Background— Chest pain is a hallmark of myocardial ischemia, but its underlying signaling mechanisms remain poorly understood. The capsaicin receptor, vanilloid receptor-1 (VR₁), is an important cation channel present on primary nociceptive neurons. We have shown that the VR₁ is expressed on sensory nerve endings of the heart. In the present study, we determined the role of VR₁s in activation of cardiac spinal afferent nerves caused by myocardial ischemia.

Methods and Results— Single-unit activity of cardiac afferents was recorded from the sympathetic chain of anesthetized ferrets. Cardiac afferents responded to 5 minutes of regional myocardial ischemia and topical application of 10 μg/mL bradykinin in a reproducible manner. Topical application of a specific VR₁ antagonist, iodoresiniferatoxin (50 μmol/L), to the receptive field of afferents produced a large attenuation of the firing activity of cardiac afferents caused by myocardial ischemia. Iodoresiniferatoxin also significantly reduced the afferent response to bradykinin applied to the receptive field. Furthermore, treatment with a VR₁ channel blocker, ruthenium red (200 μmol/L), had a similar inhibitory effect on the afferent responses to myocardial ischemia and bradykinin.

Conclusions— This study provides the first functional evidence that ischemic stimulation of cardiac spinal afferent nerves is mediated through VR₁s. The VR₁ on the cardiac sensory nerve may function as a molecular sensor to detect tissue ischemia and activate cardiac nociceptors.