RELEASE OF ENDOTHELIN IN RELATION TO TUMOR-NECROSIS-FACTOR-ALPHA IN PORCINE PSEUDOMONAS-AERUGINOSA-INDUCED SEPTIC SHOCK

Septic shock is characterized by surges of tumor necrosis factor-alpha (TNF-alpha) along with myocardial dysfunction and systemic hypotensio n. TNF-alpha promotes the release of immunoreactive endothelin (ET). B ecause TNF-alpha is elevated in septic shock, we hypothesized that ele vated levels of endothelin can contribute to cardiac dysfunction and h ypotension. We infused live Pseudomonas aeruginosa into anesthetized, hemodynamically monitored young swine and measured ET and TNF-alpha. S eptic swine developed systemic arterial hypotension and had significan tly elevated TNF-alpha (4.15 +/- .41 U/ml at 1 h versus .40 +/- .13 U/ ml at time zero) compared to control animals. ET levels were significa ntly elevated at 4 h (52.38 +/- 12.88 pg/ml vs. 10.45 +/- 1.82 pg/ml a t time zero) and correlated negatively with the decline in cardiac out put. We then passively immunized swine using anti TNF-alpha prior to t he induction of sepsis to examine if TNF played a central role in the release ET. The anti TNF-alpha effectively removed circulating TNF-alp ha bioactivity in septic animals. Anti-TNF-alpha-treated animals did n ot develop significant systemic arterial hypotension and had significa nt attenuation in endothelin (1 9.01 +/- 4.18 pg/ml at 4 h compared to 52.38 +/- 12.88 pg/ml in septic animals at 4 h) which correlated with preservation of cardiac output. TNF-alpha may cause cardiac dysfuncti on in sepsis syndrome through increased release of ET.