Hemodialysis hypotension: Interaction of inhibitors, iNOS, and the interdialytic period

Hypotension during hemodialysis in end-stage renal disease (ESRD) not expla ined by excessive ultrafiltration has been linked to an apparent increase i n the synthesis of nitric oxide (NO), The authors tested whether the induct ion of NO synthase (iNOS) by cytokines or differences in the concentrations of inhibitors of NOS or both could account for variability in the amount o f NO synthesized during hemodialysis, Plasma levels of an inhibitor of NOS, asymmetric dimethylarginine (ADMA), L-arginine, the substrate for NOS, the end-products NO2+NO3, iNOS activity in circulating buffy Goat cells, and t heir interdialytic changes were measured in 10 patients during three. treat ments. Predialysis (0') levels of ADMA were markedly elevated with a mean o f 0.008 +/- 0.002 mu moL/mL of deproteinized plasma, compared to controls w here ADMA is present in trace amounts, ADMA levels from 30 minutes to the e nd of dialysis correlated directly with the drop in blood pressure (BP), wi th levels being much higher in patients with severe hypotension. Postdialys is ADMA levels correlated directly with the 0' systolic BP and the drop in BP at the nest dialysis treatment. NOS activity was detected in two thirds of the predialysis buffy coat samples, and appeared to increase as dialysis progressed. 0' iNOS activity correlated inversely with the 0' BP, but acti vities did not differ based on percent drop in BP, iNOS activity in the 0' samples correlated inversely with the time since the last dialysis, reflect ing the greater accumulation of dialyzable inhibitors of NOS as the interva l is prolonged. The interdialytic change in iNOS activity correlated invers ely with the drop in BP. The isoform detected immunochemically in the buffy coat samples had an M-r of 130 kDa and was reactive with antihuman iNOS, T hus, iNOS is already induced in the cells of the buffy coat in many intermi ttently hemodialyzed ESRD subjects, but its expression may be masked by inh ibitors. After 60 minutes of dialysis (too brief a time for the de novo ind uction of iNOS,) the appearance of or increase in iNOS activity suggests th at an inhibitor had been removed, Because ADMA levels are associated with h igher predialysis systolic BPs that result in a greater severity of hypoten sion, reduction in ADMA concentrations would appear to play a major role in the resumption of NO synthesis by various isoforms.