Abstract 144: Interstitial Formation of Adenosine and Inosine Is Proarrhythmic Through Adenosine A1 Receptor in the Developing Heart
We previously established that exogenous adenosine (ADO) induces transient arrhythmias in the developing heart via the ADO A1 receptor (A1AR) and downstream activation of NADPH oxidase/ERK and PLC/PKC pathways.
We assessed the hypothesis that both endogenous ADO and its derived compound inosine (INO) can simultaneously act in an autocrine/paracrine manner and induce rhythm and conduction disturbances.
The validated model of the spontaneously beating heart obtained from 4-day-old chick embryos was used. The basal ADO/INO ratio determined by HPLC was approximately 10. Blockade of Equilibrative Nucleoside Transporters (ENTs) by dipyridamole, which is known to increase interstitial ADO level, induced transient atrial dysrhythmias and atrio-ventricular blocks in 70% of the hearts (n=30) and, in parallel, increased ERK2 phosphorylation. When extracellular conversion of AMP to ADO by ecto-5’-nucleotidase/CD73 was inhibited by AOPCP, the dipyridamole-induced arrhythmias were prevented. The dipyridamole-induced arrhythmias and ERK2 phosphorylation were prevented by the specific antagonist of the A1AR (DPCPX) but not by antagonists of A2AAR (SCH58261), A2BAR (MRS1754) or A3AR (MRS1523). Interestingly, inhibition by EHNA of the conversion of ADO to INO by adenosine deaminase was not proarrhythmic whereas exogenous INO (500 µM) induced arrhythmias which were prevented by DPCPX.
In conclusion, these findings suggest that endogenous ADO and INO in the interstitial compartment of the developing heart can provoke transient pacemaking and conduction disturbances via A1AR and downstream ERK activation in an autocrine/paracrine manner. Overall, our results provide new insights into the mechanisms underlying cardiac dysfunction when a hypoxic-ischemic episode induces local overproduction of ADO and INO
- © 2012 by American Heart Association, Inc.