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 (If), 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 If 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 μM) was significantly attenuated by 12 mM [K+]o (at 4 mM [K+]o, EC50= -6.31 ± 0.18; at 12 mM [K+]o, EC50= -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 If current. This is consistent with raised [K+]o protecting the myocardium from potentially adverse effects of excessive noradrenaline.