Myocardial cyclic AMP augmentation with high-dose PDEIII inhibitor in terminal warm blood cardioplegia.
OBJECTIVE
Phosphodiesterase (PDE) III inhibitors have been reported in various cellular protective activities via the cyclic adenosine monophosphate (cAMP) pathway. We investigated the effects of amrinone on ischemia/reperfusion injury and intracellular calcium (Ca2+) handling if utilized as a component of terminal warm blood cardioplegia (TWBCP).


METHODS
Anesthetized pig hearts were subjected to 90-min global ischemia with single-dose crystalloid cardioplegia, followed by 30-min reperfusion under cardiopulmonary bypass. The animals were divided into three groups according to the contents of TWBCP (n = 5 each): Control, no TWBCP; TWBCP, no additive; Amrinone, TWBCP with amrinone. The time course of cardiac function and biochemical samples were measured. Further, coronary perfusion and ventricular arrhythmia were evaluated during reperfusion.


RESULTS
Cardiac function improved with amrinone. Specifically, the amrinone group showed an increase of myocardial cAMP (p <0.05) and a suppression of creatine kinase, troponin-T, and lipid peroxide after reperfusion (p <0.05); many cases also showed much improvement of coronary perfusion and spontaneous resuscitation after global ischemia.


CONCLUSIONS
Ischemia and/or reperfusion deplete myocardial cAMP, leading to impaired Ca2+ handling and further to cardiac dysfunction. High-dose PDEIII inhibitor in TWBCP may replenish myocardial cAMP and promote rapid and sustained cardiac functional recovery with various cellular protective effects after open-heart surgery.
Ko
Yoshihiro
Y
Department of Cardiovascular Surgery, The Jikei University School of Medicine, Tokyo, Japan.
Morita
Kiyozo
K
Nagahori
Ryuichi
R
Kinouchi
Katsushi
K
Shinohara
Gen
G
Kagawa
Hiroshi
H
Hashimoto
Kazuhiro
K
D000676:Amrinone / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control; D002315:Cardiopulmonary Bypass; D002316:Cardiotonic Agents / Q000097:blood / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004195:Disease Models, Animal; D006324:Heart Arrest, Induced; D015227:Lipid Peroxidation / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000494:pharmacology*; D017680:Potassium Compounds / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D020107:Troponin T / Q000097:blood; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D017680:Potassium Compounds; D020107:Troponin T; C018369:potassium cardioplegic solution; D000242:Cyclic AMP; D003402:Creatine Kinase; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000676:Amrinone