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

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.

• Authors: S Sanada, M Kitakaze, P J Papst, H Asanuma, K Node, S Takashima, M Asakura, H Ogita, Y Liao, Y Sakata, A Ogai, T Fukushima, J Yamada, Y Shinozaki, T Kuzuya, H Mori, N Terada, M Hori
• Journal: Circulation (Circulation) Vol. 104 Issue 6 Pg. 705-10 (Aug 07 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11489779 (Publication Type: Journal Article)

Chemical References

• Cardiovascular Agents
• Enzyme Inhibitors
• Flavonoids
• Imidazoles
• Indoles
• Isoquinolines
• Maleimides
• Phosphodiesterase Inhibitors
• Pyridines
• Pyridones
• Sulfonamides
• olprinone
• Bucladesine
• Cyclic AMP-Dependent Protein Kinases
• Protein Kinase C
• Calcium-Calmodulin-Dependent Protein Kinases
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• 3',5'-Cyclic-AMP Phosphodiesterases
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Milrinone
• bisindolylmaleimide I
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors)
• Animals
• Blood Flow Velocity (drug effects)
• Bucladesine (pharmacology)
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Cardiovascular Agents (pharmacology)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism, physiology)
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Dogs
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Hemodynamics (drug effects)
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Isoquinolines (pharmacology)
• Maleimides (pharmacology)
• Milrinone (pharmacology)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism, physiology)
• Myocardial Infarction (pathology, physiopathology, prevention & control)
• Phosphodiesterase Inhibitors (pharmacology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Pyridines (pharmacology)
• Pyridones (pharmacology)
• Sulfonamides
• Ventricular Fibrillation (pathology, physiopathology, prevention & control)
• p38 Mitogen-Activated Protein Kinases