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(Circulation. 1996;94:734-741.)
© 1996 American Heart Association, Inc.

Articles

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

Antonio Zaza, MD; Marcella Rocchetti, PhD; Dario DiFrancesco, PhD

the Dipartimento di Fisiologia e Biochimica Generali, Universita di Milano, Milano, Italy.

Correspondence to Antonio Zaza, MD, Dipartimento di Fisiologia e Biochimica Generali, Via Celoria 26, 20133 Milano, Italy.

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 BaCl₂ and 2 mmol/L MnCl₂. 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.

Key Words: sinoatrial node • electrophysiology • adenosine • acetylcholine

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