This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhagat, K. Articles by Vallance, P. Search for Related Content PubMed PubMed Citation Articles by Bhagat, K. Articles by Vallance, P. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB HYDROCORTISONE

(Circulation. 1996;94:490-497.)
© 1996 American Heart Association, Inc.

Articles

Local Venous Responses to Endotoxin in Humans

Kiran Bhagat, BSc, MRCP; Joe Collier, MD, FRCP; Patrick Vallance, MD, FRCP

the Centre for Clinical Pharmacology, The Cruciform Project, University College London Medical School, UK.

Correspondence to Dr Kiran Bhagat, Centre for Clinical Pharmacology, Rayne Institute, University Street, University College London, London WCIE 6JJ, UK.

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.

Methods and 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%; 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.

Key Words: norepinephrine • shock • veins • occlusion

This article has been cited by other articles:

				S. Cuzzocrea, E. Mazzon, R. Di Paola, E. Esposito, H. Macarthur, G. M. Matuschak, and D. Salvemini A Role for Nitric Oxide-Mediated Peroxynitrite Formation in a Model of Endotoxin-Induced Shock J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 73 - 81. [Abstract] [Full Text] [PDF]

				J. Pleiner, F. Mittermayer, G. Schaller, C. Marsik, R. J. MacAllister, and M. Wolzt Inflammation-induced vasoconstrictorhyporeactivity is caused by oxidative stress J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1656 - 1662. [Abstract] [Full Text] [PDF]

				M. C. Reade and J. D. Young Editorial I: Of mice and men (and rats): implications of species and stimulus differences for the interpretation of studies of nitric oxide in sepsis Br. J. Anaesth., February 1, 2003; 90(2): 115 - 121. [Full Text] [PDF]

				D. Annane, V. Sebille, C. Charpentier, P.-E. Bollaert, B. Francois, J.-M. Korach, G. Capellier, Y. Cohen, E. Azoulay, G. Troche, et al. Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients With Septic Shock JAMA, August 21, 2002; 288(7): 862 - 871. [Abstract] [Full Text] [PDF]

				J. Pleiner, E. Heere-Ress, H. Langenberger, A. E. Sieder, M. Bayerle-Eder, F. Mittermayer, G. Fuchsjager-Mayrl, J. Bohm, B. Jansen, and M. Wolzt Adrenoceptor Hyporeactivity Is Responsible for Escherichia coli Endotoxin-Induced Acute Vascular Dysfunction in Humans Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 95 - 100. [Abstract] [Full Text] [PDF]

				D. Annane Replacement therapy with hydrocortisone in catecholamine-dependent septic shock Innate Immunity, August 1, 2001; 7(4): 305 - 309. [Abstract] [PDF]

				A. M Shah Inducible nitric oxide synthase and cardiovascular disease Cardiovasc Res, January 1, 2000; 45(1): 148 - 155. [Full Text] [PDF]

				K. Silamut, N. H. Phu, C. Whitty, G. D.H. Turner, K. Louwrier, N. T.H. Mai, J. A. Simpson, T. T. Hien, and N. J. White A Quantitative Analysis of the Microvascular Sequestration of Malaria Parasites in the Human Brain Am. J. Pathol., August 1, 1999; 155(2): 395 - 410. [Abstract] [Full Text] [PDF]

				K. Bhagat, A. D Hingoranil, M. Palacios, I. G Charles, and P. Vallance Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS Cardiovasc Res, March 1, 1999; 41(3): 754 - 764. [Abstract] [Full Text] [PDF]

				K. Bhagat and P. Vallance Inflammatory Cytokines Impair Endothelium-Dependent Dilatation in Human Veins In Vivo Circulation, November 4, 1997; 96(9): 3042 - 3047. [Abstract] [Full Text]