Modulation of the Hyperpolarization-Activated Current (I f ) by Adenosine in Rabbit Sinoatrial Myocytes

Abstract

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°C in the presence of 1 mmol/L BaCl 2 and 2 mmol/L MnCl 2 . Ado (1 μmol/L) reversibly reduced I f by 33.1±5.7% of control (n=5; P <.05). Ado (1 μmol/L) reversibly shifted I f 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 μmol/L Ado. The Ado receptor antagonist 8-PST (10 μmol/L) reversed the effect of 0.3 μmol/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 0.0796 μmol/L (n=93). The shifts in I f activation induced by Ado (0.3 μmol/L) and ACh (1 μmol/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 μmol/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.