Vasoactive substances regulate contractility in the fetal pulmonary vasculature. Cross-talk between endothelin-1 (ET-1) and cyclic GMP (cGMP) signal transduction mechanisms modulates vascular smooth muscle contraction. cGMP may inhibit ET-1-stimulated phosphoinositide turnover in the fetal pulmonary artery, resulting in decreased contractility. Third- and fourth-generation intralobular fetal pulmonary arteries were incubated with 35μCi/mL tritiated myo-inositol for 4 hr in oxygenated Krebs. Total inositol phosphates (IPs) were determined after a 30 min incubation with 1μM ET-1. IPs were isolated using anion exchange chromatography and results expressed in cpm/mg wet weight (cpm/mg). The arteries were preincubated with: sodium nitroprusside (SNP;10 μM) for 5 min; zaprinast (a cGMP phosphodiesterase inhibitor; 60 μM), 8-bromo-cGMP (8-br-cGMP; 2 mM), or 10μM BQ610 (an endothelin A receptor antagonist), for 10 min. Phosphoinositide generation by ET-1 alone was 289 ± 74 cpm/mg vs. 78± 10 cpm/mg for basal IP generation (n=3, p<0.05). This ET-1-stimulated response was not significantly altered by SNP, zaprinast or 8-br-cGMP. In contrast, BQ610 inhibited ET-1-stimulated phosphoinositide generation by 50 ± 3.3% (n=4, p<0.001). Pulmonary artery rings were harvested from areas adjacent to those arteries used for the IP study and were mounted in tissue baths for the measurement of isometric force generation. 8-br-cGMP (1 mM), zaprinast (60 μM), and BQ610 (10 μM) were added 20 min prior to the generation of ET-1 concentration response curves (1 nM-100 nM). 8-br-cGMP caused a significant rightward shift in both the threshold and EC50 concentrations of ET-1 although maximal contractions were not significantly reduced. In contrast, zaprinast had no effect on the ET-1 curves while BQ610 shifted the threshold concentration of ET-1 30 fold and depressed the response to 100 nM ET-1 by 87 ± 5.8% (p<0.001). The addition of 10 μM SNP during the maximal contraction to ET-1 in control curves caused a 34 ± 1.3% decrease in the force of contraction, in contrast to a previous study indicating that 1 μM SNP completely relaxed maximal contractions to norepinephrine (Steinhorn, et al., Am. J. Physiol. 268 (37): H1483-1489, 1995). In conclusion, BQ610 effectively inhibits ET-1 contractility and ET-1-stimulated phosphoinositide generation. cGMP modulates the contractile responses to lower concentrations of ET-1 (1-10 nM) but does not alter either contraction or phosphoinositide generation to high ET-1 concentrations in fetal pulmonary arteries.