Adenosine enhances neuroexcitability by inhibiting a slow postspike afterhyperpolarization in rabbit vagal afferent neurons

Background-Electrophysiological mechanisms by which adenosine may activate cardiac afferent neurons are unknown. Slow afterhyperpolarizations (AHPs) f ollow action potentials in a subset of vagal C afferents, rendering them in excitable. The purpose of this study was to test the hypothesis that adenos ine increases vagal neuronal excitability by blocking slow AHPs and to dete rmine the adenosine receptor subtype mediating these effects Methods and Results-Using the perforated patch-clamp technique, we identifi ed cultured adult rabbit nodose ganglion cells with slow AHPs in current-cl amp mode. Trains of 100 current pulses at 20% above threshold were injected , with an interspike interval of 100 ms, and the number of action potential s triggered were counted and reported as the action potential response rate . During adenosine (10 mu mol/L), slow AHPs were suppressed and action pote ntial response rate was augmented from 3.8+/-0.5% at baseline to 28+/-7% af ter adenosine (P=0.0009). The selective A(2)-adenosine receptor agonist NEC A but not the A(1)-adenosine agonist CCPA replicated the adenosine effect. The selective A(2A)-adenosine antagonist ZM 241385 (10 nmol/L) but not the A(1) adenosine antagonist DPCPX (5 mu mol/L) abolished the adenosine effect . We considered two alternative hypotheses: (1) A(2)-receptor-mediated supp ression of I-Ca leading to smaller increases in intracellular Ca during sti mulation, resulting in less activation of I-K(Ca) and consequent suppressio n of slow AHPs, or (2) A(2)-receptor-mediated elevation of cAMP directly su ppressing slow AHPs. Under voltage-clamp conditions, adenosine did not sign ificantly inhibit I-Ca, making the latter hypothesis more likely. Conclusions-Adenosine inhibits slow AHPs in vagal afferent neurons. This ef fect is most likely caused by A(2A)-receptor-mediated stimulation of cAMP p roduction.