Effect of a calcineurin inhibitor on Lipopolysaccharide‐induced loss of vascular tone and blood pressure decrease in conscious mice

Abstract

The immunosuppressive drug cyclosporin A (CsA) inhibits the production of nitric oxide (NO) through inhibition of the NO synthases. Especially iNOS is involved in the synthesis of large amounts of NO seen in sepsis, which leads to hypotension and multiple organ dysfunction. We hypothesized that CsA counteracts the LPS‐induced blood pressure decrease and reduced vasoreactivity in isolated murine aorta rings in a model of septic shock.To test this, blood pressure and heart rate was measured in conscious mice with indwelling catheters given a bolus (20 or 40 mg/kg) of CsA followed by continuous infusion (20 or 40 mg/kg/day) for one day before an LPS bolus was given (2 mg/kg). In vitro, studies were performed with aortic rings incubated with LPS (50 μg/ml) w/wo CsA, with CsA alone or vehicle.CsA (20 and 40 mg/kg) induced a significant increase in blood pressure (≈11 mmHg), with no effect on heart rate. After an LPS bolus, blood pressure and heart rate decreased, but there was no difference in delta blood pressure and heart rate compared to LPS alone. iNOS mRNA and protein expression was significantly reduced by CsA as well as plasma NOx excretion. CsA significantly attenuated the LPS‐induced decrease in vasoreactivity. It is concluded that CsA improve vasoreactivity in vitro while in a murine model of septic shock in vivo, CsA at 20 and 40 mg/kg did not counteract the effect of LPS on blood pressure.