Endothelial dysfunction in the pulmanory circulation after cardiopulmonary bybass : with special reference to the reactivity to acetylcholine

Abstract: The endothelium is important as a physical barrier between the bloodstream and the body tissues. It also plays an important role in the control of vasomotor tone, coagulation, and for the interaction between the vessel wall, leukocytes and platelets. One of the most important regulators released from the endothelium is nitric oxide (NO). It is released from endothelial cells after conversion of L- arginine to NO and L-citrulline. Acetylcholine stimulates this reaction through activation of the enzyme nitric-oxide synthase. Nitric oxide regulates vasomotor tone through stimulation of guanylate cyclase in the vascular smooth muscle cell. The rise in c-GMP leads to vascular smooth muscle relaxation and a reduced vascular resistance. Ischemia-reperfusion attenuates this endothelial function. During cardiopulmonary bypass (CPB) there is no blood flow through the pulmonary artery followed by reperfusion. An attenuated reaction to acetylcholine in the pulmonary circulation after CPB in children had earlier been reported. In the studies presented here, the aim was to investigate in adult patients the time course of this endothelial dysfunction after heart surgery with CPB (study I and II), to compare acetylcholine reactivity in the pulmonary circulation after surgery in coronary artery bypass grafting (CABG) patients operated with or without CPB (study III), and to test if the post-bypass endothelial dysfunction could be reduced or prevented by treatment with L-arginine, the precursor of NO, during surgery (study IV) or by pre-treatment with antioxidants; vitamin E and C combined with allopurinol and acetylcysteine (study V). Altogether 109 adult patients scheduled for elective heart surgery were included in the studies. Acetylcholine-reactivity in the pulmonary circulation was tested with measurements of the pulmonary vascular resistance, before and during an infusion of acetylcholine, using a Swan-Ganz catheter. In study 1, the acetylcholine-reactivity in the pulmonary circulation was decreased at 1-2 and 4 hours after CPB At 8 and 24 hours after CPB it had returned back to the pre-bypass level. In study 11, the response to acetylcholine immediately after weaning from CPB did not differ from the response before bypass and deteriorated first 1-2 hours later, indicating reperfusion injury. The acetylcholine-reactivity was better maintained in CABG patients operated without CPB compared to patients operated with CPB (Study 111). In contrast to experimental studies, L-arginine, tested in both a high and a low dose, was without effect. The acetylcholine-reactivity was identical to that seen in the placebo patients (study IV). However, patients pre-treated with antioxidants had a better preserved endothelial function after CPB compared to patients treated with placebo (Study V). In conclusion a reversible endothelial dysfunction in the pulmonary circulation, in terms of vasodilation in response to acetylcholine, was demonstrated after CPB The time course indicated reperfusion injury. L-arginine was without effect but pre-treatment with antioxidants had a protective effect. Patients operated without CPB, with maintained flow through the pulmonary artery during surgery, had a better response to acetylcholine.