MENTORED ORIENTED RESEARCH CAREER DEVELOPMENT AWARD

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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.