Reduction in Lung Liquid Production Caused by Nitric Oxide is Enhanced by Zaprinast † 1633

We have previously shown that nitric oxide (NO), when instilled directly into the fetal lung liquid, reduces lung liquid production (JAP 1997). We have also shown that this effect is mimicked by instilling cyclic GMP (cGMP) directly into the fetal lung liquid (Pediatr Res 1997) but not when cGMP is delivered intravascularly (Pediatr Res 1996) suggesting a local effect within the pulmonary epithelium. To further define the role of cGMP in NO induced reduction in lung liquid, we studied the effects of Zaprinast, a cGMP-specific phosphodiesterase inhibitor, on lung liquid production and pulmonary hemodynamics in twelve chronically instrumented fetal sheep at a mean gestational age of 131±3 d. Net lung luminal liquid production (Jv) was measured by plotting the change in lung luminal liquid concentration of an impermeant tracer (radiolabelled albumin or blue dextran) mixed into the lung liquid at the start of each study. Jv was measured during a 2 h baseline, then for 2 h following an intravenous dose of Zaprinast (3 mg), then for 2 h following Zaprinast and the instillation of a 10% saturated NO solution (5 ml) into the lung liquid. Results are summarized in the Table below where Qp = left pulmonary blood flow, PA = pulmonary artery pressure, CA = carotid artery pressure, LA = left atrial pressure, HR = heart rate. (* indicates P<0.01 compared to Baseline, while Y indicates P<0.01 compared to Zaprinast alone, by ANOVA.)

Table 1 No caption available.

Control (saline) instillations (n=6) caused no significant change in any variable. Zaprinast alone decreased Jv by 24% from baseline, while Zaprinast followed by NO decreased Jv by 88%. Previous studies using the same dose of NO alone in fetuses of similar gestational ages resulted in a 48% reduction in Jv. Thus, Zaprinast enhanced the effect of NO on Jv, supporting the notion that nitric oxide reduces Jv via production of cGMP. Further, the fact that Zaprinast alone also reduced Jv suggests that there is basal cGMP production in the pulmonary epithelium of late gestation fetal lambs.