INDIRECT EVIDENCE FOR STIMULATION OF NITRIC-OXIDE RELEASE BY TUMOR-NECROSIS-FACTOR-ALPHA IN HUMAN VEINS IN-VIVO

Objectives: The detrimental haemodynamic changes observed in septicaem ia are generalised vasodilation, arterial hypotension, and hyporespons iveness to vasopressor compounds, all of which could be explained by t he release of an endogenous vasodilator. Experimental and clinical evi dence suggests that tumour necrosis factor-alpha (TNF) induces the exp ression of vascular nitric oxide (NO) synthase within hours and that N O released from smooth muscle cells could be involved in the pathogene sis of septic shock. The aim of this study was to investigate the role of NO in the vascular effects of TNF. Methods: Using the dorsal hand vein compliance technique, the effect of the NO synthase inhibitor L-N -G-monomethyl-arginine (L-NMMA) on alpha(1)-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local ven ous infusion of TNF (8.7 mu g in 5 h) in 9 volunteers and in 6 volunte ers without previous cytokine exposure. Results: Mean (+/-s.e.) maximu m phenylephrine constriction (E(max)) was 73 +/- 6% and log dose-rates exerting 50% of E(max) (log ED(50)) were 3.2 +/- 0.09 (geometric mean : 1535 ng/min). Local co-administration of L-NMMA at a dose sufficient ly high to block NO formation (3.4 mu mol/min) increased venous sensit ivity to phenylephrine threefold (log ED(50) 2.8 +/- 0.1, P < 0.015; g eometric mean: 574 ng/min) whereas E(max) was similar (73 +/- 5%). In the controls the phenylephrine dose-response relationship remained una ffected by simultaneous administration of L-NMMA. Conclusions: As no b asal release of NO occurs in hand veins without previous exposure to T NF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to alpha-adrenerg ic venoconstriction. NO might, therefore, be a key mediator of haemody namic impairment in humans under conditions with known elevations of c irculating TNF, such as a septic shock.