The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathyic rats: evidence at the cannabinoid CB1 receptor.
The exercise pressor reflex (EPR) is an important neural mechanism that controls blood pressure and heart rate during static muscle contraction. It has been previously demonstrated that the EPR is exaggerated in cardiomyopathy. Both mechanically (group III) and metabolically (group IV) sensitive afferent neurons are important to this reflex in normal humans and animals. In cardiomyopathy, however, the metabolically sensitive afferents are less responsive to activation whereas the mechanically sensitive fibres are overactive. We have demonstrated that this overactivity is responsible for the exaggeration in the EPR. Of importance, we have also demonstrated that the reduced responsiveness in the group IV afferent neuron is an initiating factor in the development of the exaggerated EPR. To date, the mechanism mediating this reduced group IV responsiveness remains unclear. Given that group IV afferent neurons are activated via chemically sensitive receptors, it is logical to suggest that changes in receptor function are responsible for the blunted behaviour of group IV neurons in cardiomyopathy. In order to test this postulate, however, potential receptor candidates must first be identified. The transient receptor potential vanilloid 1 (TRPv1) receptor is a non-selective cation channel that serves as a marker of the group IV afferent neurons in the periphery. We have demonstrated that the TRPv1 is abnormal in cardiomyopathy. It has been shown that the TRPv1 receptor is colocalized with the cannabinoid 1 (CB(1)) receptor on group IV afferent neurons. Therefore, we hypothesized that the function of CB(1) receptors is abnormal in cardiomyopathy. We explored this possibility by using anandamide (AEA), an endogenously produced cannabinoid that has been shown to control blood pressure via activation of the CB(1) receptor. In these studies, we evaluated the cardiovascular responses to intra-arterial injection of AEA into the hindlimb of normal, cardiomyopathic and neonatally capsaicin-treated (NNCAP) rats (rats that lack group IV afferent neurons) to determine whether administration of AEA results in abnormal responses of group IV afferent neurons in cardiomyopathic rats. We determined that AEA controls changes in blood pressure, predominately via activation of the CB(1) receptor in this preparation. We further observed that the blood pressure response to AEA is blunted in cardiomyopathic rats when compared to normal rats. We also observed a reduced blood pressure response to AEA in NNCAP animals, indicating that AEA is acting on group IV afferent neurons in this preparation. To determine whether programmed cell death could account for the decreased responsiveness that we observed during activation of the CB(1) and TRPv1 receptors on group IV afferent neurons in heart failure, we performed terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay. We observed no evidence of cell death within the dorsal root ganglia in rats with cardiomyopathy. The data suggest that the responsiveness of CB(1) receptors on group IV afferent neurons is blunted in cardiomyopathy. Importantly, these data indicate that group IV primary afferent neurons express multiple receptor defects in cardiomyopathy that may contribute to the decreased CB(1) receptor sensitivity in this disease.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9174, USA.
Maurice A
MA
Williams
Scott A
SA
Smith
Daniel E
DE
O'Brien
Jere H
JH
Mitchell
Mary G
MG
Garry
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001095:Arachidonic Acids / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D009475:Neurons, Afferent / Q000378:metabolism* / Q000473:pathology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin; C078814:anandamide