Endothelial function during ischemia-reperfusion and effects of inhalation of nitric oxide

Abstract: The vascular endothelium is an important regulatory organ in circulatory physiology and plays a central role in the response to acute inflammation and ischemia/reperfusion. Activation and dysfunction of the pulmonary vascular endothelium are closely related to clinical findings of pulmonary dysfunction. The endothelial-derived relaxing factor, nitric oxide (NO), is a gas, which can be administered by inhalation and may have beneficial effects in clinical conditions of pulmonary dysfunction. In this thesis a ventilatory system for inhalation of NO was tested and used to evaluate the effects of inhalation of NO in humans after ischemia and reperfusion caused by cardiopulmonary bypass, and in a pig model of single lung transplantation combined with contralateral pneumonectomy. The endothelial function of isolated pulmonary artery segments from the pigs was simultaneously studied in organ baths. Finally, we tried to attenuate the endothelial dysfunction seen during organ preservation by adding NO donors to the preservation solution. The ventilatory system delivered accurate concentrations of NO in the inspiratory gas during both short and long term delivery. After cardiopulmonary bypass surgery, there was a dose-independent decrease in pulmonary vascular resistance (PVR) down to the lowest dose tested, 2 parts per million (ppm), indicating that inhalation of NO influences PVR in this condition and that the level at which the response is dose dependent is even lower. Pig lungs which had been preserved for 24 hours and then transplanted showed clinical signs of endothelial dysfunction, which were confirmed by organ bath studies. Inhalation of NO reduced PVR in the transplanted lung in a dose-dependent manner in the intervall 5-80 ppm NO. This response to inhalation of NO increased in direct correlation with the degree of endothelial dysfunction. In sham-operated pigs inhalation of NO reduced PVR less and the reduction was independent of dose. With the termination of NO inhalation there was an oxygen-dependent rebound effect, with pulmonary vasoconstriction in the sham-operated pigs, but not in the lung-transplanted pigs. Pharmacological manipulation of the NO pathways in the preservation solution did not improve endothelium-dependent relaxation after storage. Inhalation of NO in ppm doses is possible with adequate equipment and may be beneficial after cardiopulmonary bypass and lung transplantation. The response will depend on dose, duration of inhalation, endothelial function and oxygen tension.