CARNOSINE IS A NOVEL PEPTIDE MODULATOR OF INTRACELLULAR CALCIUM AND CONTRACTILITY IN CARDIAC-CELLS

Myocardial contractile failure is a common cause of morbidity and mort ality in patients with ischemic heart disease and systemic inflammator y states such as sepsis. Accumulating evidence indicates that contract ile failure is associated with dysregulation of myoplasmic calcium lev els. In a search for biochemical causes for contractile dysfunction, w e found that the dipeptide carnosine improves cardiac contractility an d tested the possibility that carnosine plays a role in the regulation of intracellular calcium. Carnosine increased contractility in a dose -dependent manner (1-10 mM) in isolated perfused rat hearts, and it al so increased free intracellular calcium levels in isolated myocytes. C arnosine increased myocyte tension via calcium release from the ryanod ine receptor calcium release channel in skinned myocardial fibers and increased open-state probability and dwell time of the isolated ryanod ine receptor calcium release channel in Lipid bilayers. In addition, w e report that carnosine sensitizes the contractile proteins to calcium . These results suggest a novel role for carnosine as a modulator of i ntracellular calcium and contractility in cardiac tissue.