Reduction of Vascular Leakage by Imatinib Is Associated With Preserved Microcirculatory Perfusion and Reduced Renal Injury Markers in a Rat Model of Cardiopulmonary Bypass

Br J Anaesth. 2018 Jun;120(6):1165-1175. doi: 10.1016/j.bja.2017.11.095. Epub 2018 Jan 17.

Abstract

Background: Cardiopulmonary bypass during cardiac surgery leads to impaired microcirculatory perfusion. We hypothesized that vascular leakage is an important contributor to microcirculatory dysfunction. Imatinib, a tyrosine kinase inhibitor, has been shown to reduce vascular leakage in septic mice. We investigated whether prevention of vascular leakage using imatinib preserves microcirculatory perfusion and reduces organ injury markers in a rat model of cardiopulmonary bypass.

Methods: Male Wistar rats underwent cardiopulmonary bypass after treatment with imatinib or vehicle (n=8 per group). Cremaster muscle microcirculatory perfusion and quadriceps microvascular oxygen saturation were measured using intravital microscopy and reflectance spectroscopy. Evans Blue extravasation was determined in separate experiments. Organ injury markers were determined in plasma, intestine, kidney, and lungs.

Results: The onset of cardiopulmonary bypass decreased the number of perfused microvessels by 40% in the control group [9.4 (8.6-10.6) to 5.7 (4.8-6.2) per microscope field; P<0.001 vs baseline], whereas this reduction was not seen in the imatinib group. In the control group, the number of perfused capillaries remained low throughout the experiment, whilst perfusion remained normal after imatinib administration. Microvascular oxygen saturation was less impaired after imatinib treatment compared with controls. Imatinib reduced vascular leakage and decreased fluid resuscitation compared with control [3 (3-6) vs 12 ml (7-16); P=0.024]. Plasma neutrophil-gelatinase-associated-lipocalin concentrations were reduced by imatinib.

Conclusions: Prevention of endothelial barrier dysfunction using imatinib preserved microcirculatory perfusion and oxygenation during and after cardiopulmonary bypass. Moreover, imatinib-induced protection of endothelial barrier integrity reduced fluid-resuscitation requirements and attenuated renal and pulmonary injury markers.

Keywords: cardiopulmonary bypass; endothelium; microcirculation.

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Capillary Permeability / drug effects*
  • Cardiopulmonary Bypass / adverse effects*
  • Cardiopulmonary Bypass / methods
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / ultrastructure
  • Imatinib Mesylate / pharmacology*
  • Inflammation Mediators / metabolism
  • Male
  • Microcirculation / drug effects
  • Microscopy, Electron
  • Oxygen Consumption / drug effects
  • Premedication / methods
  • Protein Kinase Inhibitors / pharmacology*
  • Random Allocation
  • Rats, Wistar

Substances

  • Cytokines
  • Inflammation Mediators
  • Protein Kinase Inhibitors
  • Imatinib Mesylate