BH4 supplementation reduces retinal cell death in ischaemic retinopathy.

Dysregulation of nitric oxide (NO) production can cause ischaemic retinal injury and result in blindness. How this dysregulation occurs is poorly understood but thought to be due to an impairment in NO synthase function (NOS) and nitro-oxidative stress. Here we investigated the possibility of correcting this defective NOS activity by supplementation with the cofactor tetrahydrobiopterin, BH4. Retinal ischaemia was examined using the oxygen-induced retinopathy model and BH4 deficient Hph-1 mice used to establish the relationship between NOS activity and BH4. Mice were treated with the stable BH4 precursor sepiapterin at the onset of hypoxia and their retinas assessed 48 h later. HPLC analysis confirmed elevated BH4 levels in all sepiapterin supplemented groups and increased NOS activity. Sepiapterin treatment caused a significant decrease in neuronal cell death in the inner nuclear layer that was most notable in WT animals and was associated with significantly diminished superoxide and local peroxynitrite formation. Interestingly, sepiapterin also increased inflammatory cytokine levels but not microglia cell number. BH4 supplementation by sepiapterin improved both redox state and neuronal survival during retinal ischaemia, in spite of a paradoxical increase in inflammatory cytokines. This implicates nitro-oxidative stress in retinal neurones as the cytotoxic element in ischaemia, rather than enhanced pro-inflammatory signalling.

CAPILLARY LEAK AND EDEMA AFTER RESUSCITATION: THE POTENTIAL CONTRIBUTION OF REDUCED ENDOTHELIAL SHEAR STRESS CAUSED BY HEMODILUTION.

ABSTRACT: Normal shear stress is essential for the normal structure and functions of the microcirculation. Hemorrhagic shock leads to reduced shear stress due to reduced tissue perfusion. Although essential for the urgent restoration of cardiac output and systemic blood pressure, large volume resuscitation with currently available solutions causes hemodilution, further reducing endothelial shear stress. In this narrative review, we consider how the use of currently available resuscitation solutions results in persistent reduction in endothelial shear stress, despite successfully increasing cardiac output and systemic blood pressure. We consider how this reduced shear stress causes (1) a failure to restore normal vasomotor function and normal tissue perfusion thus leading to persistent tissue hypoxia and (2) increased microvascular endothelial permeability resulting in edema formation and impaired organ function. We discuss the need for clinical research into resuscitation strategies and solutions that aim to quickly restore endothelial shear stress in the microcirculation to normal.