Local venous responses to endotoxin in humans.
BACKGROUND
Septic shock is characterized by arterial and venous dilatation and decreased responsiveness to vasoconstrictors. We have developed a method to explore the effects and mechanisms of action of administration of endotoxin into a blood vessel in vivo.


RESULTS
Endotoxin was instilled into a dorsal hand vein for 1 hour and then removed. A dose-response curve to norepinephrine was constructed before and 1, 2, 3, and 4 hours after endotoxin. In a separate study, dose-response curves to norepinephrine were constructed in two separate veins on the same hand, only one of which received endotoxin. Sympathetic-mediated venoconstrictor responses were also studied. Cyclooxygenase inhibitors, nitric oxide synthase inhibitors, and hydrocortisone were used to explore the mechanisms of the effects seen. Endotoxin caused a rightward shift in the dose-response curve to norepinephrine. The effect was greatest at 1 hour (maximal constriction: before endotoxin, 87 +/- 4%; after endotoxin, 52 +/- 8%; occlusion n = 4; P < .05) and returned to normal by 4 hours. In addition, deep-breath venoconstrictor responses were abolished in the endotoxin-treated vein. Instillation of endotoxin daily for 3 days resulted in the development of tolerance (maximal constriction to norepinephrine after endotoxin; day 1, 39 +/- 6%; day 2, 67 +/- 7%; day 3, 85 +/- 7%). Cyclooxygenase and/or nitric oxide synthase inhibitors did not alter the response to endotoxin, whereas prior administration of hydrocortisone abolished the effects.


CONCLUSIONS
Instillation of endotoxin caused a glucocorticoid-inhibitable hyporesponsiveness to the constrictor effects of norepinephrine and abolished sympathetically induced and drug-induced venoconstriction. This acute response does not appear to be mediated by nitric oxide or prostanoids. Direct vascular tolerance to endotoxin occurs on repeated administration.
Bhagat
K
K
Centre for Clinical Pharmacology, University College London Medical School, UK.
Collier
J
J
Vallance
P
P
D000328:Adult; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006225:Hand / Q000098:blood supply; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009638:Norepinephrine / Q000494:pharmacology; D013997:Time Factors; D014661:Vasoconstriction; D014680:Veins / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D006854:Hydrocortisone; D009638:Norepinephrine