The endothelin system and cardiopulmonary dysfunction in porcine endotoxin shock

Abstract: The endothelium-derived peptide endothelin-1, acting via the endothelinA and endothelinB receptors, possesses strong vasoconstrictive properties shown to affect pulmonary and systemic circulation as well as cardiac function. During septic and endotoxin shock a marked increase in circulating plasma endothelin-1 levels is observed which is associated with morbidity, cardiac dysfunction and lung injury. Also metabolites of the cyclooxygenase pathway are increased in these conditions. The aims of the present thesis were to study the involvement of the endothelin system in endotoxin shock with special reference to pulmonary and cardiovascular dysfunction by the use of nonselective and selective endothelin receptor antagonists. Further, to elucidate the contribution to pulmonary hypertension by cyclooxygenase products. The studies were conducted in a porcine endotoxin shock model. Pulmonary and systemic haemodynamics, cardiac function, splenic, intestinal and renal blood flows together with lung compliance, gas exchange, acid-base balance and tissue prepro endothelin-1 mRNA, plasma big endothelin-1and endothelin-1-like immunoreactivity levels were measured. Endotoxin induced a hypodynamic shock with a biphasic pulmonary hypertension, a decrease in cardiac output, stroke volume, mean arterial blood pressure, an impaired pulmonary gas exchange and a systemic metabolic acidosis. This was associated with an increase in prepro endothelin-1mRNA, plasma big endothelin-1and endothelin-1-like immunoreactivity levels. Pretreatment with a nonselective endothelin receptor antagonist reduced basal vascular tone in the pulmonary, systemic and splenic circulation. The late phase of endotoxin-induced pulmonary hypertension was counteracted and cardiac output, stroke volume, splenic and intestinal blood flow were increased. A further elevation of plasma endothelin-1-like immunoreactivity but not in tissue prepro endothelin-1 mRNA or plasma big endothelin-1-like immunoreactivity levels was seen. By combining the pretreatment with cyclooxygenase inhibition also the early phase of pulmonary hypertension was counteracted. During established shock, administration of nonselective endothelin receptor antagonists abolished the pulmonary hypertension, reversed the decrease in cardiac index, counteracted a diminished stroke volume index and resulted in higher coronary blood flow compared to control animals. No negative effect on cardiac contractility was seen. Further, alveolar content of protein and leukocytes were decreased and the metabolic acidosis was counteracted. Selective endothelinA receptor antagonism during established shock was also effective in counteracting endotoxin-induced pulmonary hypertension but was essentially without effects on cardiac function, metabolic acidosis and plasma endothelin-1-like immunoreactivity levels. Selective endothelinB receptor antagonism resulted in cardiovascular collapse and death. Combining the two selective antagonists resulted in similar enhancements in pulmonary and cardiovascular function as nonselective endothelin receptor antagonism. In conclusion: In the present hypodynamic endotoxin shock model, profound effects on pulmonary and cardiovascular functions are seen. The cyclooxygenase pathway participates in the early phase of pulmonary hypertension whereas in the late phase the endothelin system is involved, largely via the endothelinA receptor. Both endothelin receptor types are involved in the disturbances in systemic circulation and cardiac function. Endothelin receptor antagonism does not affect endothelin-1synthesis but increases plasma endothelin- I-like immunoreactivity levels further, most probably due to antagonism of the endothelinB receptor. In porcine endotoxin shock, pulmonary and cardiovascular dysfunction occurs simultaneously with an increased production of endothelin-1, reflected in an increase in plasma endothelin-1 like immunoreactivity levels. Thus, the endothelin system is deeply involved in the cardiopulmonary dysfunction in the current model, and a simultaneous blockade of both the endothelinA and endothelinB receptor counteracts these disturbances, even when administered during established shock.