利钠肽对更年期高血压病的疗效及其作用机制的研究

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Hypertension is a major risk factor for cardiovascular disease. Premenopausal women have been shown to have lower blood pressure than age-matched men. Conversely,following menopause when estradiol levels decreased, the prevalence rate of hypertension and associated cardiovascular disease in women is increased, even higher than men. However, the mechanisms responsible for climacteric hypertension have not been completely elucidated. Natriuretic peptide (NP) has potent diuretic, natriuretic and vasodilatory effects and plays an important role in regulation of blood pressure. In our study, the NP levels in plasma significantly increased and the expression of NP receptors in heart significantly decreased in two different rat (Spontaneously Hypertensive Rats and Dahl Salt-Sensitive Rats) models of postmenopausal hypertension, and preliminarily reveals NPs may be involved in pathogenesis of climacteric hypertension. To further evaluate the role of NP system in the pathogenesis of climacteric hypertension, the therapeutic effects of M-ANP, an novel NP, on blood pressure, cardiac and renal function and its effects on NP system, sympathetic nerves system and RAS will be observed. Taken together, the present study was to establish NP system plays an important role in the pathogenesis of postmenopausal hypertension and M-ANP is a new and potent therapeutic agent for the prevention and treatment of postmenopausal hypertension and associated cardiovascualr disease.

高血压及相关心血管疾病是当今威胁女性健康和生命的主要疾病之一。女性在更年期前高血压患病率略低于男性，但在更年期后迅速升高，甚至高于男性。然而，目前对于女性更年期高血压病的发病机制尚不明确。利钠肽系统主要参与体内利尿、利钠及扩血管等作用，其表达与稳定性对血压调控有着重要的作用。我们在前期研究中发现绝经期后高血压大鼠血浆心房利钠肽、脑钠肽、氨基端脑钠肽前体水平及血浆肾素活性均显著升高，左心室NPR-A、AT1受体的mRNA表达水平显著下调，BNP的 mRNA表达水平显著上调，初步揭示利钠肽系统参与了更年期高血压病的发病机制。本课题拟通过静脉给药方式观察一种新型利钠肽M-ANP对绝经期后高血压大鼠的治疗效果及其对交感神经、肾素-血管紧张素及利钠肽系统的影响，进一步明确利钠肽对女性更年期高血压的疗效及作用机制，为女性更年期高血压及相关心血管疾病的预防和治疗提供坚实的理论依据。

心血管疾病是目前严重威胁人类生命健康的最主要疾病，是女性死亡和致残的首位原因。女性在更年期前患病率略低于男性，但在更年期后迅速升高，甚至高于男性。然而，目前对于女性更年期高血压发病机制尚不明确。M-ANP是一种新型的排钠性利尿剂，主要参与体内利尿、利钠及扩血管作等作用，其表达与稳定性对血压调控有着重要作用。然而目前M-ANP对更年期高血压的疗效及作用机制尚不明确。本课题建立两种不同类型，即老龄雌性SHRs和去卵巢Dah1盐敏感性大鼠作为绝经期后高血压模型，观察血压、肾功能改变及利钠肽系统、交感神经及肾素-血管紧张素系统之间的相互关系及性别差异。在两种绝经期高血压模型中均发现血压明显增高，肾功能损伤（尿蛋白和尿氧化应激标记物均显著升高），血浆心房利钠肽、脑钠肽、氨基端脑钠肽前体水平活性均显著升高，血浆肾上腺素及去甲肾上腺素显著升高，血浆中肾素及AngII 显著升高。在老龄雌性SHRs肾脏肾小球、肾内髓质和肾动脉利钠肽受体结合度显著降低；在肾直血管束受体结合度显著增高；去卵巢Dah1盐敏感性大鼠发现氧化应激不是导致绝经后大鼠盐敏性高血压的发生的独立因子，发挥较小的作用。以上结果显示利钠肽系统参与了更年期高血压的发病机制，并揭示在大鼠绝经期后高血压模型中利钠肽系统与交感神经及肾素-血管紧张素系统之间相互关系及性别差异。最后， 观察M-ANP治疗后血压明显降低，尿量明显增加，肾功明显改善，血浆ANP、BNP、NT-proBNP等生物标志物水平明显降低，说明M-ANP通过降低血浆利钠肽水平等干预作用发挥降低血压的生物活性效应，是一种有效的可以治疗女性更年期高血压的利尿剂， 为女性更年期高血压及相关心血管疾病的预防和治疗提供坚实的理论基础。