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.

Activation of central GABAB receptors offsets the cyclosporine counteraction of endotoxic cardiovascular outcomes in conscious rats

“…In the other study, the same cardiovascular and inflammatory responses elicited by endotoxemia were largely eliminated after consequent administration of CSA . This latter study finding is consistent with the capacity of CSA to increase vascular tone and blood pressure (BP) , decrease vascular expression of inducible nitric oxide synthase , and reduce nitric oxide production in macrophages exposed to inflammatory stimuli . Moreover, it emphasizes the importance of CSA as a potential therapeutic strategy for the management of endotoxic inflammatory and cardiovascular insults.…”

Quantification of microcirculatory blood flow: a sensitive and clinically relevant prognostic marker in murine models of sepsis

“…In both models of sepsis, CO and stroke volume were found to decline initially, indicating impaired cardiac function as of 6 h, consistent with previous reports ( 27 , 29 , 51 ) ( Table 2 ). Neither the presence of a telemetry probe during echocardiographic recording, nor the induction of anesthesia and echocardiographic monitoring in telemetered mice was found to alter the hemodynamic profile relative to uninstrumented mice or previous reports ( 27 , 29 , 35 , 46 , 50 , 51 ), suggesting that both techniques can be used in concert without mutual interference.…”

Effect of Resveratrol on Blood Rheological Properties in LPS-Challenged Rats

“…This result indicates that the low dose of LPS challenge in the healthy rats resulted in a slight decrease in the blood pressure that was on behalf of a mild abdominal infection. The results from the work of Staehr et al (2013) showed that LPS bolus led to significant decreases in MAP (by approximately 30 mmHg) and heart rate (50% of baseline); moreover, the continuous infusion of cyclosporine A (CsA, 20 or 40 mg/kg/24 h), which is similar to Res, did not demonstrate an obvious effect on MAP and heart rate at 0–24 h after LPS administration. In the present work, the Res treatment had no obvious effect on the MAP levels of the rats subjected to LPS challenge, which was similar with the role of CsA in the previous study (Staehr et al, 2013).…”