Potentiation of the negative dromotropic effect of adenosine by rapid heart rates: possible ionic mechanism.
Adenosine-induced slowing of atrioventricular nodal conduction is a rate-dependent process that is potentiated by the A(1)-adenosine receptor allosteric enhancer, PD 81,723. The ionic mechanisms underlying these phenomena were investigated in guinea pig isolated hearts and single atrial myocytes by measuring the atrium-to-His bundle (A-H) interval and using patch-clamp recordings, respectively.A decrease in atrial cycle length from 300 to 190 ms decreased the concentration of adenosine needed to cause atrioventricular nodal block from 7.8 +/- 1.0 to 2.6 +/- 0.7 micromol/L (P < 0.001). Ba(2+) (100 micromol/L), a selective blocker of the adenosine-activated inward rectifier K(+) current I(K,ADO) in the atrioventricular node, failed to abolish this rate-dependent effect of adenosine. PD 81,723 (5 micromol/L) potentiated the negative dromotropic effect of adenosine even after I(K,ADO) was blocked by Ba(2+) and after attenuation of I(Ca,L) by adenosine was prevented by 8-Br-cAMP (1.5 mmol/L). In atrial myocytes, adenosine augmented a time- and voltage-dependent K(+) current (Ado-I(K)). Ado-I(K) was more sensitive to adenosine than I(K,ADO) (EC(50) values, 0.8 versus 1.4 micromol/L, P < 0.01). PD 81,723 blocked I(K,ADO), but potentiated Ado-I(K). Ado-I(K) was insensitive to Ba(2+) (P = 0.98), whereas it was blocked by chromanol 293B (5 micromol/L, P < 0.001). Unlike I(K,ADO), Ado-I(K) increased during rapid stimulation of myocytes (P < 0.001). Adenosine augments a time- and voltage-dependent K(+) current, Ado-I(K). The pharmacological and kinetic properties of Ado-I(K) are consistent with it playing an important role in the negative dromotropic effect of adenosine at lower concentrations of the nucleoside, at fast heart rates and in the presence of PD 81,723.
Department of Anesthesiology, University of Florida, Gainesville, Florida 32610-0254, USA.
Anatoly E
AE
Martynyuk
Aleksey
A
Zima
Christoph N
CN
Seubert
Timothy E
TE
Morey
Luiz
L
Belardinelli
Donn M
DM
Dennis
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001283:Atrioventricular Node / Q000166:cytology / Q000502:physiology*; D004357:Drug Synergism; D004558:Electric Stimulation; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D015221:Potassium Channels; D013876:Thiophenes; C075004:PD 81723; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000241:Adenosine; D011188:Potassium