Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors - The role of protein kinase A and p38 mitogen-activated protein kinase
S. Sanada et al., Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors - The role of protein kinase A and p38 mitogen-activated protein kinase, CIRCULATION, 104(6), 2001, pp. 705-710
Citations number
34
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Background-Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodyn
amic status of heart failure via inotropic/vasodilatory effects attributabl
e to the increase in intracellular cAMP level. Direct cardioprotection by P
DEIII-Is and its underlying mechanisms, however, have not been identified.
We tested the infarct size-limiting effect of PDEIII-Is and the roles of cA
MP, 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, fol
lowed by 6 hours of reperfusion. Olprinone was also examined with an intrac
oronary 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. Eit
her PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which retu
rned to control levels in 30 minutes. Collateral flow and percent risk area
were identical for all groups. Both PDEIII-Is and db-cAMP increased myocar
dial 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 blun
ted by either H89 (35.5 +/-6.4%) or SB203580 (32.6 +/-5.9%), but not by GF1
09203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influ
ence infarct size.
Conclusions-Pretreatment with PDEIII-Is has cardioprotective effects via cA
MP-, PKA-, and p38 MAPK-dependent but PKC-independent mechanisms in canine
hearts.