Indices of activity of the nitric oxide system in hemodialysis patients

Abstract

Arginine deficiency and/or increased levels of circulating nitric oxide (NO) synthesis (NOS) inhibitors can cause reduced NOS, which may contribute to hypertension in patients with end-stage renal disease (ESRD). To test these hypotheses, NO oxidation products (NO 2 + NO 3 = NO x ) and cyclic guanosine monophosphate (cGMP), the vasodilatory second messenger of NO, were measured in the blood, urine, and dialysate effluent of hemodialysis (HD) patients and compared with the blood and urine of healthy subjects. The subjects ate a controlled low-nitrate diet (∼330 μmol/d) for 48 hours before and during blood, dialysis effluent, and 24-hour urine collection. NO x output was significantly reduced in HD patients versus controls (552 ± 51 v 824 ± 96 μmol/24 h; P < 0.001), whereas cGMP output was not low versus controls. Plasma arginine level was normal and plasma levels of citrulline and the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA), were markedly elevated in patients with ESRD versus controls. Systolic blood pressure was greater in HD patients compared with controls despite concurrent antihypertensive therapy in most patients with ESRD. These studies suggest NO production is low in patients with ESRD undergoing HD, possibly because of the increased ratio of plasma ADMA to arginine. Index WordsEnd-stage renal disease; hypertension; arginine; cyclic guanosine monophosphate (cGMP); endogenous nitric oxide synthases (NOS) inhibitors Nitric oxide (NO) is a potent vasodilator made from L-arginine by the enzymatic action of several widely distributed nitric oxide synthases (NOSs). The constitutively expressed, vascular endothelial and brain-type NOSs have major roles in the physiological control of vascular tone and kidney function, and many of these actions are mediated by cyclic guanosine monophosphate (cGMP). 1,2 NO deficiency can be produced experimentally by the administration of substituted L-arginine analogues that function as competitive inhibitors of NOS. Chronic experimental NOS inhibition in animals produces hypertension, and NOS may be defective in some individuals with primary and secondary hypertension. 3 Hypertension is particularly prevalent in hemodialysis (HD) patients with end-stage renal disease (ESRD), 4-7 and there are valid reasons to suspect NO deficiency might occur and contribute to the hypertension in this population. We previously reported that patients with ESRD undergoing peritoneal dialysis (PD) produce less NO, indicated by the removal rate of the stable inert oxidation products of NO (NO 2 In addition, the plasma levels of naturally occurring compounds that inhibit the L-arginine-NO pathway accumulate in patients with ESRD. For example, plasma levels of asymmetric dimethylarginine (ADMA) increase in HD patients, possibly to concentrations that inhibit NOS, although this remains controversial. 9,10 This, together with plasma arginine levels in the low-normal range, 9,11 means the ratio of plasma levels of endogenous NOS inhibitors to Larginine is high in patients wit...

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

“…1 By this measure, the total amount of NO X 'excreted' in a 24-h period is decreased in patients with end-stage renal disease (ESRD) receiving peritoneal dialysis or hemodialysis, as well as in CKD patients with approximately 25% residual renal function compared with controls ( Figure 1). [2][3][4] Similar conclusions have been reached by Blum et al 5 and Wever and colleagues 6 (the latter group measured conversion of 15 N 2 -labeled arginine to citrulline in people with CKD). Although Lau and co-workers reported increased rates of arginine conversion to citrulline in ESRD patients 7 -perhaps reflecting activation of inducible nitric oxide synthase [NOS] by hemodialysis-most evidence indicates that total NO production is decreased in humans with CKD or ESRD compared with healthy individuals.…”

“…Indeed, renal L-arginine synthesis is significantly reduced (to approximately 40% of normal levels) in CKD patients; 24 however, plasma levels of L-arginine in patients with renal disease are at the low end of the normal range and are always well in excess of the K m of NOS enzymes. [2][3][4] Further, net endogenous L-arginine synthesis is preserved in ESRD patients, 7 presumably because of compensatory increases in production by nonrenal tissues.…”

“…For example, lysine and ornithine have high affinity for CAT1, but their concentrations are either low or normal in uremia. 24,29,30 Concentrations of the endogenous methylated arginines ADMA and symmetric dimethylarginine (SDMA) are increased in the plasma of ESRD and CKD patients, [2][3][4]15,[31][32][33][34] and these arginines are transported by the y+ CAT family of membrane transporters. 35,36 Both ADMA and SDMA have a relatively high affinity for CAT1 and inducible CAT2, 35,36 but in vitro, maximal uremic levels of ADMA (10 μmol/l) are too low to compete with L-arginine for membrane transporters.…”

“…There is no doubt that plasma levels of ADMA are elevated in ESRD 2,3,15,[31][32][33][34] but is this functionally significant? When cultured endothelial cells from several species and locations in the circulation were exposed to a 1 in 5 dilution of plasma from an ESRD patient, the rate of NO production decreased as a result of the presence of a competitive inhibitor of NOS.…”

The Relationship among Asymmetric Dimethylarginine (ADMA) Levels, Residual Renal Function, and Left Ventricular Hypertrophy in Continuous Ambulatory Peritoneal Dialysis Patients

“…[8,13,14] While some studies reported ADMA levels 2-6 greater in CAPD patients, [13,14] Kielstein et al did not report any difference of ADMA levels in CAPD patients and healthy subjects. [8] Additionally, there are several reports suggesting increased cardiovascular risk in hemodialysis and CAPD patients with high serum levels of ADMA.…”