Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors: The role of protein kinase A and p38 mitogen-activated protein kinase

Shoji Sanada, Masafumi Kitakaze, Philip J. Papst, Hiroshi Asanuma, Koichi Node, Seiji Takashima, Masanori Asakura, Hisakazu Ogita, Yulin Liao, Yasuhiko Sakata, Akiko Ogai, Tomi Fukushima, Junko Yamada, Yoshiro Shinozaki, Tsunehiko Kuzuya, Hidezo Mori, Naohiro Terada, Masatsugu Hori

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89 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)705-710
Number of pages6
JournalCirculation
Volume104
Issue number6
DOIs
Publication statusPublished - 2001 Aug 7

Keywords

  • Infarction
  • Kinases
  • Phosphodiesterase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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