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).


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 mumol/L) reversibly reduced I(f) by 33.1 +/- 5.7% of control (n = 5; P < .05). Ado (1 mumol/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 mumol/L Ado. The Ado receptor antagonist 8-PST (10 mumol/L) reversed the effect of 0.3 mumol/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 mumol/L (n = 93). The shifts in I(f) activation induced by Ado (0.3 mumol/L) and ACh (1 mumol/ 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 mumol/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.
Zaza
A
A
Dipartimento di Fisiologia e Biochimica Generali, Università di Milano, Italy.
Rocchetti
M
M
DiFrancesco
D
D
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D002712:Chlorides / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D006329:Heart Conduction System; D017895:Manganese Compounds / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D018408:Patch-Clamp Techniques; D058915:Purinergic P1 Receptor Antagonists; D011817:Rabbits; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D017609:Barium Compounds; D002712:Chlorides; D017895:Manganese Compounds; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C024986:barium chloride; D004533:Egtazic Acid; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000241:Adenosine; D000109:Acetylcholine; C025340:manganese chloride