Vasodilator effects phospodiesterase 1 and 5 inhibitors during postnatal pulmonary maturation L. Moreno, F. Pérez-Vizcaíno, A. Cogolludo, B Losada, M. Moro, C. Lugnier*, J. Tamargo. Dept. of Pharmacology. Univ. Complutense. Madrid. *CNRS-UMR 7034. Illkirch.

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During the first days of extrauterine life, pulmonary vascular resistance is progressively reduced to reach the pulmonary pressure values of the adult (Haworth et al., 1981). A maturational increase in NO bioactivity plays a key role in this process (Pérez-Vizcaíno et al., 2002). Phosphodiesterases (PDE) regulate NO bioactivity through the degradation of cyclic nucleotides. In the present study, we have analysed: a) the effects of PDE5 inhibitors sildenafil (SIL), dipyridamole (DIP) and zaprinast (ZAP) and the PDE1 inhibitor vinpocetine (VIN) in isolated pulmonary arteries during postnatal maturation and b) the role of PDE in the NO-dependent pulmonary maturation.

Endothelium denuded intrapulmonary artery rings (0.5-1 mm of internal diameter) from male piglets of 3-18 h (newborn) or 2-3 weeks of age were mounted in Krebs solution for isometric force recording and stimulated with U46619 (100 nM). PDE activity was measured in arterial homogenates by a two step assay using [³H]-Cyclic GMP.

The PDE inhibitors produced vasodilator responses with the following order of potency: SIL >> DIP > ZAP >> VIN (Table 1) and these effects were not modified by postnatal development. The effects of PDE5 inhibitors were unaffected by the presence of endothelium but markedly inhibited by the guanylate cyclase inhibitor 1 µM ODQ (E_max was reduced from 56±6% to 26 ±7%). The peak of the transient vasodilator responses to NO gas increased with postnatal age (Table 1) but was not affected by PDE5 or PDE1 inhibition. However, the half-life of the vasodilator response to 200 nM NO was similar in the two age groups (85±8 and 88±17 s, respectively) but was significantly increased by 10 µM ZAP, 1 µM DIP and 3 nM SIL (e.g. in newborns, half life increased to 139±17, 216±50, 141±16 s, respectively) but not by 30 µM VIN (88±7 s). The vasodilator response to nitroprusside (NP, Table 1) was potentiated (p< 0.05) by SIL in a concentration-dependent manner in both age groups animals but not by 30 µM VIN. Both total and PDE5 cGMP-dependent activity increased with postnatal age (65±10 and 108±10 pmol mg^-1 min^-1 of PDE5 cyclic GMP-dependent activity for newborn and 2-3 week old piglets, respectively).

Table 1. pIC₃₀ values of NO, NP and PDE inhibitors.

Means ± s.e. means of 6-18 experiments. S3 and S10 indicate in the presence of 3 and 10 nM SIL, respectively). ** P < 0.01 vs newborn (Students' t test).

All these results suggest that PDE5 is a key regulator of NO-induced vasodilation in the postnatal pulmonary arteries. PDE5 inhibition is able to produce pulmonary vasodilation even in the absence of a functional endothelium and potentiates the vasodilator response to exogenously added NO and NP. However, PDE5 is not responsible for the maturation of NO bioactivity during the first days of extrauterine life.

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Perez-Vizcaino et al., (2002). Am. J. Physiol. 283, L839-L848.