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

Publisher Website
Google Scholar
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.