Mitochondrial injury underlies hyporeactivity of arterial smooth muscle in severe shock

Our previous data showed membrane hyperpolarization of arteriolar smooth muscle cells (ASMCs) caused by adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)) activation contributed to vascular hyporeactivity in shock. Despite supply of oxygen and nutrients, vascular hyporeactivity to vasoconstrictor agents still remains, which may result from low ATP level. The study was designed to investigate shock-induced mitochondrial changes of rat ASMCs in the genesis and treatment of hypotension in severe shock.

The animals were divided into four groups: controls, hemorrhagic shock, CsA+shock (preadministration of cyclosporin A before bleeding), and ATR+CsA+shock (preadministration of atractyloside, followed by CsA and bleeding). ASMCs were isolated and the ultrastructure and function of ASMC mitochondria and the vasoresponsiveness to norepinephrine (NE) was measured on microcirculatory preparations.

Ultrastructurally, the hemorrhagic shock group showed swollen mitochondria with poorly defined cristae. In this group, the number of ASMCs with low mitochondrial membrane potential (Δψ(m)) was increased by 49.7%, and the intracellular ATP level was reduced by 82.1%, which led to activation of K(ATP) plasma membrane channels with resultant ASMC hyperpolarization and low vasoreactivity. These changes were reduced in the CsA+shock group. When mitochondrial damage was aggravated by ATR in the ATR+CsA+shock group, the CsA did not protect. Compared to the shock group, vasoresponsiveness to NE was much improved in the CsA+shock group.

Mitochondrial ASMC dysfunction is involved in the genesis of reduced vasoreactivity in severe shock. Mitochondrial protection may therefore be a new approach in the treatment of shock-induced hypotension.