Although the origins and mechanisms of pathophysiological conditions in cardiac tissue are definitely diverse, they usually alter cardiac contractility by affecting the intracellular Ca2+ . No drug is yet available that modulates intracellular calcium by interacting with the Na+- Ca2+ exchanger. However, the exchanger can be indirectly modulated by some drugs. For example, the antiarrhythmic drug digoxin (otherwise known as digitalis) or its derivatives reduce a transmembrane Na+ -gradient by increasing the cytosolic concentrations of Na+. Subsequently the Na+ - Ca2+ exchange declines, causing an elevation of intracellular Ca2+ and heartbeat.
In search of better peptide inhibitors, we have recently found that a set of structurally related cyclic hexapeptides inhibit Na+- Ca2+ exchange in the cardiac sarcolemma vesicles. Despite this progress, the inhibitory cyclic peptides attribute some structural and pharmocokinetic disadvantages. Our current research project is directed at developing a membrane permeable inhibitor of Na+- Ca2+ exchange which can access to the cytosolic side of the cell membrane. Specifically, we are seeking 1) to modify a peptide structure with the intention of improving the inhibitory potency, membrane permeability and resistance of the peptide to proteolytic enzymes and chemical oxidatio; 2) to add the specific "address" sequence to test a specific peptide-lipid interaction; 3) to elucidate the kinetic mechanisms of the peptide induced inhibition.
Cell permeable and selective inhibitors of the Na+-Ca2+ exchanger may provide a new tool for experimental and clinical cardiology and for general cell biology as well. In the long run, novel inhibitors of the Na+-Ca2+ exchanger can be developed with improved pharmocokinetics and pharmacodynamics that could be used for controlling the intracellular calcium and heartbeat. This could open new better possibilities for therapeutic treatment of specific heart diseases, such as congestive heart failure, arrhythmia, cardiomyopathy etc.
