Roles of Na<SUP>&#8290;</SUP>-Ca<SUP>2&#8290;</SUP> Exchange in the Negative Force-Frequency Relationship

Roles of Na<SUP>&#8290;</SUP>-Ca<SUP>2&#8290;</SUP> Exchange in the Negative Force-Frequency Relationship

<P> 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&#8275;10<SUP>&#8291;5</SUP> 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<SUP>&#8290;</SUP>-Ca<SUP>2&#8290;</SUP> exchange was blocked by Na<SUP>&#8290;</SUP> and Ca<SUP>2&#8290;</SUP> depletion in the Krebs Hensleit buffer (0 Na<SUP>&#8290;</SUP>-0 Ca<SUP>2&#8290;</SUP> KHB), the twitch amplitudes increased in a frequency-dependent manner, changing the negtive staircase into the positve one. Meanwhile, the 0 Na<SUP>&#8290;</SUP>-0 Ca<SUP>2&#8290;</SUP> 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 <SUP>45</SUP>Ca 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 Ca<SUP>2&#8290;</SUP> losses. Monensin pretreatment enhanced the rate of this Ca<SUP>2&#8290;</SUP> loss. Taken together, it is concluded that Na<SUP>&#8290;</SUP>-Ca<SUP>2&#8290;</SUP> exchange extrudes more SR released Ca<SUP>2&#8290;</SUP> out of the cell in proportion to the frequency, resulting in the negative rate staircase in the rat LA.