Abstract 1774 Poster Session I, Saturday, 5/1 (poster 90)

Nitric oxide (NO) stimulates soluble guanylate cyclase to produce the vasodilator cGMP. In the lung, cGMP is hydrolyzed primarily by the Type 5 phosphodiesterase (PDE5). We studied the effects of E4021, a highly selective inhibitor of PDE5, in near term fetal lambs. In the first protocol, fifth generation pulmonary arteries (PA) and veins (PV) (n = 6) were isolated and studied using standard tissue bath techniques. Vessels were pretreated with indomethacin and preconstricted with norepinephrine. E4021 (0.001 µM-10 µM) relaxed PA from control lambs by 57 ± 10% (maximal relaxation at 10 µM), a response which was completely blocked by the non-specific NO synthase (NOS) inhibitor, L-nitro arginine (LNA). PV from control lambs relaxed completely to 0.1 µM E4021 (p < 0.05 vs PA), a response not inhibited by LNA. In the second protocol, near term fetal lambs (n = 8) were instrumented for chronic vascular access and measurement of net lung liquid production (Jv). Hemodynamic responses to a left pulmonary artery (LPA) infusion of E4021 (30 µg/min for 20 min) were measured before and after an LPA infusion of LNA (1 mg/min for 30 min). E4021 did not change LPA pressure, aortic pressure, or any blood gas value. However, it significantly increased pulmonary blood flow (QLPA) and decreased PVR. LNA significantly blocked the pulmonary hemodynamic effects of E4021. E4021 decreased Jv, a response that was unaffected by LNA (n = 5). The table represents the data expressed as a mean ± SEM. *p < 0.05 vs baseline by ANOVA. We conclude that E4021 increases pulmonary blood flow in fetal lambs by a NOS-dependent increase in cGMP in the pulmonary arterial vasculature. In contrast, E4021 decreases net lung liquid production by a mechanism independent of NOS. We speculate that this effect is in part due to the potent effects of E4021 in pulmonary veins, and that cGMP may be produced by an alternate source in these vessels.

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