Cardiac intracellular Na+ and Ca2+ homeostasis is regulated by the concerte
d action of ion channels, pumps and exchangers. The Na+, K+-ATPase produces
the electrochemical concentration gradient for Na+, which is the driving f
orce for Ca2+ removal from the cytosol via the Na+/Ca2+ exchange. Reduction
of this gradient by increased intracellular Na+ concentration leads to cel
lular Ca2+ overload resulting in arrhythmias and contractile dysfunction. N
a+ and Ca2+ overload-associated arrhythmias can be produced experimentally
by inhibition of Na+ efflux (digitalis-induced intoxication) and by abnorma
l Na+ influx via modulated Nat channels (veratridine, DPI 201-106; hypoxia)
or via the Naf, H+ exchanger. Theoretically, blockers of Na+ and Ca2+ chan
nels, inhibitors of abnormal oscillatory release of Ca2+ from internal stor
es or modulators of the Na+, Ca2+ and Na+, H+ exchanger activities could pr
otect against cellular Na+ and Ca2+ overload.
Three exemplary drugs that prevent Na+ and Ca2+ overload, i.e. the benzothi
azolamine R56865, the methylenephenoxydioxy-derivative CP-060S, and the ben
zoyl-guanidine Hoe 642, a Na+, H+ exchange blocker, are briefly reviewed wi
th respect to their efficacy on digitalis-, veratridine- and ischaemia/repe
rfusion-induced arrhythmias. (C) 1999 The Italian Pharmacological Society.