Raised extracellular potassium attenuates the sympathetic modulation of sino-atrial node pacemaking in the isolated guinea-pig atria

Intense exercise or myocardial ischaemia can significantly increase both the concentration of extracellular potassium ([K(+)](o)) and cardiac sympathetic nerve activity. Since changes in [K(+)](o) modulate membrane currents involved in sino-atrial node pacemaking, in particular the voltage-sensitive hyperpolarization-activated current (I(f)), we investigated whether raised [K(+)](o) (from 4 mM to 8 or 12 mM) could directly affect the heart rate response to cardiac sympathetic nerve stimulation (SNS). In the isolated guinea-pig atrial-right stellate ganglion preparation, raised [K(+)](o) significantly decreased the maximum diastolic potential, amplitude and maximum rate of rise of the upstroke of sino-atrial node pacemaker action potentials in 8 and 12 mM [K(+)](o) (P <0.05). At 12 mM [K(+)](o) these effects were associated with significant decreases in baseline heart rate (4 mM [K(+)](o) = 187 +/- 5 beats min(-1) (bpm); 12 mM = 144 +/- 11 bpm; P <0.05) and the heart rate response to SNS (1, 3 and 5 Hz; P <0.05). A 10 increase in the baseline heart rate with sympathetic activation (3 Hz) was associated with a significant enhancement of the slope of the pacemaker diastolic depolarization at 4 mM [K(+)](o) (increased by 16 +/- 6 ; n = 7; P <0.05), but not with raised [K(+)](o). When the I(f) current was blocked with 2 mM caesium (n = 8), 12 mM [K(+)](o) had no effect on baseline heart rate and the heart rate response to 3 Hz SNS. The heart rate response to bath-applied noradrenaline (0.01-100 microM) was significantly attenuated by 12 mM [K(+)](o) (at 4 mM [K(+)](o,) EC(50) = -6.31 +/- 0.18; at 12 mM [K(+)](o,) EC(50) = -5.80 +/- 0.10; n = 6, ANOVA, P <0.05). In conclusion, extreme physiological levels of [K(+)](o) attenuate the positive chronotropic response to cardiac sympathetic activation due to decreased activation of the I(f) current. This is