Affiliation:
1. 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.).
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
92 articles.
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