H-89, a non-specific inhibitor of protein kinase A, promotes post-ischemic cardiac contractile recovery and reduces infarct size.

Abstract

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.

• Authors: Siyanda Makaula, Amanda Lochner, Sonia Genade, Michael N Sack, Moneeb M Awan, Lionel H Opie
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 45 Issue 4 Pg. 341-7 (Apr 2005) ISSN: 0160-2446 [Print] United States
• PMID: 15772523 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Isoquinolines
• Protein Kinase Inhibitors
• Sulfonamides
• Cyclic AMP-Dependent Protein Kinases
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Animals
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Isoquinolines (pharmacology, therapeutic use)
• Male
• Myocardial Contraction (drug effects, physiology)
• Myocardial Infarction (drug therapy, enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rats
• Rats, Long-Evans
• Recovery of Function (drug effects, physiology)
• Sulfonamides (pharmacology, therapeutic use)