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In Piglet Pulmonary Arteries: Activity, Expression, Effects of PDE5 Inhibitors, and Role of the Nitric Oxide/Cyclic GMP Pathway

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In Piglet Pulmonary Arteries: Activity, Expression, Effects of PDE5 Inhibitors, and Role of the Nitric Oxide/Cyclic GMP Pathway 0031-3998/04/5604-0563 PEDIATRIC RESEARCH Vol. 56, No. 4, 2004 Copyright © 2004 International Pediatric Research Foundation, Inc. Printed in U.S.A. Postnatal Maturation of Phosphodiesterase 5 (PDE5) in Piglet Pulmonary Arteries: Activity, Expression, Effects of PDE5 Inhibitors, and Role of the Nitric Oxide/Cyclic GMP Pathway LAURA MORENO, BEGOÑA LOSADA, ANGEL L. COGOLLUDO, FEDERICA LODI, CLAIRE LUGNIER, EDUARDO VILLAMOR, MANUEL MORO, JUAN TAMARGO, AND FRANCISCO PÉREZ-VIZCAÍNO Department of Pharmacology (L.M., A.L.C., F.L., J.T., F.P.-V.), Department of Pediatrics (B.L., M.M.), School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain, Laboratoire de Pharmacologie et Physico-Chimie (C.L.), CNRS-UMR 7034, 67401 Illkirch, France, and Department of Pediatrics (E.V.), University Hospital Maastricht, Research Institute Growth and Development, Maastricht 6202 AZ, The Netherlands ABSTRACT After birth and during the first days of extrauterine life, cGMP hydrolytic activity and PDE5 protein expression increased pulmonary arterial pressure is progressively reduced to reach the with postnatal age. All these results suggest that PDE5 is a key adult values. We hypothesized that changes in PDE5 activity regulator of NO-induced vasodilation in the postnatal pulmonary might be involved in the pulmonary postnatal maturation of the arteries. PDE5 inhibition is able to produce pulmonary vasodi- nitric oxide (NO)/cGMP pathway. The PDE5 inhibitor sildenafil lation even in the absence of a functional endothelium and produced vasorelaxant responses in isolated pulmonary arteries. potentiates the vasorelaxant response to exogenous NO and These effects were similar in newborn (3–18 h) and 2-wk-old nitroprusside. However, PDE5 is not responsible for the matu- piglets, unchanged by endothelium removal, and markedly in- rational increase of NO bioactivity during the first days of hibited by the soluble guanylyl cyclase inhibitor ODQ. The peak extrauterine life. (Pediatr Res 56: 563–570, 2004) of the transient vasorelaxant response to NO gas increased with postnatal age but was unaffected by PDE inhibition. However, the duration of the response to NO was significantly increased. Abbreviations The vasorelaxant response to sodium nitroprusside was potenti- ANP, atrial natriuretic peptide ated by sildenafil in both age groups. The PDE5 inhibitors NO, nitric oxide dipyridamole and zaprinast, produced qualitatively similar ef- PDE, cyclic nucleotide phosphodiesterase (EC 3.1.4.17) fects but with lower potency. Both total and PDE5-dependent PPHN, persistent pulmonary hypertension of the newborn Successful adaptation of the newborn to postnatal conditions (1,3). Several groups have consistently reported a low activity requires a dramatic transition of the pulmonary circulation. of the NO/cGMP pathway for smooth muscle vasodilation During the first minutes of extrauterine life, as the lung be- during the first hours of extrauterine life in rabbit, lamb, and comes responsible for blood oxygenation and there is a marked piglet pulmonary arteries (4–8). This NO activity increases reduction in pulmonary vascular resistance (1,2). A second during the first 2 wk in parallel with the postnatal reduction in phase of pulmonary vascular resistance reduction takes place pulmonary arterial pressure. Some infants fail to achieve or over the first 2 wk of extrauterine life in pigs and humans to sustain the normal decrease in pulmonary vascular resistance at reach the pulmonary pressure values characteristic of the adult birth, which leads to severe respiratory distress and hypoxemia, referred to as PPHN (1,9). Received September 26, 2003; accepted April 16, 2004. cGMP is a key second messenger in the regulation of Correspondence: Francisco Pérez-Vizcaíno, Ph.D., Department of Pharmacology, School of Medicine, University Complutense, E-28040 Madrid, Spain; email: vascular smooth muscle tone (10) whose intracellular concen- [email protected] trations are tightly controlled by the balance between its syn- Supported by grants from CICYT (SAF 2002/02304) and CAM (08.4/0036.2001). A. C. and L.M. were supported by FIS and by Ministerio de Educación Cultura y Deporte, thesis and hydrolysis. cGMP is synthesized by a family of respectively. guanylyl cyclases (10), whose activities are mainly controlled DOI: 10.1203/01.PDR.0000139412.58594.D0 by NO and ANP. cGMP is hydrolyzed by cyclic nucleotide 563 564 MORENO ET AL. PDE, a superfamily of isozymes consisting of at least 11 maximal contractile response to KCl in previous experiments. families, PDE1 to PDE11 (11,12). Thus, the vasodilator/ The contraction was measured by an isometric force transducer antiproliferative effects of NO and ANP in the pulmonary using data acquisition software and hardware as previously circulation can be limited by the activity of PDE. PDE5 is a described (8,29). Rings were precontracted with the thrombox- ␣ ␣ cGMP-specific PDE isoform whereas PDE1 can hydrolyze ane A2 mimetic 9,11-dideoxy-11 ,9 -epoxymethano- Ϫ7 both cAMP and cGMP, and both isoforms are abundant in the prostaglandin F2␣ (U46619, 10 M) which induced a submaxi- lung (11–14). PDE5 activity is increased in pulmonary arteries mal contractile response (430 Ϯ 31 mg, n ϭ 32 and 1012 Ϯ 76 from rats with chronic hypoxia-induced pulmonary hyperten- mg, n ϭ 40, in newborn and 2-wk-old piglets, respectively). In sion (14) and in lambs with pulmonary hypertension after in previous experiments, these contractions were equally effective utero aortopulmonary vascular graft placement (15) or with in the two age groups when expressed as a percentage of the PPHN induced by compression of the ductus arteriosus in utero responses induced by 40 mM KCl (8). Then, concentration- (16). Moreover, the specific PDE5 inhibitor sildenafil has been response curves to the PDE inhibitors, sodium nitroprusside, recently reported to be a selective pulmonary vasodilator useful and forskolin were carried out by cumulative addition of the for the treatment of adult pulmonary hypertension (17–19). In drugs. As sildenafil was the most potent and selective PDE5 addition, sildenafil lowers pulmonary vascular resistance in an inhibitor, this drug was preferentially used for further experi- experimental model of PPHN (20) and anecdotal use of silde- ments. Due to the rapid disappearance of NO gas in the bath, nafil in PPHN have also been reported (21). Maturational the curves to NO were performed in a noncumulative fashion changes in PDE5 activity and expression have been reported in by addition of increasing volumes of Krebs solution saturated mouse, rat, and sheep whole lung homogenates and proposed with NO. In some experiments, U46619-stimulated rings were to be involved in the postnatal decrease in pulmonary vascular treated for 20 min with the soluble guanylyl cyclase inhibitor resistance (22–24). However, in the lung, PDE5 is present, at ODQ (3 ␮M), the nonselective inhibitor of NO synthase (NOS) least, in pulmonary arteries, pulmonary veins, trachea, bronchi, N-nitro-L-arginine methyl ester (L-NAME) (0.1 mM) or the and epithelium (25–28), and little is known about the matura- selective inhibitor of the inducible form of NOS (iNOS) tion of PDE5 specifically in pulmonary arteries and its func- 1400W (10 ␮M). The concentration-response curves to NO or tional role in the regulation of the NO/cGMP pathway in the nitroprusside were also performed in arteries pretreated for 20 pulmonary circulation during early life. min in the presence of PDE inhibitors at concentrations pro- Therefore, we hypothesized that PDE activity could modulate ducing threshold vasorelaxant responses (10–30%). To prepare vascular tone and the vasorelaxant responses to the NO/cGMP the NO saturated solutions, a 20-mL vial of Krebs solution was pathway in neonatal pulmonary arteries and that changes in PDE5 initially bubbled with N2 for 15 min and then continuously activity and PDE5 protein expression might be involved in the bubbled with NO (450 ppm) as described (29). The concen- postnatal maturation of the NO/cGMP pathway. tration of NO in the saturated solution was measured by an amperometric NO-sensitive electrode (ISO-NO, WPI, Sara- METHODS sota, FL). The vehicle DMSO at the maximal concentration used (0.1%) had no significant effect on U46619-induced tone All the procedures conform with the Guide for the Care and or NO-induced vasorelaxation. Use of Laboratory Animals (National Institutes of Health Western blot analysis. Pulmonary arteries were isolated, publication No. 85-23, revised 1996) and were approved by our frozen in liquid nitrogen, and stored at Ϫ80°C. Piglet mesen- institutional review board. teric arteries of a similar diameter and piglet platelets were Tissue preparation. Male piglets of 3–18 h (newborn, n ϭ used as positive controls. Platelets were obtained by centrifug- 32) or 15–20 d of age (2 wk, n ϭ 40) from a local farm were ing citrated (3.8%) blood at 120 g for 10 min, the supernatant used in this study. The lungs were rapidly immersed in cold was further centrifuged at 1000 g for 10 min and the pellet (4°C) Krebs solution (composition in mM: NaCl 118, KCl stored at Ϫ80°C. Frozen arteries and platelets were homoge- ␮ 4.75, NaHCO3 25, MgSO4 1.2, CaCl2 2.0, KH2PO4 1.2, and nized in a glass potter in 300 L of a buffer of the following glucose 11). The pulmonary arteries (third branch with an composition: 10 mM HEPES (pH 8), 10 mM KCl, 1 mM internal diameter of about 0.5–1.5 mm) were carefully dis- EDTA, 1 mM EGTA, 1 mM DTT, 40 ␮g/mL aprotinin, 4 sected free of surrounding tissue and cut into rings of 2–3mm ␮g/mL leupeptin, 4 ␮g/mL N␣-p-tosyl-L-lysine chloromethyl length (8,29). Except where otherwise stated, the endothelium ketone, 5 mM NaF, 10 mM Na2MoO4, 1 mM NaVO4, and 0.5 was removed by gently rubbing the intimal surface of the rings mM phenylmethanesulfonyl fluoride.
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