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Differential effects of vasopressin and norepinephrine on vascular reactivity in a long-term rodent model of sepsis

Barrett, LK; Orie, NN; Taylor, V; Stidwill, RP; Clapp, LH; Singer, M; (2007) Differential effects of vasopressin and norepinephrine on vascular reactivity in a long-term rodent model of sepsis. CRIT CARE MED , 35 (10) 2337 - 2343. 10.1097/01.CCM.0000281861.72907.17.

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Abstract

Objective: There is escalating interest in the therapeutic use of vasopressin in septic shock. However, little attention has focused on mechanisms underlying its pressor hypersensitivity, which contrasts with the vascular hyporesponsiveness to catecholamines. We investigated whether a long-term rodent model of sepsis would produce changes in endogenous levels and pressor reactivity to exogenous norepinephrine and vasopressin comparable with those seen in septic patients.Design: In vivo and ex vivo animal study.Setting: University research laboratory.Subjects: Male adult Wistar rats.Interventions and Measurements: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Biochemical and hormonal profiles were measured at time points up to 48 hrs. Pressor responses to intravenous norepinephrine, vasopressin, and F-180, a selective V, receptor agonist, were measured at 24 hrs. Contractile responses to these drugs were assessed in mesenteric arteries taken from animals at 24 hrs using wire myography. Comparisons were made against sham operation controls.Main Results: Septic rats became unwell and hypotensive, with a mortality of 64% at 48 hrs (0% in controls). Plasma norepinephrine levels were elevated in septic animals at 24 hrs (1968 +/- 490 vs. 492 +/- 90 pg/mL in controls, p =.003), whereas vasopressin levels were similar in the two groups (4.5 +/- 0.8 vs. 3.0 +/- 0.5 pg/mL, p = not significant). In vivo, the pressor response to norepinephrine was markedly reduced in the septic animals, but responses to vasopressin and F-180 were relatively preserved. In arteries from septic animals, norepinephrine contractions were decreased (efficacy as measured by maximum contractile response, E-max: 3.0 +/- 0.3 vs. 4.7 +/- 0.2 mN, p <.001). In contrast, the potency of vasopressin (expressed as the negative log of the concentration required to produce 50% of the maximum tension, pD(2): 9.1 +/- 0.04 vs. 8.7 +/- 0.05, p <.001) and F-180 (pD(2) 8.2 +/- 0.04 vs. 7.6 +/- 0.02, p <.001) was enhanced (n >= 6 for all groups).Conclusions: This long-term animal model demonstrates changes in circulating vasoactive hormones similar to prolonged human sepsis, and decreased pressor sensitivity to norepinephrine. Ex vivo sensitivity to vasopressin agonists was heightened. This model is therefore appropriate for the further investigation of mechanisms underlying vasopressin hypersensitivity, which may include receptor or calcium-handling alterations within the vasculature.

Type: Article
Title: Differential effects of vasopressin and norepinephrine on vascular reactivity in a long-term rodent model of sepsis
DOI: 10.1097/01.CCM.0000281861.72907.17
Keywords: septic shock, vasopressin, norepinephrine, rat, mesenteric artery, myography, VASODILATORY SEPTIC SHOCK, NITRIC-OXIDE SYNTHASE, ARGININE-VASOPRESSIN, OXYTOCIN RELEASE, CONSCIOUS RATS, IN-VITRO, RESPONSES, ENDOTOXIN, INFUSION, SYSTEM
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Internal Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: http://discovery.ucl.ac.uk/id/eprint/134882
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