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

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.

• Authors: Mette Stæhr, Apameh Khatam-Lashgari, Paul M Vanhoutte, Pernille B L Hansen, Boye L Jensen
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 465 Issue 10 Pg. 1467-75 (Oct 2013) ISSN: 1432-2013 [Electronic] Germany
• PMID: 23689317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcineurin Inhibitors
• Lipopolysaccharides
• Phenylephrine
• Nitric Oxide
• Cyclosporine
• Nitric Oxide Synthase Type II

Topics

• Animals
• Aorta (drug effects, physiopathology)
• Blood Pressure (drug effects)
• Bradycardia (drug therapy)
• Calcineurin Inhibitors
• Cyclosporine (administration & dosage, pharmacology, therapeutic use)
• Endotoxemia (drug therapy, physiopathology)
• Heart Rate (drug effects)
• Hypotension (drug therapy)
• Injections, Intravenous
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• Nitric Oxide (blood)
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Phenylephrine (pharmacology)
• Vasoconstriction (drug effects)