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


METHODS
In vivo and ex vivo animal study.


METHODS
University research laboratory.


METHODS
Male adult Wistar rats.


METHODS
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 V1 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.


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, Emax: 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, pD2: 9.1 +/- 0.04 vs. 8.7 +/- 0.05, p < .001) and F-180 (pD2 8.2 +/- 0.04 vs. 7.6 +/- 0.02, p < .001) was enhanced (n > or = 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.
Barrett
Lucinda K
LK
Wolfson Institute for Biomedical Research, and the Department of Medicine, University College London, London, UK.
Orie
Nelson N
NN
Taylor
Valerie
V
Stidwill
Raymond P
RP
Clapp
Lucie H
LH
Singer
Mervyn
M
D000818:Animals; D004195:Disease Models, Animal; D009638:Norepinephrine / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy*; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*; D014666:Vasomotor System / Q000187:drug effects*; D014667:Vasopressins / Q000097:blood / Q000627:therapeutic use*
C110660:F-180 vasoconstrictor peptide; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D009638:Norepinephrine