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Mechanisms of vasopressin hypersensitivity in septic shock

Barrett, LK; (2008) Mechanisms of vasopressin hypersensitivity in septic shock. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Patients in prolonged, catecholamine-refractory septic shock have plasma vasopressin levels inappropriately low for their hypotension, yet show enhanced responses to exogenously administered hormone. I hypothesised that altered vasopressin signalling within vascular smooth muscle is responsible for this heightened sensitivity. Both vasopressin and the catecholamine, norepinephrine vasoconstrict via sarcolemmal G protein- coupled receptors. Diversity in the calcium signalling pathways downstream of these receptors may explain the differential effect of sepsis on vascular reactivity to the two hormones. To investigate this, I characterised a long-term fluid-resuscitated, rat model of faecal peritonitis, and examined in-vivo reactivity to these vasopressors. In subsequent ex-vivo studies performed on mesenteric resistance arteries taken from these animals, I compared concentration-response characteristics, calcium mobilisation pathways, and calcium-tension relationships for the two agonists, using wire myography and fluorescence microscopy. I also measured hormone levels in a cohort of septic and non-septic intensive care patients and undertook preliminary myography studies on human small mesenteric arteries. In prolonged illness, vasopressin levels were not elevated in either the septic rats or in septic patients, despite hypotension and organ dysfunction. Pressor responses to norepinephrine, but not vasopressin, were diminished in septic rats. This pattern of reactivity was mirrored ex-vivo, with decreased efficacy of norepinephrine, but increased potency of vasopressin. Differences were apparent in the calcium mobilisation pathways contributing to norepinephrine- and vasopressin-induced responses in septic vessels, with a greater reliance on store-operated calcium channels with vasopressin, compared to voltage- gated calcium channels with norepinephrine. The norepinephrine calcium- tension relationship was similar in sham and septic vessels but, for vasopressin, there was evidence of agonist-specific increased calcium sensitivity of the contractile apparatus in the septic tissues. In conclusion, my long-term septic model was able to satisfactorily mimic the clinical scenario. I demonstrated increased vasoconstriction to vasopressin suggesting enhanced receptor coupling to calcium signalling. Vasopressin, but not norepinephrine, may be able to both effectively mobilise calcium in septic vascular smooth muscle and sensitise the contractile apparatus to its effect. In addition to providing insight into the phenomenon of vasopressin hypersensitivity in septic shock, this work supports modulation of calcium mobilisation channels and/or sensitisation pathways as a potential new therapeutic paradigm.

Type: Thesis (Doctoral)
Title: Mechanisms of vasopressin hypersensitivity in septic shock
Identifier: PQ ETD:593321
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity.
URI: https://discovery.ucl.ac.uk/id/eprint/1445995
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