Caffeine stimulates the reverse mode of Na+/Ca2+ exchanger in ferret ventricular muscle

This study investigated the effect of caffeine on the sarcolemmal mechanism s involved in intracellular calcium control. Ferret cardiac preparations we re treated with ryanodine and thapsigargin in order to eliminate the sarcop lasmic reticulum (SR) function. This treatment abolished caffeine contractu re irreversibly in normal solution. The perfusion with K-free medium that b locked the Na+-K+ pump resulted in a recovery of slow relaxing caffeine con tractures similar to Na-free contractures. The amplitude of caffeine contra ctures was dependent on the bathing [caffeine]o and [Ca2+](o). Divalent cat ions Ni2+ and Cd2+, which have an inhibitory effect on the Na+/Ca2+ exchang er, produced dose-dependent inhibition of caffeine responses with apparent Ki of 780 +/- 19 and 132 +/- 5 muM, respectively. Caffeine also caused dose -dependent inhibition of Na-free contractures (Ki = 4.62 +/- 1.5 mM), and t he reduction or removal of [Na+](o) exerted an inhibitory effect on caffein e contractures (Ki = 73.5 +/- 17.12 mM). These experiments indicate that th e increase in resting tension following exposure to caffeine was mediated b y Na+/Ca2+ exchanger, which represents an additional element of complexity in caffeine action on cardiac muscle.