doi: 10.1161/hc3201.092216
(Circulation. 2001;104:705.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors
The Role of Protein Kinase A and p38 Mitogen-Activated Protein Kinase
From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, and the Department of Physiological Science, Tokai University School of Medicine, Isehara (Y. Shinozaki, H.M.), Japan; and the Department of Pediatrics, National Jewish Medical Research Center, Denver, Colo (P.J.P., N.T.).
Correspondence to Masafumi Kitakaze, MD, PhD, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan. E-mail kitakaze{at}medone.med.osaka-u.ac.jp
Background—— Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size–limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs.
Methods and Results—— Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal–regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X. Both PDEIII-Is and db-cAMP reduced infarct size (19.1±4.1%, 17.5±3.3%, and 20.3±4.8%, respectively, versus 36.1±6.2% control, P<0.05 each). Furthermore, the effect of olprinone was blunted by either H89 (35.5±6.4%) or SB203580 (32.6±5.9%), but not by GF109203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influence infarct size.
Conclusions—— Pretreatment with PDEIII-Is has cardioprotective effects via cAMP-, PKA-, and p38 MAPK–dependent but PKC-independent mechanisms in canine hearts.
Key Words: phosphodiesterase • infarction • kinases
This article has been cited by other articles:
 |
|
 |
|
  Q. Ke, Y.-F. Xiao, J. A. Bradbury, J. P. Graves, L. M. DeGraff, J. M. Seubert, and D. C. Zeldin Electrophysiological Properties of Cardiomyocytes Isolated from CYP2J2 Transgenic Mice Mol. Pharmacol., October 1, 2007; 72(4): 1063 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Spear, S. K. Prabu, D. Galati, H. Raza, H. K. Anandatheerthavarada, and N. G. Avadhani beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2459 - H2466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. K. Yadav and R. Medhamurthy Dynamic Changes in Mitogen-Activated Protein Kinase (MAPK) Activities in the Corpus Luteum of the Bonnet Monkey (Macaca radiata) during Development, Induced Luteolysis, and Simulated Early Pregnancy: A Role for p38 MAPK in the Regulation of Luteal Function Endocrinology, April 1, 2006; 147(4): 2018 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Prabu, H. K. Anandatheerthavarada, H. Raza, S. Srinivasan, J. F. Spear, and N. G. Avadhani Protein Kinase A-mediated Phosphorylation Modulates Cytochrome c Oxidase Function and Augments Hypoxia and Myocardial Ischemia-related Injury J. Biol. Chem., January 27, 2006; 281(4): 2061 - 2070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Robinet, G. Hoizey, and H. Millart PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of {beta}1-adrenergic preconditioning Cardiovasc Res, June 1, 2005; 66(3): 530 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Inserte, D. Garcia-Dorado, M. Ruiz-Meana, L. Agullo, P. Pina, and J. Soler-Soler Ischemic preconditioning attenuates calpain-mediated degradation of structural proteins through a protein kinase A-dependent mechanism Cardiovasc Res, October 1, 2004; 64(1): 105 - 114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sanada, H. Asanuma, O. Tsukamoto, T. Minamino, K. Node, S. Takashima, T. Fukushima, A. Ogai, Y. Shinozaki, M. Fujita, et al. Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C Circulation, July 6, 2004; 110(1): 51 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.A. Wuyts, B.M. Vanaudenaerde, L.J. Dupont, M.G. Demedts, and G.M. Verleden Modulation by cAMP of IL-1{beta}-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells Eur. Respir. J., August 1, 2003; 22(2): 220 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-Y. Hung, J.-W. Huang, C.-T. Chen, P.-H. Lee, and T.-J. Tsai Pentoxifylline modulates intracellular signalling of TGF-{beta} in cultured human peritoneal mesothelial cells: implications for prevention of encapsulating peritoneal sclerosis Nephrol. Dial. Transplant., April 1, 2003; 18(4): 670 - 676. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Pearson and M. H. Cobb Cell Condition-dependent Regulation of ERK5 by cAMP J. Biol. Chem., December 6, 2002; 277(50): 48094 - 48098. [Abstract] [Full Text] [PDF]
|
|