The role of endothelin converting enzyme inhibition during group B streptococcus-induced pulmonary hypertension in newborn piglets

An endothelin-converting enzyme mediates the conversion from low-potency pro-endothelin to potent endothelin-1 (ET-1). Increased ET-1 levels have been observed in pulmonary hypertension of various etiologies in infants. We hypothesized that increased ET-1 levels induce pulmonary hypertension during group B Streptococcus (GBS) infusion, and this can be attenuated by the administration of an endothelin-converting enzyme inhibitor (ECEI). Twenty-two unanesthetized, chronically instrumented newborn piglets received a continuous infusion of GBS (3.5 x 10(8) colony-forming units/kg/min) while exposed to 100% O2. They were randomly assigned to receive a placebo (PL) or an ECEI (phosphoramidon, 30 mg/kg i.v.) 15 min after sustained pulmonary hypertension. Comparison of hemodynamic measurements and arterial blood gases at baseline and over the first 210 min from the onset of pulmonary hypertension was performed between groups. GBS infusion caused significant increases in mean pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), and PVR/SVR, and significant decreases in cardiac output, pH, and base excess. After the administration of ECEI, a significant reduction in pulmonary artery pressure (p < 0.0001), PVR (p < 0.001), and PVR/SVR (p < 0.01) and an improvement in cardiac output (p < 0.01) were observed during GBS infusion. The decrease in pH (p < 0.001) and base excess (p < 0.001) during GBS infusion was less marked after the administration of ECEI compared with the PL. Plasma ET-1 levels were obtained in 20 additional piglets; levels were significantly lower in the ECEI compared with PL after 3 h of GBS infusion (p < 0.02). All animals in the ECEI group survived the study period as opposed to 25% survival in the PL group (p < 0.001). These data suggest that the increased circulating ET-1 levels mediate, in part, the GBS-induced pulmonary hypertension.