Semester

Summer

Date of Graduation

1999

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Christine Baylis.

Abstract

Hypertension and other cardiovascular complications are the major causes of hospitalization and death in patients with chronic renal diseases (CRD). Our laboratory has previously reported that total nitric oxide (NO) production is decreased in CRD. The overall objective in my present series of studies is to investigate the alterations of endothelial NO system and the possible mechanisms in CRD.;In the study on CRD patients who still have residual renal function (∼30% of normal GFR), we found that the plasma from these patients did not affect L-arginine transport into endothelial cells but significantly inhibited endothelial nitric oxide synthase (eNOS) activity from some of these CRD patients. We established that this difference is related to the plasma concentration of asymmetric dimethyl arginine (ADMA).;In the study of patients with end stage renal disease (ESRD), we found that plasma from all of these patients inhibited both L-arginine transport and eNOS activity in vitro. In the long term, inhibition of L-arginine transport into endothelial cells may cause intracellular L-arginine deficiency which might further reduce endothelial NO synthesis. Dialysis can partially improve the inhibition of L-arginine transport, but did not reverse the inhibition of NOS activity. In separate studies, we found that excess L-arginine can reverse the inhibition of NO synthesis in vitro, caused by the uremic plasma. Besides the L-arginine analogs, we have found that urea inhibited L-arginine transport into endothelial cells both in six hours and one week incubation, and eNOS activity after one week incubation. The inhibition of L-arginine transport by urea is not competitive with L-arginine for the y+ transporter system and this inhibition is reversible when the uremic medium is replaced with normal cell medium.;Finally, in our in vivo experiments, we did not find a direct inhibitory effect of uremic levels of urea over 7 days period on NO production, nor was there any alteration of blood pressure or renal vascular resistance in conscious rats with normal renal function. Therefore, normal renal function is very important in maintaining and/or compensating for the effect of high BUN on the vascular endothelial NO: L-arginine system.

Download

Share

COinS