Increased plasma tetrahydrobiopterin in septic shock is a possible therapeutic target

Abstract

Hemoperfusion with a column of polymyxin B immobilized on fibers (PMX) has been used to adsorb endotoxin in-patients with septic shock. PMX hemoperfusion (PMX-H) increases blood pressure (BP) too rapidly for the effect to be attributable to endotoxin removal. Since inducible NO synthase (iNOS) is known to be involved in the profound hypotension, we hypothesized that a decrease of tetrahydrobiopterin (BH 4), an essential cofactor of iNOS, might account for the rapid effect of PMX-H on BP, if plasma BH 4 is increased concomitantly with NO in septic shock patients and if PMX can decrease BH 4. BH 4 was evaluated by measuring total biopterin, which can include derivatives of BH 4 by using high-performance liquid chromatography (HPLC). We confirmed that PMX fabric time dependently decreased total biopterin concentration in vitro. The plasma level of total biopterin in shock patients was indeed markedly elevated compared with that in volunteers (131.1±33.4 vs. 10.4±1.1 nM, n=5, P<0.01). Level of NO metabolites (NOx) were 173.9±104.7 versus 28.7±11.6 μM ( P<0.01). In beagles, plasma total biopterin was 44.7±6.9 nM at baseline, reached 118±28.6 nM after lipopolysaccharide (LPS) injection, and fell to 70.2±15.8 nM after PMX-H. Plasma NOx concentration was increased from 15.2±4.2 to 41.0±7.5 μM by LPS treatment. BP was 130±11.3 mmHg at baseline, 82.2±8.3 mmHg at 14 h after LPS, and 115.2±16.0 mmHg after PMX-H. In rats, plasma total biopterin was 88.8±1.5 nM at baseline, 383.7±144.2 nM after LPS and 177.0±14.2 nM after PMX-H. Plasma NOx was also increased after LPS (from 34.6±4.4 to 1445.6±376.0 nM). The marked increase in total biopterin concomitantly with NOx in septic shock patients and its reduction by PMX-H in animal models of septic shock are consistent with our hypothesis, and appear to justify further research on BH 4 removal as a potential therapeutic target.