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 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.
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 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.
Authors: Qing Lou; Alexey V Glukhov; Brian Hansen; Lori Hage; Pedro Vargas-Pinto; George E Billman; Cynthia A Carnes; Vadim V Fedorov Journal: Heart Rhythm Date: 2012-09-14 Impact factor: 6.343
Authors: Victor P Long; Ingrid M Bonilla; Stephen Baine; Patric Glynn; Sanjay Kumar; Karsten Schober; Kent Mowrey; Raul Weiss; Nam Y Lee; Peter J Mohler; Sandor Györke; Thomas J Hund; Vadim V Fedorov; Cynthia A Carnes Journal: Life Sci Date: 2019-11-18 Impact factor: 5.037