The Group IV Afferent Neuron Expresses Multiple Receptor Alterations in Heart Failure: Evidence at the Cannabinoid (CB1) Receptor

Heart failure results in an exaggeration of the cardiovascular response to exercise mediated, in part, by overactivity of the exercise pressure reflex (EPR). Abnormalities in the metabolic component of the EPR (group IV primary afferent neurons in skeletal muscle) initiate this alteration. Anandamide (AEA), an endogenous cannabinoid, activates both the transient receptor potential vanilloid receptor (TPRv1) and the CB1 which are colocalized on group IV primary afferent neurons. We have shown that the pressor response to AEA is reduced in heart failure animals and in animals lacking group IV neurons (neonatal capsaicin treatment [NNCAP]) when compared to control animals. The receptor at which AEA produces the pressor response remains unclear. Therefore, the purpose of this investigation was to determine the receptor involved in the AEA induced pressor responses and alterations of the group IV afferent neuron in heart failure. Hindlimb intra‐arterial injections of AEA resulted in dose related increases in mean arterial pressure (MAP) in normal decerebrate (n=9), heart failure (n=7) and NNCAP treated rats, (n=6). We observed no effect of the selective TRPv1 antagonist, capsazepine, on the AEA induced pressor response whereas the selective CB1 antagonist, AM281, significantly reduced the pressor response. We performed TUNEL assay on dorsal root ganglia to evaluate programmed cell death of the group IV neuron and observed no evidence of apoptosis in cardiomyopathic rats. These data indicate that the AEA induced pressor response is mediated via the CB1 receptor in this preparation. Additionally, blunted pressor responses to AEA, together with a blunted response to TRPv1 activation, in cardiomyopathic rats suggests that the group IV primary afferent neurons express multiple receptor alterations in heart failure.