GENDER&NEUROPETITDE Y-CATECHOLAMINE SYSTEM HYPERTENSION

性别

• 批准号: 3432546
• 负责人: ZOFIA ZUKOWSKA
• 金额: $ 2.31万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-25 至 1995-08-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3432546
• 关键词: antiadrenergic agents; blood chemistry; calcium channel blockers; cardiovascular disorder epidemiology; cardiovascular stress test; catecholamines; echocardiography; estrogens; gender difference; hemodynamics; hormone regulation /control mechanism; human subject; hypertension; menstrual cycle; neuropeptide Y; ovariectomy; physiologic stressor; progesterone; sympathetic nervous system; testosterone; ventricular hypertrophy

Hypertension and related cardiovascular diseases are more prevalent in men than in premenopausal women. This may relate to sex differences in the cardiovascular system and the sympathoadrenomedullary system (SAS) responses to stress. Estrogens (E) appear to attenuate whereas testosterone (T) may enhance cardiovascular responsiveness. The SAS is now known to contain not only catecholamines (CA) but also neuropeptide Y (NPY), a potent non-adrenergic vasoconstrictor released from the sympathetic nerves during intense activation and implicated in hypertension, stroke and coronary artery disease. In rats, but not in normal humans, an additional source of circulating NPY is derived from aggregating platelets, also during stress; whether this occurs in humans under some pathophysiological conditions has not been determined. Studies of the parent grant showed that mature male rats respond to stress with greater pressor, CA and NPY responses than females. The overall hypothesis of the parent grant is that the NPY-CA system (from SAS and/or platelets) contributes to cardiovascular gender differences in rats by being "down-regulated" by E and/or "up-regulated", by T. The current proposal will extend this hypothesis to men and premenopausal women, normotensive and with mild essential hypertension, and focus on the role of E. Experiments will evaluate effects of physiological changes of E during phases of the menstrual cycle, and changes due to ovariectomy (with and without E supplementation) on hemodynamic, NPY (plasma and platelet-derived) and CA responses to two types of stress: cold pressor test and graded treadmill exercise. In hypertensives, cardiovascular structural changes will be assessed in retinal vessels (the degree of hypertensive retinopathy) and by left ventricular hypertrophy (echocardiogram), and correlated with resting sex hormone levels, and NPY-CA responsiveness to stress. Finally, the contribution of NPY to sex differences in pressor responses to stress in normotensives and hypertensives will be studied by either blocking NPY actions with NPY antagonist, if such becomes available for clinical research, or by altering the NPY system with adrenergic blockers (which antagonize adrenergic responses but enhance NPY release) and calcium channel blocker (which blocks vasoconstriction of both CA and NPY). The novelty of this proposal is that it investigates the role of NPY in sex differences in human hypertension of which very little is known. These studies will increase the clinical value of the parent grant, which is based on rat models, and both will contribute to an area of research which has largely been neglected. Their results may help to determine whether NPY is associated with exaggerated cardiovascular changes during stress and hypertension, and, thus, identify high-risk individuals who in the future might benefit from treatment directed against the peptide.

男性的高血压和相关心血管疾病更为普遍 比绝经前妇女。 这可能与性别差异有关 心血管系统和交感神经肾上腺素系统（SAS） 对压力的反应。 雌激素（E）似乎减弱 睾丸激素（T）可能增强心血管反应性。 SAS现在是 已知不仅包含儿茶酚胺（CA），还包含神经肽Y （NPY），一种有效的非肾上腺素能血管收缩剂 强烈激活期间的交感神经 高血压，中风和冠状动脉疾病。 在老鼠中，但不在 正常人，循环NPY的附加来源是从中得出的 在压力期间，聚集血小板；这是否发生在人类 在某些病理生理条件下尚未确定。 研究 父母的赠款表明，成熟的雄性大鼠应对压力 比女性更大的压力，CA和NPY反应。 总体假设 父母的赠款是NPY-CA系统（来自SAS和/或血小板） 通过成为大鼠的心血管性别差异 由E和/或“上调”，T。当前的提案“下调” 将向男性和绝经前妇女扩展这一假设 并使用轻度的基本高血压，并专注于E的作用。 实验将评估E期间E的生理变化的影响 月经周期的阶段，以及由于卵巢切除术而发生的变化（带有和 在血液动力学，NPY（血浆和等离子体和 血小板衍生的）和CA对两种压力的反应：冷压 测试和分级跑步机运动。 在高血压中，心血管 结构性变化将在视网膜血管中进行评估（该程度 高血压视网膜病）和左心室肥大 （超声心动图），与静息性激素水平相关，并且 NPY-CA对压力的反应。 最后，NPY对性的贡献 正常敏化和压力压力的反应差异和 高血压将通过用NPY阻止NPY动作来研究高血压 对抗者，如果可以用于临床研究或通过更改 具有肾上腺素阻滞剂的NPY系统（拮抗肾上腺素能 响应但增强了NPY释放）和钙通道阻滞剂（它们 阻止CA和NPY的血管收缩。 该提议的新颖性 是它研究了NPY在人类性别差异中的作用 高血压很少知道。 这些研究将增加 父母赠款的临床价值，基于大鼠模型，以及 两者都将有助于研究领域 被忽视。 他们的结果可能有助于确定NPY是否相关 在压力和高血压期间夸张的心血管变化， 因此，确定未来可能受益的高风险个人 来自针对肽的治疗。