Roles of Na+-Ca2+ exchange in the negative force-frequency relationship

ABSTRACT

Frequency-force relationships (FFR) were studied in electrically field stimulated rat left atria (LA) by reducing the stimulation frequency from resting 3 Hz to test frequencies (0.1-1 Hz) for 5 minutes. The twitch amplitudes of LA elicited the typical negative staircases with 3-phased changes the initial rapid increase, the second decrease and the following plateau at test frequencies. Verapamil (3 X 10-5 M) pretreatment elicited frequency-dependent suppression of the twitch amplitudes, exaggerating the negative staircase. Monensin pretreatment enhanced not the peak but the plateau amplitudes in a concentration-dependent manner. When the Na+-Ca2+ exchange was blocked by Na+ and Ca2+ depletion in the Krebs Hensleit buffer (0 Na+-0 Ca2+ KHB), the twitch amplitudes increased in a frequency-dependent manner, changing the negtive staircase into the positve one. Meanwhile, the 0 Na+-0 Ca2+ KHB applicationinduced enhancement was strongly suppressed by caffeine (5 mM) pretreatment. Only dibucaine among the local anesthetics increased the basal tone during frequency reduciton. There were no differences in 45Ca uptakes between 0.3 Hz and 3 Hz stimulation except at 1 min when it was significantly low at 0.3 Hz than 3 Hz, illustrating net Ca2+ losses. Monensin pretreatment enhanced the rate of this Ca2+ loss. Taken together, it is concluded that Na+-Ca2+ exchange extrudes more SR released Ca2+ out of the cell in proportion to the frequency, resulting in the negative rate staircase in the rat LA.