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The calcineurin inhibitor cyclosporine A improves lipopolysaccharide-induced vascular dysfunction but does not rescue from cardiovascular collapse in endotoxemic mice

  • Molecular and cellular mechanisms of disease
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Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The calcineurin inhibitor cyclosporine A (CsA) improves survival in endotoxemic mice. It was hypothesized that CsA counteracts the bradycardia and hypotension characteristic of endotoxemia. Vascular reactivity was determined in lipopolysaccharide (LPS; 50 μg/mL)-treated mouse aortic rings suspended in a myograph. Arterial blood pressure and heart rate were measured continuously with indwelling catheters in conscious mice treated with CsA and a bolus injection of LPS (2 mg/kg). The α1-adrenoceptor agonist phenylephrine induced stable tension of aortic rings that were attenuated significantly by LPS. Co-incubation of rings with LPS and CsA (1 × 10−7 mol/L–1 × 10−5 mol/L) restored vascular reactivity to phenylephrine. Intravenous administration of CsA (20 and 40 mg/kg/day) to mice induced a significant increase (by approximately 10 mmHg) in mean arterial blood pressure (MAP), with no effect on heart rate. An LPS bolus led to significant decreases in MAP (by approximately 30 mmHg) and heart rate (to 50 % of baseline). CsA-treated LPS-mice exhibited higher MAP at some (20 mg/kg) or all (40 mg/kg) time points after LPS. The decrease in MAP (Δ pressure) was similar between vehicle- and CsA-treated groups. The 50 % decrease in heart rate was not affected by CsA. Inducible nitric oxide synthase (iNOS) mRNA and protein levels in LPS-treated mice organs and plasma NO x concentration were significantly reduced by CsA. It is concluded that in a murine model of endotoxemia, increased peripheral vascular resistance and suppression of systemic NO formation by cyclosporine A are not sufficient to prevent cardiovascular collapse, which is caused primarily by compromised cardiac function.

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Acknowledgements

We thank Vivi Monrad, Lis Teusch and Kenneth Andersen for expert technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by The Danish Heart Association; The Novo Nordisk Foundation; Alfred Andersens Fund; The Danish Research Council for Health and Disease; The Danish Cardiovascular Research Academy; The AP Møller Foundation and Leo Pharma´s Hypertensionslegat.

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Authors and Affiliations

  1. Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark

    Mette Stæhr, Apameh Khatam-Lashgari, Pernille B. L. Hansen & Boye L. Jensen

  2. Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong

    Paul M. Vanhoutte

  3. Department of Pharmacy, King Saud University, Riyadh, Saudi Arabia

    Paul M. Vanhoutte

  4. Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, J. B. Winslowsvej 21, 3, 5000, Odense C, Denmark

    Boye L. Jensen

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  1. Mette Stæhr
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Correspondence to Boye L. Jensen.

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Stæhr, M., Khatam-Lashgari, A., Vanhoutte, P.M. et al. The calcineurin inhibitor cyclosporine A improves lipopolysaccharide-induced vascular dysfunction but does not rescue from cardiovascular collapse in endotoxemic mice. Pflugers Arch - Eur J Physiol 465, 1467–1475 (2013). https://doi.org/10.1007/s00424-013-1290-4

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  • DOI: https://doi.org/10.1007/s00424-013-1290-4

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