H-89, a non-specific inhibitor of protein kinase A, promotes post-ischemic cardiac contractile recovery and reduces infarct size.
Myocardial ischemia is associated with increased production of cyclic adenosine monophosphate (cAMP), with potentially deleterious effects. We hypothesized that the ischemia-induced activation of cAMP-dependent protein kinase A (PKA), could beneficially be inhibited by a PKA-inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline-sulfonamide (H-89). H-89 when given to isolated perfused rat hearts before 30 minutes of global ischemia-reperfusion improved postischemic function and decreased infarct size. In another series, H-89 administered prior to preconditioning by 10 minutes of transient global ischemia decreased PKA activity (measured at the end of the preconditioning protocol) and augmented postischemic mechanical recovery. H-89 given for 5 minutes before the 10 minutes of transient ischemia further decreased infarct size from 13.4 +/- 1.0% (preconditioning alone) to 7.0 +/- 0.93 (P < 0.01). In a third series, forskolin (0.3 muM, 5 minutes, 10 minutes washout prior to ischemia) increased PKA activity and reduced infarct size. Prior H-89 decreased PKA activity after 5 minutes of forskolin and further reduced infarct size versus forskolin alone. In conclusion, three procedures increased postischemic recovery and reduced infarct size: H-89; preconditioning by transient ischemia; or forskolin as a preconditioning-mimetic. PKA-inhibition by H-89 further decreased infarct size beyond preconditioning or forskolin. Despite the reservation that H-89 could be non-selective in its actions, we propose H-89 as a candidate cardioprotective agent.
Makaula
Siyanda
S
Hatter Institute for Cardiology Research and Servier Heart Failure Laboratory, University of Cape Town Faculty of Health Sciences, South Africa.
Lochner
Amanda
A
Genade
Sonia
S
Sack
Michael N
MN
Awan
Moneeb M
MM
Opie
Lionel H
LH
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide