Faculty Bibliography

Hauswirth et al. (1968) proposed that epinephrine acts on i(KK2) by adding its own positive charge to the external membrane surface near the i(KK2) channel. This hypothesis was tested by using noncationic compounds, theophylline and R07-2956, which mimicked epinephrine's effects on pacemaker activity and on i(KK2). In maximally effective doses, theophylline or R07-2956 occluded the effect of epinephrine, indicating a shared final common mechanism. Since theophylline and R07-2956 are noncationic at pH 7.4, the common mechanism cannot be a direct change in external surface charge. On the contrary, epinephrine does not interfere with the voltage shift produced by La(+++), which is thought to modify the external surface charge. The results argue against the original hypothesis but leave open the possibility that an alteration in internal surface charge generates the observed voltage shift. The potency of theophylline and R07-2956 as phosphodiesterase inhibitors suggests that the final common mechanism begins with the elevation of intracellular cyclic AMP, leading to a saturable process which limits the voltage shift's magnitude. This hypothesis is used to generate dose-response curves describing the combined effects of epinephrine and theophylline, and these are compared with experimental data

Epinephrine promotes spontaneous activity in cardiac Purkinje fibers through its action on the pacemaker potassium current (i(KK2)). The mechanism of the acceleratory effect was studied by means of a voltage clamp technique. The results showed that the hormone speeds the deactivation of i(KK2) during pacemaker activity by displacing the kinetic parameters of i(KK2) toward less negative potentials. This depolarizing voltage shift is the sole explanation of the acceleratory effect since epinephrine did not alter the rectifier properties of i(KK2), or the underlying inward leakage current, or the threshold for i(NNa). The dose dependence of the voltage shift in the i(KK2) activation curve was similar in 1.8 and 5.4 mM [Ca](o). The maximal voltage shift (usually approximately 20 mV) was produced by epinephrine concentrations of > 10(-6) M. The half-maximal effect was evoked by 60 nM epinephrine, nearly an order of magnitude lower than required for half-maximal effect on the secondary inward current (Carmeliet and Vereecke, 1969). The beta-blocker propranolol (10(-6) M) prevented the effect of epinephrine (10(-7)M) but by itself gave no voltage shift. Epinephrine shifted the activation rate coefficient alpha(8) to a greater extent than the deactivation rate coefficient beta(8), and often steepened the voltage dependence of the steady-state activation curve. These deviations from simple voltage shift behavior were discussed in terms of possible mechanisms of epinephrine's action on the i(KK2) channel