Blockade of Ca2+ dependent rat atrial slow action potentials by adenosine and lanthanum.

Abstract

The effects of different [Ca2+]0 in the presence of variable [Na+]0 (100 to 37 mM) on the slow action potentials were studied in isolated rat atria in the presence of 25 mM K+ plus 10−6 M isoproterenol. Two modes of electrical stimulation were used, sustained stimulation at 0.5 Hz (“steady-state” mode), and stimulation by a single stimulus after rest periods of 2 to 5 min (“1st response” mode). With the first type of stimulation, and for [Ca2+]0 between 0.5 and 10 mM and [Na+]0 between 100 and 65 mM, the slow action potential overshoot increased linearly with the logarithm of the [Ca2+]0 (28.4 mV per 10-fold change in [Ca2+]0). However, elevation of [Ca2+]0 above 10 mM caused depression of the overshoot. This overshoot depression by high [Ca2+]0 was accentuated if [Na+]0 was decreased to 37 mM. With the “1st response” mode of stimulation, the overshoot — log [Ca2+]0 relationship was linear within a wider [Ca2+]0 range (0.5 to 25 mM), and was less sensitive to further decreases in [Na+]0. It is suggested that rat atria slow action potentials are generated by selective influx of Ca2+ but not Na+, and that the depression of amplitudes observed a high [Ca2+]0 and low [Na+]0 is due to a decrease in the Na2+ exchange mechanism which results in a higher [Ca2+]i, and not to a decrease in the inward Na+ current. Adenosine produced a parallel downward displacement of the overshoot to log [Ca2+]0 relationship. This adenosine effect was concentration dependent, independent of [Ca2+]0 and the frequency of stimulation. In contrast, the effects of 0.4 mM La3+ were dependent on the [Ca2+]0 and on the frequency of stimulation. Adenosine also produced a downward shift of the relationship between maximal rate of rise of the slow action potential and membrane resting potential in such a manner that its effects cannot be attributed to changes in inactivation potential of the slow channels. Hence, adenosine and La3+ depress the slow Ca2+ action potentials by two different mechanisms. Adenosine may act by 1) decreasing the number of functional slow channels, 2) decreasing the conductance of the individual channels, or 3) altering the kinetic properties of these channels. La3+ may act by competing with Ca2+ for membrane binding sites. These membrane binding sites appear to be characterized by frequency dependence.