SMOKING AND CALCIUM AND BLOOD PRESSURE REGULATION

这项建议涉及两个主要的调查领域：1）进一步 研究吸烟相关血管疾病的新机制， 香烟和尼古丁对血栓素A2（TXA2）和 将使用经验证的放射免疫测定法（RIA）研究前列环素（PGI2） 和气相色谱质谱（GCMS）技术。 这些研究 将扩展我们最初的观察结果，表明烟草抑制PGI2 慢性吸烟者的生产。 长期吸烟者和非吸烟者将吸入 不同的含尼古丁香烟和接收尼古丁直接在 口香糖 PGI_2和TXA_2的变化与血浆尼古丁和 可替宁水平 具体的肾上腺素能激动剂和拮抗剂将在 研究肾上腺素能神经系统在吸烟中的作用 前列腺素（PG）的变化。 研究肾和肾外PGI2 第二代，6酮PGF1 α和2，3二或6酮PGF1 α将被 使用RIA和GCMS测定尿液中的含量。 血清中的TXB2离体和 将通过GCMS验证的RIA测量尿液，以确定全身和 尼古丁和吸烟后肾脏产生TXA2。 PGI2和PGE2的作用 在维持肾血流量（RBF）中起重要作用， 在BP监管中。 因此，吸烟对PG水平、RBF和 血压将在某些疾病状态下测定，如充血性心脏病 PG可能在血管内稳态中发挥重要作用。 2)在第二个研究领域，钙（Ca+2）和 Ca+2通道阻滞对全身和肾脏PGE 2和PGI 2产生的影响 血液动力学和醛固酮合成将在正常和 评估Ca+2在1）血管调节，2） 血管舒张PG产生，和3）醛固酮合成。 方法将 包括给予正常受试者非加压或加压Ca+2输注， 单独或与PG抑制剂、肾上腺素能拮抗剂或慢Ca+2通道联合使用 阻滞剂。 全身和肾脏血流动力学的无创测定 将获得并与PG水平相关。 受试者一期 醛固酮增多症将接受Ca+2阻滞剂和血流动力学和醛固酮 水平确定。 初步数据表明，PGI2在 调节Ca+2的血管收缩作用和Ca+2阻滞剂降低血压， 显著降低原发性醛固酮增多症患者的醛固酮水平。

This proposal involves two major areas of investigation: 1) To further study a new mechanism of smoking related vascular disease, the effect of cigarettes and nicotine on the balance between thromboxane A2(TXA2) and prostacyclin (PGI2) will be studied using validated radioimmunoassay (RIA) and gas chromatography mass spectrometry (GCMS) techniques. These studies will extend our initial observations showing that tobacco inhibits PGI2 production in chronic smokers. Chronic smokers and nonsmokers will inhale varying nicotine containing cigarettes and receive nicotine directly in a gum. PGI2 and TXA2 changes will be correlated with plasma nicotine and cotinine levels. Specific adrenergic agonists and antagonists will be studied to determine the role of adrenergic nervous system in smoking related prostaglandin (PG) changes. To study renal and extrarenal PGI2 generation, 6 keto PGF1 alpha and 2,3 dinor 6 keto PGF1 alpha will be assayed in urine using RIA and GCMS. TXB2 exvivo in serum and TXB2 in urine will be measured via GCMS validated RIA to determine systemic and renal TXA2 generation after nicotine and smoking. PGI2 and PGE2 play important roles in maintaining renal blood flow (RBF) and may be important in Bp regulation. Therefore, the effect of smoking on PG levels, RBF, and Bp will be determined in certain disease states such as congestive heart failure where PG's may play an important role in vascular homeostasis. 2) In the second area of investigation, the effect of calcium (Ca+2) and Ca+2 channel blockade on PGE2 and PGI2 production, systemic and renal hemodynamics, and aldosterone synthesis will be studied in normal and hypertensive man to evaluate the role of Ca+2 in 1) vascular regulation, 2) vasodilatory PG production, and 3) aldosterone synthesis. Approaches will include giving normal subjects nonpressor or pressor Ca+2 infusions either alone or with PG inhibitors, adrenergic antagonists, or slow Ca+2 channel blockers. Noninvasive determinations of systemic and renal hemodynamics will be obtained and correlated with PG levels. Subjects with primary aldosteronism will receive Ca+2 blockers and hemodynamics and aldosterone levels determined. Preliminary data suggests that PGI2 plays a key role in modulating Ca+2's vasoconstrictive action and Ca+2 blockers lower Bp and markedly reduce aldosterone levels in subjects with primary aldosteronism.