Repetitive preischemic infusion of phosphodiesterase III inhibitor olprinone elicits cardioprotective effects in the failing heart after myocardial infarction.
Beta-adrenergic (BA) signaling including cAMP-protein kinase A (PKA) pathway has been implicated in the mechanism of ischemic preconditioning (IPC). However, effect of IPC on the failing heart, in which BA signaling is supposed to be altered, is left to be determined. To assess a role of BA signaling in IPC, levels of beta2-adrenergic receptor (B2AR) mRNA were quantified by real time RT-PCR, and in vivo intracardiac function was evaluated in post-MI heart. The effect of IPC on post-MI heart was then determined with an isolated heart perfusion system. Finally, cardioprotective effect of repetitive preischemic infusion of phosphodiesterase III inhibitor olprinone (30 microM), which is known to increase myocardial cAMP levels, was evaluated with/without PKA inhibitor H-89 (2 microM). B2AR mRNA levels in post-MI heart were significantly reduced compared to non-MI heart. IPC was not effective in post-MI heart. Repetitive preischemic infusion of olprinone increased peak developed pressure (94.6 +/- 6.3 vs. 62.8 +/- 4.9%, OLP vs. control, p < 0.05) and decreased infect size (15.2 +/- 0.4 vs. 33.5 +/- 2.5%, OLP vs. control, p < 0.01). These effects were abolished by H-89. These results may indicate that repetitive preischemic infusion of olprinone mimics IPC through cAMP-PKA pathway in post-MI heart, and that BA signaling plays a crucial role in IPC response.
Nomura
Yukiya
Y
Department of Thoracic and Cardiovascular Surgery, Osaka Medical College, Takatsuki, Osaka, Japan.
Horimoto
Hitoshi
H
Mieno
Shigetoshi
S
Nakahara
Ken-ichi
K
Okawa
Hirohisa
H
Yoshida
Masataka
M
Shinjiro
Sasaki
S
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D003326:Coronary Circulation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007511:Ischemia; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011312:Pressure; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D012333:RNA, Messenger; C059498:olprinone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3