دورية أكاديمية
Calcium desensitisation in late polymicrobial sepsis is associated with loss of vasopressor sensitivity in a murine model.
العنوان: | Calcium desensitisation in late polymicrobial sepsis is associated with loss of vasopressor sensitivity in a murine model. |
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المؤلفون: | Reddi BA; Intensive Care Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000, Australia, benjamin.reddi@adelaide.edu.au., Beltrame JF, Young RL, Wilson DP |
المصدر: | Intensive care medicine experimental [Intensive Care Med Exp] 2015 Dec; Vol. 3 (1), pp. 36. Date of Electronic Publication: 2015 Jan 31. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Springer-Verlag, GmbH Country of Publication: Germany NLM ID: 101645149 Publication Model: Print-Electronic Cited Medium: Print ISSN: 2197-425X (Print) Linking ISSN: 2197425X NLM ISO Abbreviation: Intensive Care Med Exp Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: Heidelberg, Germany : Springer-Verlag, GmbH |
مستخلص: | Background: Sepsis is characterised by diminished vasopressor responsiveness. Vasoconstriction depends upon a balance: Ca(2+)-dependent myosin light-chain kinase promotes and Ca(2+)-independent myosin light-chain phosphatase (MLCP) opposes vascular smooth muscle contraction. The enzyme Rho kinase (ROK) inhibits MLCP, favouring vasoconstriction. We tested the hypothesis that ROK-dependent MLCP inhibition was attenuated in late sepsis and associated with reduced contractile responses to certain vasopressor agents. Methods: This is a prospective, controlled animal study. Sixteen-week-old C57/BL6 mice received laparotomy or laparotomy with caecal ligation and puncture (CLP). Antibiotics, fluids and analgesia were provided before sacrifice on day 5. Vasoconstriction of the femoral arteries to a range of stimuli was assessed using myography: (i) depolarisation with 87 mM K(+) assessed voltage-gated Ca(2+) channels (L-type, Cav1.2 Ca(2+) channels (LTCC)), (ii) thromboxane A2 receptor activation assessed the activation state of the LTCC and ROK/MLCP axis, (iii) direct PKC activation (phorbol-dibutyrate (PDBu), 5 μM) assessed the PKC/CPI-17 axis independent of Ca(2+) entry and (iv) α1-adrenoceptor stimulation with phenylephrine (10(-8) to 10(-4) M) and noradrenaline (10(-8) to 10(-4) M) assessed the sum of these pathways plus the role of the sarcoplasmic reticulum (SR). ROK-dependent MLCP activity was indexed by Western blot analysis of P[Thr855]MYPT. Parametric and non-parametric data were analysed using unpaired Student's t-tests and Mann-Whitney tests, respectively. Results: ROK-dependent inhibition of MLCP activity was attenuated in both unstimulated (n = 6 to 7) and stimulated (n = 8 to 12) vessels from mice that had undergone CLP (p < 0.05). Vessels from CLP mice demonstrated reduced vasoconstriction to K(+), thromboxane A2 receptor activation and PKC activation (n = 8 to 13; p < 0.05). α1-adrenergic responses were unchanged (n = 7 to 12). Conclusions: In a murine model of sepsis, ROK-dependent inhibition of MLCP activity in vessels from septic mice was reduced. Responses to K(+) depolarisation, thromboxane A2 receptor activation and PKC activation were diminished in vitro whilst α1-adrenergic responses remained intact. Inhibiting MLCP may present a novel therapeutic target to manage sepsis-induced vascular dysfunction. |
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تواريخ الأحداث: | Date Created: 20150729 Date Completed: 20150728 Latest Revision: 20200930 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC4512972 |
DOI: | 10.1186/s40635-014-0036-8 |
PMID: | 26215803 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2197-425X |
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DOI: | 10.1186/s40635-014-0036-8 |