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(Circulation. 2001;103:1325.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Adenosine Enhances Neuroexcitability by Inhibiting a Slow Postspike Afterhyperpolarization in Rabbit Vagal Afferent Neurons

Holly R. Middlekauff, MD; Andrea Doering, PhD; James N. Weiss, MD

From the Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, Los Angeles, Calif.

Correspondence to Holly R. Middlekauff, MD, UCLA Department of Medicine, Division of Cardiology, 47-123 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail hmiddlek{at}medicine.medsch.ucla.edu

Background—Electrophysiological mechanisms by which adenosine may activate cardiac afferent neurons are unknown. Slow afterhyperpolarizations (AHPs) follow action potentials in a subset of vagal C afferents, rendering them inexcitable. The purpose of this study was to test the hypothesis that adenosine increases vagal neuronal excitability by blocking slow AHPs and to determine the adenosine receptor subtype mediating these effects.

Methods and Results—Using the perforated patch-clamp technique, we identified cultured adult rabbit nodose ganglion cells with slow AHPs in current-clamp mode. Trains of 100 current pulses at 20% above threshold were injected, with an interspike interval of 100 ms, and the number of action potentials triggered were counted and reported as the action potential response rate. During adenosine (10 µmol/L), slow AHPs were suppressed and action potential response rate was augmented from 3.8±0.5% at baseline to 28±7% after adenosine (P=0.0009). The selective A₂-adenosine receptor agonist NECA but not the A₁-adenosine agonist CCPA replicated the adenosine effect. The selective A_2A-adenosine antagonist ZM 241385 (10 nmol/L) but not the A₁ adenosine antagonist DPCPX (5 µmol/L) abolished the adenosine effect. We considered two alternative hypotheses: (1) A₂-receptor–mediated suppression of I_Ca leading to smaller increases in intracellular Ca during stimulation, resulting in less activation of I_K(Ca) and consequent suppression of slow AHPs, or (2) A₂-receptor–mediated elevation of cAMP directly suppressing slow AHPs. Under voltage-clamp conditions, adenosine did not significantly inhibit I_Ca, making the latter hypothesis more likely.

Conclusions—Adenosine inhibits slow AHPs in vagal afferent neurons. This effect is most likely caused by A_2A-receptor–mediated stimulation of cAMP production.

Key Words: adenosine • nervous system • receptors

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