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Vol. 101, No. 1, 2012
Issue release date: December 2011
Section title: Original Paper
Free Access
Neonatology 2012;101:28–39
(DOI:10.1159/000326270)

Effect of a Phosphodiesterase 5 Inhibitor on Pulmonary and Cerebral Arteries of Newborn Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

Fike C.D.a · Kaplowitz M.a · Zhang Y.a · Dantuma M.b · Madden J.A.b
aDepartment of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn., and bResearch Services Zablocki VAMC and Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisc., USA
email Corresponding Author

Abstract

Background: The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations. Objectives: To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA. Methods: Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined. Results: Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups. Conclusions: Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.

© 2011 S. Karger AG, Basel


  

Key Words

  • Cerebral autoregulation
  • Phosphodiesterase 5 expression
  • Zaprinast
  • Middle cerebral arteries

References

  1. Atz AM, Wessel DL: Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91:307–310.
  2. Baquero H, Soliz A, Neira F, Venegas ME, Sola A: Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117:1077–1083.
  3. Chaudhari M, Vogel M, Wright C, Smith J, Haworth SG: Sildenafil in neonatal pulmonary hypertension due to impaired alveolarization and plexiform pulmonary arteriopathy. Arch Dis Child Fetal Neonatal Ed 2005;90:F27-F28.

    External Resources

  4. Hon K, Cheung K, Siu K, Leung T, Yam M, Fok T, Ng P: Oral sildenafil for treatment of severe pulmonary hypertension in an infant. Biol Neonate 2005;88:109–112.
  5. Erickson S, Reyes J, Bohn D, Adatia I: Sildenafil (Viagra) in childhood and neonatal pulmonary hypertension. J Am Coll Cardiol 2002;39:402.

    External Resources

  6. Juliana AE, Abbad FCB: Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Eur J Pediatr 2005;164:626–629.
  7. Keller RL, Hamrick SEG, Kitterman JA, Fineman JR, Hawgood S: Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Pediatric Crit Care Med 2004;5:184–187.
  8. Kumar S: Indian doctor in protest after using Viagra to save ‘blue babies’. Brit Med J 2002;325:181.
  9. Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS: Sildenafil prevents rebound pulmoanry hypertension after withdrawal of nitric oxide in children. Am J Resp Crit Care Med 2006;174:1042–1047.
  10. Nassi N, Daniotti M, Agostiniani S, Lombardi E, Favilli S, Donzelli GP: Sildenafil as ‘first line therapy’ in pulmonary persistent hypertension of the newborn? J Matern Fetal Neonatal Med 2010;23:104–105.

    External Resources

  11. Raja SG, Nayak SH: Sildenafil: emerging cardiovascular indications. Ann Thorac Surg 2004;78:1496–1506.

    External Resources

  12. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, Butrous G, Petros A, Lange P, Redington AN: Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003;108(suppl II):167–173.

    External Resources

  13. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS: Intravenous sildenafil and inhaled nitric oxide: a randomized trial in infants after cardiac surgery. Intensive Care Med 2003;29:1996–2003.
  14. Reiss I, Schaible T, van den Hout L, Capoluo I, Allegaert K, van Heijst A, Gorett Silva M, Greenough A, Tibboel D, CDH EURO Consortium: Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354–364.
  15. Travadi JN, Patole SK: Phosphodiesterase inhibitors for persistent pulmonary hypertension in the newborn. Pediatr Pulmonol 2003;36:529–535.
  16. Rabe KF, Tenor H, Dent G: Identification of PDE isozymes in human pulmonary artery ad effect of selective PDE inhibitors. Am J Physiol Lung Cell Mol Physiol 1994;266:536–543.
  17. Van Staveren WC, Steinbusch HW, Ittersum MMV, Repaske DR, Goy MF, Kotera J, Omori K, Beavo JA, Vente JD: mRNA expression patterns of the cGMP-hydrolyzing phosphodiesterases types 2, 5, and 9 during development of the rat brain. J Comp Neurolo 2003;467:566–580.
  18. Pierce CM, Petros AJ, Fielder AR: No evidence for severe retinopathy of prematurity following sildenafil. Br J Ophthalmol 2005;89:250.
  19. Schwarz ER, Kapur V, Rodriquez J, Rastogi S, Rosanio S: The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res 2007;19:139–148.
  20. Ramaekers VT, Casaer P, Daniels H, Marchal G: Upper limits of brain blood flow autoregulation in stable infants of various conceptual ages. Early Hum Dev 1990;24:249–258.
  21. Fike CD, Kaplowitz MR: Effect of chronic hypoxia on pulmonary vascular pressures in isolated lungs of newborn pigs. J Appl Physiol 1994;77:2853–2862.
  22. Fike CD, Kaplowitz MR: Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs. J Appl Physiol 1996;81:2078–2087.
  23. Fike CD, Pfister SL, Kaplowitz MR, Madden JA: Cyclooxygenase contracting factors and altered pulmonary vascular responses in chronically hypoxic newborn piglets. J Appl Physiol 2002;92:67–74.
  24. Shimoda L, Norens N, Jeutter D, Madden J: Flow-induced resposes in piglet isolated cerebral arteries. Ped Res 1996;39:574–583.
  25. Fike CD, Aschner JL, Zhang Y, Kaplowitz MR: Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn pigs. Am J Physiolo Lung Cell Mol Physiol 2004;286:1244–1254.

    External Resources

  26. Turley JE, Nelin LE, Kaplowitz MR, Zhang Y, Fike CD: Exhaled nitric oxide is decreased at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiolo Lung Cell Mol Physiol 2003;284:489–500.
  27. Binns-Loveman KM, Kaplowitz MR, Fike CD: Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Pedatric Pulmonology 2005;40:72–80.

    External Resources

  28. Dukarm RC, III FCM, Russell JA, Steinhorn RH: Pulmonary and systemic effects of the phsophodiesterase inhibitor dipyridamole in newborn lambs with persistent pulmonary hypertension. Pediatr Res 1998;44:831–837.
  29. Dukarm RC, Russell JA, III FCM, Perry BJ, Steinhorn RH: The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. Am J Resp Crit Care Med 1999;160:858–865.
  30. Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR: Chronic pulmonary hypertension increases fetal lung cGMP activity. Am J Physiolo Lung Cell Mol Physiol 1998;275:L931–L941.
  31. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, Clark M, Winkler JD, Bloch KD, Zapol WM: Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001;29:1000–1005.
  32. Tulloh RM, Hislop AA, Boels PJ, Deutsch J, Haworth SG: Chronic hypoxia inhibits postnatal maturation of procine intrapulmonary artery relaxation. Am J Physiolo Heart Circ Physiol 1997;272:H2436–H2445.
  33. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, Zapol WM: Sildenafil is a pulmonary vasodilator in awake lambs with pulmonary hypertension. Anesthesiology 2000;92:1702–1712.
  34. Murray F, MacLean MR, Pyne NJ: Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002;137:1187–1194.
  35. Pourcyrous M, Parfenova H, Leffler CW: The effects of orally administered sildenafil (Viagra) on cerebral circulation in newborn pigs. FASEB J 2006;20:A295.

    External Resources

  36. Nagdyman N, Fleck T, Bitterling B, Ewert P, Abdul-Khaliq H, Stiller B, Hubler M, Lange PE, Berger F, Schulze-Neick I: Influence of intravenous sildenafil on cerebral oxygenation measured by near-infrared spectroscopy in infants after cardiac surgery. Pediatr Res 2006;59:462–465.
  37. Kruuse C, Thomsen LL, Jacobsen TB, Olesen J: The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab 2002;22:1124–1131.
  38. Kruuse C, Thomsen LL, Birk S, Olesen J: Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003;126:241–247.
  39. Royl G, Balkaya M, Lehmann S, Lehnardt S, Stohlmann K, Lindauer U, Endres M, Dirnagl U, Meisel A: Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. Brain Res 2009;1265:148–157.
  40. Kruuse C, Rybalkin SD, Khurana TS, Jansen-Olesen I, Olesen J, Edvinsson L: The role of cGMP hydrolyzing phosphodiesterases 1 and 5 in cerebral artery dilatation. Eur J Pharmacol 2001;420:55–65.
  41. Li L, Jiang Q, Zhang L, Ding G, Zhang ZG, Li Q, Ewing JR, Lu M, Panda S, Ledbetter KA, Whitton PA, Chopp M: Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res 2007;1132:185–192.
  42. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M: Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 2002;33:2675–2680.
  43. Zhang L, Zhang RL, Wang Y, Zhang C, Zhang ZG, Meng H, Chopp M: Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 2005;36:847–852.
  44. Zhang R, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M: Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 2006;83:1213–1219.
  45. Morgan JC, Alhatou M, Oberlies J, Johnston KC: Transient ischemic attack and stroke associated with sildenafil (viagra) use. Neurology 2001;57:1730–1731.
  46. Marsh C, Marden B, Newsome R: Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. J Br Ophthalmol 2004;88:306–307.
  47. Francis SH, Turko IV, Corbin JD: Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 2001;65:1–52.
  48. Jeffery TK, Wanstall JC: Phosphodiesterase III and V inhibitors on pulmonary artery from pulmonary hypertensive rats: differences between early and established pulmonary hypertension. J Cardiovasc Pharmacol 1998;32:213–219.
  49. Bredt DS, Snyder SH: Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 1994;63:175–195.

  

Author Contacts

Candice D. Fike, MD
Department of Pediatrics, Vanderbilt University School of Medicine and
the Monroe Carell Jr. Children’s Hospital at Vanderbilt
2215 B Garland Ave., 1125 MRB IV/Light Hall, Nashville, TN 37232-0656 (USA)
Tel. +1 615 936 8403, E-Mail Candice.fike@vanderbilt.edu

  

Article Information

Received: August 11, 2010
Accepted after revision: February 14, 2011
Published online: July 26, 2011
Number of Print Pages : 12
Number of Figures : 9, Number of Tables : 0, Number of References : 49

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 101, No. 1, Year 2012 (Cover Date: December 2011)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations. Objectives: To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA. Methods: Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined. Results: Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups. Conclusions: Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.

© 2011 S. Karger AG, Basel


  

Author Contacts

Candice D. Fike, MD
Department of Pediatrics, Vanderbilt University School of Medicine and
the Monroe Carell Jr. Children’s Hospital at Vanderbilt
2215 B Garland Ave., 1125 MRB IV/Light Hall, Nashville, TN 37232-0656 (USA)
Tel. +1 615 936 8403, E-Mail Candice.fike@vanderbilt.edu

  

Article Information

Received: August 11, 2010
Accepted after revision: February 14, 2011
Published online: July 26, 2011
Number of Print Pages : 12
Number of Figures : 9, Number of Tables : 0, Number of References : 49

  

Publication Details

Neonatology (Fetal and Neonatal Research)

Vol. 101, No. 1, Year 2012 (Cover Date: December 2011)

Journal Editor: Halliday H.L. (Belfast), Speer C.P. (Würzburg)
ISSN: 1661-7800 (Print), eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 8/11/2010
Accepted: 2/14/2011
Published online: 7/26/2011
Issue release date: December 2011

Number of Print Pages: 12
Number of Figures: 9
Number of Tables: 0

ISSN: 1661-7800 (Print)
eISSN: 1661-7819 (Online)

For additional information: http://www.karger.com/NEO


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Atz AM, Wessel DL: Sildenafil ameliorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999;91:307–310.
  2. Baquero H, Soliz A, Neira F, Venegas ME, Sola A: Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117:1077–1083.
  3. Chaudhari M, Vogel M, Wright C, Smith J, Haworth SG: Sildenafil in neonatal pulmonary hypertension due to impaired alveolarization and plexiform pulmonary arteriopathy. Arch Dis Child Fetal Neonatal Ed 2005;90:F27-F28.

    External Resources

  4. Hon K, Cheung K, Siu K, Leung T, Yam M, Fok T, Ng P: Oral sildenafil for treatment of severe pulmonary hypertension in an infant. Biol Neonate 2005;88:109–112.
  5. Erickson S, Reyes J, Bohn D, Adatia I: Sildenafil (Viagra) in childhood and neonatal pulmonary hypertension. J Am Coll Cardiol 2002;39:402.

    External Resources

  6. Juliana AE, Abbad FCB: Severe persistent pulmonary hypertension of the newborn in a setting where limited resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Eur J Pediatr 2005;164:626–629.
  7. Keller RL, Hamrick SEG, Kitterman JA, Fineman JR, Hawgood S: Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Pediatric Crit Care Med 2004;5:184–187.
  8. Kumar S: Indian doctor in protest after using Viagra to save ‘blue babies’. Brit Med J 2002;325:181.
  9. Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny DJ, Shekerdemian LS: Sildenafil prevents rebound pulmoanry hypertension after withdrawal of nitric oxide in children. Am J Resp Crit Care Med 2006;174:1042–1047.
  10. Nassi N, Daniotti M, Agostiniani S, Lombardi E, Favilli S, Donzelli GP: Sildenafil as ‘first line therapy’ in pulmonary persistent hypertension of the newborn? J Matern Fetal Neonatal Med 2010;23:104–105.

    External Resources

  11. Raja SG, Nayak SH: Sildenafil: emerging cardiovascular indications. Ann Thorac Surg 2004;78:1496–1506.

    External Resources

  12. Schulze-Neick I, Hartenstein P, Li J, Stiller B, Nagdyman N, Hubler M, Butrous G, Petros A, Lange P, Redington AN: Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 2003;108(suppl II):167–173.

    External Resources

  13. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS: Intravenous sildenafil and inhaled nitric oxide: a randomized trial in infants after cardiac surgery. Intensive Care Med 2003;29:1996–2003.
  14. Reiss I, Schaible T, van den Hout L, Capoluo I, Allegaert K, van Heijst A, Gorett Silva M, Greenough A, Tibboel D, CDH EURO Consortium: Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology 2010;98:354–364.
  15. Travadi JN, Patole SK: Phosphodiesterase inhibitors for persistent pulmonary hypertension in the newborn. Pediatr Pulmonol 2003;36:529–535.
  16. Rabe KF, Tenor H, Dent G: Identification of PDE isozymes in human pulmonary artery ad effect of selective PDE inhibitors. Am J Physiol Lung Cell Mol Physiol 1994;266:536–543.
  17. Van Staveren WC, Steinbusch HW, Ittersum MMV, Repaske DR, Goy MF, Kotera J, Omori K, Beavo JA, Vente JD: mRNA expression patterns of the cGMP-hydrolyzing phosphodiesterases types 2, 5, and 9 during development of the rat brain. J Comp Neurolo 2003;467:566–580.
  18. Pierce CM, Petros AJ, Fielder AR: No evidence for severe retinopathy of prematurity following sildenafil. Br J Ophthalmol 2005;89:250.
  19. Schwarz ER, Kapur V, Rodriquez J, Rastogi S, Rosanio S: The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems. Int J Impot Res 2007;19:139–148.
  20. Ramaekers VT, Casaer P, Daniels H, Marchal G: Upper limits of brain blood flow autoregulation in stable infants of various conceptual ages. Early Hum Dev 1990;24:249–258.
  21. Fike CD, Kaplowitz MR: Effect of chronic hypoxia on pulmonary vascular pressures in isolated lungs of newborn pigs. J Appl Physiol 1994;77:2853–2862.
  22. Fike CD, Kaplowitz MR: Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs. J Appl Physiol 1996;81:2078–2087.
  23. Fike CD, Pfister SL, Kaplowitz MR, Madden JA: Cyclooxygenase contracting factors and altered pulmonary vascular responses in chronically hypoxic newborn piglets. J Appl Physiol 2002;92:67–74.
  24. Shimoda L, Norens N, Jeutter D, Madden J: Flow-induced resposes in piglet isolated cerebral arteries. Ped Res 1996;39:574–583.
  25. Fike CD, Aschner JL, Zhang Y, Kaplowitz MR: Impaired NO signaling in small pulmonary arteries of chronically hypoxic newborn pigs. Am J Physiolo Lung Cell Mol Physiol 2004;286:1244–1254.

    External Resources

  26. Turley JE, Nelin LE, Kaplowitz MR, Zhang Y, Fike CD: Exhaled nitric oxide is decreased at an early stage of hypoxia-induced pulmonary hypertension in newborn piglets. Am J Physiolo Lung Cell Mol Physiol 2003;284:489–500.
  27. Binns-Loveman KM, Kaplowitz MR, Fike CD: Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Pedatric Pulmonology 2005;40:72–80.

    External Resources

  28. Dukarm RC, III FCM, Russell JA, Steinhorn RH: Pulmonary and systemic effects of the phsophodiesterase inhibitor dipyridamole in newborn lambs with persistent pulmonary hypertension. Pediatr Res 1998;44:831–837.
  29. Dukarm RC, Russell JA, III FCM, Perry BJ, Steinhorn RH: The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. Am J Resp Crit Care Med 1999;160:858–865.
  30. Hanson KA, Ziegler JW, Rybalkin SD, Miller JW, Abman SH, Clarke WR: Chronic pulmonary hypertension increases fetal lung cGMP activity. Am J Physiolo Lung Cell Mol Physiol 1998;275:L931–L941.
  31. Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L, Clark M, Winkler JD, Bloch KD, Zapol WM: Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 2001;29:1000–1005.
  32. Tulloh RM, Hislop AA, Boels PJ, Deutsch J, Haworth SG: Chronic hypoxia inhibits postnatal maturation of procine intrapulmonary artery relaxation. Am J Physiolo Heart Circ Physiol 1997;272:H2436–H2445.
  33. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, Zapol WM: Sildenafil is a pulmonary vasodilator in awake lambs with pulmonary hypertension. Anesthesiology 2000;92:1702–1712.
  34. Murray F, MacLean MR, Pyne NJ: Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Br J Pharmacol 2002;137:1187–1194.
  35. Pourcyrous M, Parfenova H, Leffler CW: The effects of orally administered sildenafil (Viagra) on cerebral circulation in newborn pigs. FASEB J 2006;20:A295.

    External Resources

  36. Nagdyman N, Fleck T, Bitterling B, Ewert P, Abdul-Khaliq H, Stiller B, Hubler M, Lange PE, Berger F, Schulze-Neick I: Influence of intravenous sildenafil on cerebral oxygenation measured by near-infrared spectroscopy in infants after cardiac surgery. Pediatr Res 2006;59:462–465.
  37. Kruuse C, Thomsen LL, Jacobsen TB, Olesen J: The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab 2002;22:1124–1131.
  38. Kruuse C, Thomsen LL, Birk S, Olesen J: Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain 2003;126:241–247.
  39. Royl G, Balkaya M, Lehmann S, Lehnardt S, Stohlmann K, Lindauer U, Endres M, Dirnagl U, Meisel A: Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. Brain Res 2009;1265:148–157.
  40. Kruuse C, Rybalkin SD, Khurana TS, Jansen-Olesen I, Olesen J, Edvinsson L: The role of cGMP hydrolyzing phosphodiesterases 1 and 5 in cerebral artery dilatation. Eur J Pharmacol 2001;420:55–65.
  41. Li L, Jiang Q, Zhang L, Ding G, Zhang ZG, Li Q, Ewing JR, Lu M, Panda S, Ledbetter KA, Whitton PA, Chopp M: Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res 2007;1132:185–192.
  42. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M: Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 2002;33:2675–2680.
  43. Zhang L, Zhang RL, Wang Y, Zhang C, Zhang ZG, Meng H, Chopp M: Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 2005;36:847–852.
  44. Zhang R, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M: Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 2006;83:1213–1219.
  45. Morgan JC, Alhatou M, Oberlies J, Johnston KC: Transient ischemic attack and stroke associated with sildenafil (viagra) use. Neurology 2001;57:1730–1731.
  46. Marsh C, Marden B, Newsome R: Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. J Br Ophthalmol 2004;88:306–307.
  47. Francis SH, Turko IV, Corbin JD: Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 2001;65:1–52.
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