Adenosine is released during myocardial ischemia and can cause angina-like chest pain when given by intracoronary administration. We tested the hypothesis that intracoronary adenosine activates cardiac sympathetic afferent fibers and results in reflex sympathoexcitation. In dogs with sinoaortic denervation and vagotomy, we administered 2 mg of adenosine into the left anterior descending artery over 2 min. Before dipyridamole infusion, intracoronary adenosine resulted in no change in blood pressure or renal sympathetic nerve activity. After dipyridamole infusion, which blocks adenosine uptake, intracoronary adenosine resulted in a peak increase in sympathetic activity of 34 +/- 7%. We also investigated the adenosine-receptor subtype responsible for this sympathoexcitatory response. We found that the adenosine1 agonist N6-cyclopentyladenosine elicited a dose-dependent sympathoexcitatory response similar to adenosine but that the adenosine2 agonist 5'-(N-cyclopropyl)carboxamidoadenosine failed to elicit a sympathoexcitatory response. We conclude that adenosine activates cardiac sympathetic afferent fibers and leads to a sympathoexcitatory response due to activation of adenosine1 receptors.