Indirect evidence for stimulation of nitric oxide release by tumour necrosis factor-alpha in human veins in vivo.
OBJECTIVE
The detrimental haemodynamic changes observed in septicaemia are generalised vasodilation, arterial hypotension, and hyporesponsiveness to vasopressor compound, all of which could be explained by the release of an endogenous vasodilator. Experimental and clinical evidence suggests that tumour necrosis factor-alpha (TNF) induces the expression of vascular nitric oxide (NO) synthase within hours and that NO released from smooth muscle cells could be involved in the pathogenesis 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-NG-monomethyl-arginine (L-NMMA) on alpha 1-adrenergic responsiveness (phenylephrine 1.25-8000 ng/min) was studied after prolonged local venous infusion of TNF (8.7 micrograms in 5 h) in 9 volunteers and in 6 volunteers without previous cytokine exposure.


RESULTS
Mean (+/- s.e.) maximum phenylephrine constriction (Emax) was 73 +/- 6% and log dose-rates exerting 50% of Emax (log ED50) were 3.2 +/- 0.09 (geometric mean: 1535 ng/min). Local co-administration of L-NMMA at a dose sufficiently high to block NO formation (3.4 mumol/min) increased venous sensitivity to phenylephrine threefold (log ED50 2.8 +/- 0.1, P < 0.015; geometric mean: 574 ng/min) whereas Emax was similar (73 +/- 5%). In the controls the phenylephrine dose-response relationship remained unaffected by simultaneous administration of L-NMMA.


CONCLUSIONS
As no basal release of NO occurs in hand veins without previous exposure to TNF these results provide direct evidence for induction of NO formation in the human vasculature and consecutive resistance to alpha-adrenergic venoconstriction. NO might, therefore, be a key mediator of haemodynamic impairment in humans under conditions with known elevations of circulating TNF, such as a septic shock.
Simper
D
D
Department of Internal Medicine, University Hospital, Basel, Switzerland.
Strobel
W M
WM
Linder
L
L
Haefeli
W E
WE
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D012772:Shock, Septic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014664:Vasodilation / Q000502:physiology*; D014680:Veins / Q000378:metabolism; D019323:omega-N-Methylarginine
D014409:Tumor Necrosis Factor-alpha; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase