CARDIOPULMONARY BYPASS AND CIRCULATORY ARREST INCREASE ENDOTHELIN-1 PRODUCTION AND RECEPTOR EXPRESSION IN THE LUNG

Background: Endothelin-1 has been shown to be a mediator of pulmonary hypertension after cardiopulmonary bypass and deep hypothermic circula tory arrest. It is not known whether the mechanism is increased produc tion of endothelin-1 or alterations in expression of endothelin-1 rece ptors in the lung. This study was designed to test the hypothesis that circulatory arrest increases endothelin-1 mRNA levels and endothelin- 1 receptor expression in the lung. Methods and results: Twenty-four pi glets (7 to 30 days old) were studied randomly either at baseline (con trols, n = 12) or after cardiopulmonary bypass with 30 minutes of circ ulatory arrest (deep hypothermic circulatory arrest, n = 12). Lungs an d pulmonary arteries were harvested immediately after hemodynamic data collection. Deep hypothermic circulatory arrest significantly increas ed pulmonary vascular resistance (p < 0.01). Deep hypothermic circulat ory arrest also produced a significant increase in endothelin-1 mRNA l evels in the pulmonary arteries (149 +/- 55 pg vs 547 +/- 111 pg, p = 0.007). There was no significant change in the pulmonary parenchymal e ndothelin-1 mRNA levels (4102 +/- 379 pg vs 4623 +/- 308 pg, p = 0.32) . Ligand binding studies of the lung parenchyma revealed a single spec ific endothelin-1 binding site with an EC(50) value (effective concent ration causing 50% of the maximum response) of about 1 x 10(-8) mol/L, consistent with the endothelin B subtype. Deep hypothermic circulator y arrest resulted in a significant increase in the number of endotheli n-1 receptors in the lung (109 +/- 6 fmol/mg total protein to 135 +/- 9 fmol/mg total protein, p = 0.02). Conclusions: Deep hypothermic circ ulatory arrest increases production of endothelin-1 by the pulmonary v ascular endothelium. Endothelin-1 production in the pulmonary parenchy ma does not change. Expression of endothelin B receptors in the pulmon ary parenchyma also increases after cardiopulmonary bypass with deep h ypothermic circulatory arrest. This study supports the hypothesis that deep hypothermic circulatory arrest results in pulmonary vascular end othelial activation with increased endothelin-1 mRNA production.