Sinus slowing and pacemaker shift caused by adenosine in rabbit SA node

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Abstract
Adenosine has a negative chronotropic effect in a number of species. The studies reported here were undertaken to characterize further the effects of adenosine using isolated perfused rabbit hearts and isolated SA node tissue. In the isolated perfused hearts (n=9) the threshold doses for slowing by adenosine and 2-chloroadenosine, an adenosine analog, were 1×10−5 M and 1×10−7 M, respectively. In the isolated hearts adenosine, in addition to slowing sinus rate, also caused a change in the activation pattern of the right atrium. During adenosine infusion the earliest site of activation shifted from the SA node region to the right atria near the crista terminalis. The pacemaker shift was reversible upon washout of adenosine. The adenosine-induced shift in pacemaker could also be demonstrated using microelectrode recordings in the isolated SA node preparation that included the crista terminalis and some of the surrounding tissue. During control the activation of SA node preceded that of the crista terminalis (CT) by 44±4.1 ms (n=11). Adenosine infusion caused an increase in cycle length and, in addition shifted the earliest site of activation from the SA node region to CT, i.e., in the presence of adenosine CT preceded SA node activation by 26.68±3.2 ms. All the effects were reversible after washout of adenosine. Adenosine also caused conduction block within the sinus node. No effect on the action potentials or on conduction in the CT was observed. In small preparations (250×250 μm) which precludes pacemaker shift (n=18), adenosine and 2-chloroadenosine slowed the rate and caused a decrease in rate of phase four depolarization. The threshold for adenosine and 2-chloro-adenosine was 1×10−5 M and 3×10−7, respectively. Associated with pacemaker slowing was an increase in the maximum diastolic potential with a concomitant increase in the maximum rate of rise of the action potential. Adenosine had no effect on the SA node action potential duration or amplitude. The results were similar to those observed for acetylcholine, however, the adenosine effects were blocked by aminophylline but not by atropine. Adenosine-induced sinus slowing and pacemaker shift may be of importance during periods of metabolically compromised myocardium such as hypoxia and ischemia where there is increased production of adenosine.