Modulation of the hyperpolarization-activated current (I-f) by adenosine in rabbit sinoatrial myocytes

Background Modulation of sinoatrial pacemaking by adenosine (Ado) in the absence of concomitant adrenergic stimulation (direct modulation) has been attributed to activation of a K+ conductance. In the present study, we evaluated the direct effects of Ado on the pacemaking current I-f and tested their interaction with those of acetylcholine (ACh). Methods and Results Rabbit sinoatrial myocytes were patch-clamped at 35 degrees C in the presence of 1 mmol/L BaCl2 and 2 mmol/L MnCl2. Ado (1 mu mol/L) reversibly reduced I-f by 33.1+/-5.7% of control (n=5; P<.05). Ado (1 mu mol/L) reversibly shifted If midactivation potential by -6.63+/-1.18 mV (n=4; P<.05). Fully activated I-f conductance (0.262+/-0.037 versus 0.254+/-0.036 nS/pF; n=6, NS) and reversal potential (-17.35+/-0.99 versus -18.01+/-1.42 mV; n=6, NS) were not changed by 10 mu mol/L Ado. The Ado receptor antagonist 8-PST (10 mu mol/L) reversed the effect of 0.3 mu mol/L Ado by 64.9+/-4.2% (n=6; P<.05). Ado maximally shifted the I-f activation curve by -5.85 mV, with a half-maximal concentration of 0.0795 mu mol/L (n=93). The shifts in I-f activation induced by Ado (0.3 mu mol/L) and ACh (1 mu mol/L) separately were -4.89+/-0.05 and -8.84+/-0.51 mV, respectively; concomitant Ado and ACh superfusion shifted activation by -9.7+/-0.45 mV (NS versus ACh alone; n=9). Threshold Ado concentrations dose-dependently reduced the rate of spontaneous pacemaker activity (eg, -18.8+/-3.4% at Ado 0.03 mu mol/L). Conclusions Submicromolar Ado directly inhibits I-f and slows pacemaking in sinoatrial myocytes; the mode of I-f inhibition is similar to that previously described for ACh. Thus, Ado may exert local modulation of sinus rate through signaling pathways similar to those used by ACh.