活动大鼠的胃内压变化（mmHg·s）。诱导糖尿病后，雄性和雌性大鼠的GE均延迟。然而，糖尿病雌性大鼠的GE延迟程度明显高于糖尿病雄性大鼠。与雄性对照组相比，健康雌性对照大鼠胃nNOS表达和一氧化氮能舒张明显升高，同时胃内压显著降低。与雄性大鼠相比，健康雌性大鼠中nNOSα的活性二聚体形式和二聚体与单体的比例也更高（P<0.05）。糖尿病雌性大鼠而非雄性大鼠在胃nNOSα二聚化和一氧化氮能舒张方面均表现出显著（P<0.05）损伤，同时胃内压升高。我们的数据提供了证据，表明女性在健康状态下可能对一氧化氮能机制有更大的依赖性。此外，糖尿病似乎对女性一氧化氮能系统的影响比对男性更大。总之，这些变化可能解释了女性更容易患糖尿病性胃功能障碍的原因。
