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The Pharmaceutical Society of Korea (대한약학회)
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DA-8159, a Potent cGMP Phosphodiesterase Inhibitor, Attenuates Monocrotaline-Induced Pulmonary Hypertension in Rats

  • Published : 2003.08.01
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Abstract

In this study, we evaluated the effects of oral administration of DA-8159, a selective phosphodiesterase-5 inhibitor, on the development of pulmonary hypertension (PH) induced by monocrotaline (MCT). Rats were administered either MCT (60 mg/kg) or saline. MCT-treated rats were divided into three groups and received orally administered vehicle, or 1 mg/kg or 5 mg/kg of DA-8159, twice a day for twenty-one days. The MCT group demonstrated increased right ventricular weights, medial wall thickening in the pulmonary arteries, myocardial fibrosis and the level of plasma cyclic guanosine monophosphate (cGMP), along with decreased body weight gains. However, DA-8159 markedly and dose-dependently reduced the development of right ventricular hypertrophy and medial wall thickening. DA-8159 also amplified the increase in plasma cGMP level and significantly increased the level of lung cGMP, compared with the MCT group. Although the body weight gain was still lower from the saline-treated control group, DA-8159 demonstrated a significant increase in body weight gains, in both 1 mg/kg and 5 mg/kg groups, when compared with the MCT group. In myocardial morphology, MCT-induced myocardial fibrosis was markedly prevented by DA-8159. These results suggest that DA-8159 may be a useful oral treatment option for PH.

Keywords

References

  1. Abrams, D., Schulze-Neick, I., and Magee, A. G., Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension. Heart, 84, E4 (2000) https://doi.org/10.1136/heart.84.2.e4
  2. Barst, R. J., Rubin, L. J., Long, W. A., McGoon, M. D., Rich, S., Badesch, D. B., Groves, B. M., Tapson, V. F., Bourge, R. C., Brundage, B. H., Koerner, S. K., Langleben, D., Keller, C. A., Murali, S., Uretsky, B. F., Clayton, L. M., Jobsis, M. M., Blackburn, S. D., Shortino, D., and Crow, J. W., A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N. Engl. J. Med., 334, 296-302 (1996)⨀ₙ얖⨀⨀ȄĀᣦ⨀ゴ얖⨀裺⨀ĄȀ?⨀낰얖⨀裺⨀ĄȀᣩ⨀얖⨀裺⨀ĄȀ㣩⨀®얖⨀裺⨀ĄȀ䣩⨀?얖⨀裺⨀ĄȀ飨⨀₭얖⨀裺⨀ĄȀ壩⨀䂬얖⨀裺⨀ĄȀ棩⨀傳얖⨀裺⨀ĄȀ⨀悫얖⨀裺⨀ĄȀ磩⨀肪얖⨀裺⨀ĄȀ裩⨀炲얖⨀裺⨀ĄȀ⨀邱얖⨀裺⨀ĄȀࣩ⨀ꂩ얖⨀裺⨀ĄȀ飩⨀삨얖⨀裺⨀ĄȀ꣩⨀얖⨀裺⨀ĄȀ룩⨀§얖⨀裺⨀ĄȀ죩⨀₦얖⨀裺⨀ĄȀ?⨀䂥얖⨀裺⨀ĄȀ⨀?얖⨀裺⨀ĄȀ⨀얖⨀裺⨀ĄȀ࣪⨀ᣃ얖⨀裺⨀ĄȀ https://doi.org/10.1056/NEJM199602013340504
  3. Braner, D. A., Fineman, J. R., Chang, R., and Soifer, S. J., M&B 22948, a cGMP phosphodiesterase inhibitor, is a pulmonary vasodilator in lambs. Am. J. Physiol., 264, H252-H258 (1993)
  4. Cassis, L. A., Rippetoe, P. E., Soltis, E. E., Painter, D. J., Fitz, R., and Gillespie, M. N., Angiotensin II and monocrotaline-induced pulmonary hypertension: effect of losartan (DuP 753), a nonpeptide angiotensin type 1 receptor antagonist. J. Pharmacol. Exp. Ther., 262, 1168-1172 (1992)
  5. Chen, L., Gan, X. T., Haist, J. V., Feng, Q., Lu, X., Chakrabarti, S., and Karmazyn, M., Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the $Na^+-H^+$ exchange inhibitor cariporide. J. Pharmacol. Exp. Ther., 298, 469-476 (2001)
  6. Cohen, A. H., Hanson, K., Morris, K., Fouty, B., McMurty, I. F., Clarke, W., and Rodman, D. M. Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. J. Clin. Invest., 97, 172-179 (1996) https://doi.org/10.1172/JCI118386
  7. Dinerman, J. L., Lowenstein, C. J., and Snyder, S. H., Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ. Res., 73, 217-222 (1993) https://doi.org/10.1161/01.RES.73.2.217
  8. Dukarm, R. C., Russell, J. A., Morin, F. C $3^{rd}$., Perry, B. J., and Steinhorn, R. H., The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation. Am. J. Respir. Crit. Care. Med., 160, 858-865 (1999) https://doi.org/10.1164/ajrccm.160.3.9809120
  9. Dundore, R. L., Clas, D. M., Wheeler, L. T., Habeeb, P. G., Bode, D. C., Buchholz, R. A., Silver, P. J., and Pagani, E. D., Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats. Eur. J. Pharmacol., 249, 293-297 (1993) https://doi.org/10.1016/0014-2999(93)90525-M
  10. Frostell, C., Fratacci, M. D., Wain, J. C., Jones, R., and Zapol, W. M., Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation, 83, 2038-2047 (1991) https://doi.org/10.1161/01.CIR.83.6.2038
  11. Hanasato, N., Oka, M., Muramatsu, M., Nishino, M., Adachi, H., and Fukuchi, Y., E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. Am. J. Physiol., 277, L225-L232 (1999) https://doi.org/10.1152/ajpcell.1999.277.2.C225
  12. Kodama, K. and Adachi, H., Improvement of mortality by long-term E4010 treatment in monocrotaline-induced pulmonary hypertensive rats. J. Pharmacol. Exp. Ther., 290, 748-752 (1999)
  13. McMahon, T. J., Ignarro, L. J., and Kadowitz, P. J., Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed. J. Appl. Physiol., 74, 1704-1711 (1993) https://doi.org/10.1152/jappl.1993.74.4.1704
  14. Nakazawa, H., Hori, M., Ozaki, H., and Karaki, H., Mechanisms underlying the impairment of endothelium-dependent relaxation in the pulmonary artery of monocrotaline-induced pulmonary hypertensive rats. Br. J. Pharmacol., 128, 1098-1104 (1999) https://doi.org/10.1038/sj.bjp.0702878
  15. Pepke-Zaba, J., Higenbottam, T. W., Dinh-Xuan, A. T., Stone, D., and Wallwork, J., Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet, 338, 1173-1174 (1991) https://doi.org/10.1016/0140-6736(91)92033-X
  16. Pichardo, J., Palace, V., Farahmand, F., and Singal, P. K., Myocardial oxidative stress changes during compensated right heart failure in rats. Mol. Cell Biochem., 196, 51-57 (1999) https://doi.org/10.1023/A:1006914111957
  17. Polson, J. B. and Strada, S. J., Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Annu. Rev. Pharmacol. Toxicol., 36, 403-427 (1996) https://doi.org/10.1146/annurev.pa.36.040196.002155
  18. Prasad, S., Wilkinson, J., and Gatzoulis, M. A., Sildenafil in primary pulmonary hypertension. N. Engl. J. Med., 343, 1342 (2000) https://doi.org/10.1056/NEJM200011023431814
  19. Rich, S., Dantzker, D. R., Ayres, S. M., Bergofsky, E. H., Brundage, B. H., Detre, K. M., Fishman, A. P., Goldring, R. M., Groves, B. M., and Koerner S. K. Primary pulmonary hypertension. A national prospective study. Ann. Intern. Med., 107, 216-223 (1987) https://doi.org/10.7326/0003-4819-107-2-216
  20. Rosenberg, H. C. and Rabinovitch, M., Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am. J. Physiol., 255, H1484-H1491 (1998)
  21. Rosenkrantz, J. G., Lynch, F. P., and Vogel, J. H., Hypoxic pulmonary hypertension: its modification by dipyridamole. J. Surg. Res., 12, 330-333 (1972) https://doi.org/10.1016/0022-4804(72)90115-1
  22. Schermuly, R. T., Krupnik, E., Tenor, H., Schudt, C., Weissmann, N., Rose, F., Grimminger, F., Seeger, W., Walmrath, D., and Ghofrani, H. A., Coaerosolization of phosphodiesterase inhibitors markedly enhances the pulmonary vasodilatory response to inhaled iloprost in experimental pulmonary hypertension. Maintenance of lung selectivity. Am. J. Respir. Crit. Care. Med., 164, 1694-1700 (2001a) https://doi.org/10.1164/ajrccm.164.9.2105060
  23. Schermuly, R. T., Roehl, A., Weissmann, N., Ghofrani, H. A., Leuchte, H., Grimminger, F., Seeger, W., and Walmrath, D., Combination of nonspecific PDE inhibitors with inhaled prostacyclin in experimental pulmonary hypertension. Am. J. Physiol. Lung Cell Mol. Physiol., 281, L1361-L1368 (2001b) https://doi.org/10.1152/ajplung.2001.281.6.L1361
  24. Schultze, A. E. and Roth, R. A., Chronic pulmonary hypertension- the monocrotaline model and involvement of the hemostatic system. J. Toxicol. Environ. Health B Crit. Rev., 1, 271-346 (1998) https://doi.org/10.1080/10937409809524557
  25. Shim, H. J., Lee, E. J., Kim, S. H., Yoo, M., Kim, W. B., Lee, H. S., and Lee, M. G., Pharmacokinetics and metabolism of DA-8159, A new PDE5 inhibitor. 8th Asia-Pacific Society for Impotence Research & Exhibition. Thailand, OR5-5 (2001)
  26. Takahashi, T., Kanda, T., Inoue, M., Suzuki, T., Kobayashi, I., Kodama, K., and Nagai, R., A selective type V phosphodiesterase inhibitor, E4021, protects the development of right ventricular overload and medial thickening of pulmonary arteries in a rat model of pulmonary hypertension. Life Sci., 59, PL371-PL377 (1996) https://doi.org/10.1016/S0024-3205(96)00554-1
  27. Thomas, M. K., Francis, S. H., and Corbin, J. D., Characterization of a purified bovine lung cGMP-binding cGMP phosphodiesterase. J. Biol. Chem., 265, 14964-14970 (1990)
  28. Troncy, E., Francoeur, M., and Blaise, G., Inhaled nitric oxide: clinical applications, indications, and toxicology. Can. J. Anaesth., 44, 973-988 (1997) https://doi.org/10.1007/BF03011970
  29. Weimann, J., Ullrich, R., Hromi, J., Fujino, Y., Clark, M. W., Bloch, K. D., and Zapol, W. M., Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology, 92, 1702-1712 (2000) https://doi.org/10.1097/00000542-200006000-00030
  30. Wilkens, H., Guth, A., Konig, J., Forestier, N., Cremers, B., Hennen, B., Bohm, M., and Sybrecht, G. W., Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation, 104, 1218-1222 (2001) https://doi.org/10.1161/hc3601.096826
  31. Yamaguchi, K., Oka, M., Nishino, M., Hanasato, N., Kira, S., and Fukuchi, Y., E4021, a cGMP phosphodiesterase inhibitor, is a selective pulmonary vasodilator in chronically hypoxic pulmonary hypertensive rats. Nihon Kokyuki Gakkai Zasshi, 36, 23-28 (1998)
  32. Zhao, L., Mason, N. A., Morrell, N. W., Kojonazarov, B., Sadykov, A., Maripov, A., Mirrakhimov, M. M., Aldashev, A., and Wilkins, M. R., Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation, 104, 424-428 (2001) https://doi.org/10.1161/hc2901.093117
  33. Ziegler, J. W., Ivy, D. D., Wiggins, J. W., Kinsella, J. P., Clarke, W. R., and Abman, S. H., Effects of dipyridamole and inhaled nitric oxide in pediatric patients with pulmonary hypertension. Am. J. Respir. Crit. Care Med., 158, 1388-1395 (1998) https://doi.org/10.1164/ajrccm.158.5.9710117