MENTORED ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

建议（改编自申请人的摘要）：有一个非常 CRF患者心血管疾病发病率和死亡率高。 胰岛素 抵抗力、血脂异常和高血压形成一组危险因素 在这些患者中。 这些风险因素之间可能存在联系 这使肾衰竭患者更容易发生心血管疾病 疾病（CVD）。 本申请的目的是测试是否失调 胰岛素介导的NEFA抑制与A1- 中度CRF患者肾上腺素能受体血管反应性。 在 为了实现这一目标，将努力实现以下具体目标， 中度慢性肾病患者：1）测定血浆NEFA 浓度和胰岛素介导的NEFA周转; 2）确定A1-肾上腺素能 受体血管反应性;和3）确定提高和 降低NEFA对A1-肾上腺素能受体血管反应性的影响。 的结果 这些在中度CRF患者中进行的研究将与血压正常的患者进行比较 和肾功能正常的高血压对照。 首先，NEFA将 在使用两阶段高胰岛素血症 正葡萄糖钳夹 随后，基线A1-肾上腺素能受体血管 反应性将通过测定加压敏感性来测量， 去氧肾上腺素，一种选择性A1肾上腺素能受体激动剂。 为了评估 NEFAs对血管反应性、升压敏感性、 将在NEFA升高后，通过输注 肝素抗凝和通过输注烟酸减少NEFA， 并与基线升压反应进行比较。 如果NEFA调节A1-肾上腺素能 受体血管反应性，那么候选人将确定 胰岛素增敏剂曲格列酮对NEFA和A1-肾上腺素能 受体血管反应性 这项研究提出的是至关重要的定义 肾功能衰竭中可能与高血压相关的脂质异常 在这个人群中。 这项研究可能为潜在的 心血管危险因素、血脂异常、胰岛素抵抗之间的联系 和高血压。 此外，这项研究还应奠定基础， 新的治疗策略旨在预防高血压患者的血管疾病， 心血管风险患者。

PROPOSAL (Adapted from the applicant's abstract): There is an extraordinarily high cardiovascular morbidity and mortality in patients with CRF. Insulin resistance, dyslipidemia and hypertension form a cluster of risk factors present in these patients. There may be a link between these risk factors which predisposes patients with renal failure to accelerated cardiovascular disease (CVD). The goal of this application is to test whether dysregulation of insulin-mediated suppression of NEFA is associated with enhanced A1- adrenergic receptor vascular reactivity in patients with moderate CRF. In order to accomplish this goal, the following specific aims will be pursued in patients with moderate chronic renal disease: 1) determine plasma NEFA concentrations and insulin-mediated NEFA turnover; 2) determine A1-adrenergic receptor vascular reactivity; and 3) determine the effects of raising and lowering NEFAs on A1-adrenergic receptor vascular reactivity. The results of these studies in patients with moderate CRF will be compared to normotensive and hypertensive controls with normal renal function. First, NEFAs will be measured before and after utilization of a two-stage hyperinsulinemic euglycemic clamp. Subsequently, baseline A1-adrenergic receptor vascular reactivity will be measured by determining pressor sensitivity to phenylephrine, a selective A1-adrenergic receptor agonist. In order to assess the effect of NEFAs on vascular reactivity, pressor sensitivity to phenylephrine will be measured after elevation of NEFAs via infusion of intralipid with heparin and reduction of NEFAs via infusion of nicotinic acid, and compared to baseline pressor responses. If NEFAs modulate A1-adrenergic receptor vascular reactivity, then the candidate will determine the effects of the insulin-sensitizing agent, troglitazone, on NEFAs and A1-adrenergic receptor vascular reactivity. The research proposed is critical in defining lipid abnormalities in renal failure which may be associated with hypertension in this population. This research may provide further support for a potential link between the cardiovascular risk factors, dyslipidemia, insulin resistance and hypertension. In addition, this research should lay the groundwork for new treatment strategies aimed to prevent vascular disease in the high cardiovascular risk patients.