Angiotensin II receptor type 1 blockade improves hyporesponsiveness to vasopressors in septic shock.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Angiotensin II Type 1 Receptor Blockers/*pharmacology ; Arterial Pressure/*drug effects ; Hypotension/*drug therapy ; Losartan/*pharmacology ; Renin-Angiotensin System/*drug effects ; Shock, Septic/*drug therapy ; Vasoconstriction/*drug effects ; Vasoconstrictor Agents/*pharmacology; Angiotensin II/metabolism ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Hypotension/metabolism ; Hypotension/microbiology ; Hypotension/physiopathology ; Inflammation Mediators/blood ; Rats, Wistar ; Receptor, Angiotensin, Type 2/drug effects ; Receptor, Angiotensin, Type 2/metabolism ; Shock, Septic/metabolism ; Shock, Septic/microbiology ; Shock, Septic/physiopathology ; Rats
    • Abstract:
      Sepsis activates the renin-angiotensin system and the production of angiotensin II, which has a key role in the regulation of blood pressure through AT 1 receptors. However, excessive activation of AT 1 receptor is associated with deleterious effects. We investigated the consequences of a differential blockade of AT 1 receptor caused by two doses of losartan (0.25 mg/kg or 15 mg/kg, s.c), a selective AT 1 receptor antagonist on sepsis outcome. These doses reduced the effect of angiotensin II in normal rats by 30% and >90% 8 h after administration, respectively, but only the higher dose maintained its inhibitory effect (~70%) 24 h after injection. Sepsis was induced by cecal ligation and puncture (CLP). Losartan was injected 2 h after CLP and parameters were evaluated 6 and 24 h after CLP. Septic rats developed hypotension and hyporesponsiveness to vasoconstrictors, an intense inflammatory process and increase in plasma markers of organ dysfunction. The lower dose of losartan improved the vasoconstrictive response to phenylephrine and angiotensin II, reduced lung myeloperoxidase and prevented leukopenia 24 h after CLP, but it did not reduce NOS-2 expression, plasma IL-6 levels or organ injury parameters of septic rats. On the other hand, the higher dose of losartan worsened the response to vasoconstrictors, potentiated the hypotension and increased further levels of creatine, urea and lactate in septic rats. Therefore, an early and partial blockade of AT 1 receptor with a low dose of losartan may counteract sepsis-induced refractoriness to vasoconstrictors thus providing an opportunity to improve the outcome of this condition.
      (Copyright © 2021 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Angiotensin II; Renin-angiotensin system; Sepsis; Vascular dysfunction
    • Accession Number:
      0 (Agtr2 protein, rat)
      0 (Angiotensin II Type 1 Receptor Blockers)
      0 (Inflammation Mediators)
      0 (Receptor, Angiotensin, Type 2)
      0 (Vasoconstrictor Agents)
      11128-99-7 (Angiotensin II)
      JMS50MPO89 (Losartan)
    • Publication Date:
      Date Created: 20210222 Date Completed: 20210518 Latest Revision: 20240226
    • Publication Date:
      20240226
    • Accession Number:
      10.1016/j.ejphar.2021.173953
    • Accession Number:
      33617825