The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathyic rats

Evidence at the cannabinoid CB 1 receptor

Maurice A. Williams, Scott A. Smith, Daniel E. O'brien, Jere H. Mitchell, Mary G. Garry

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 (CB1) receptor on group IV afferent neurons. Therefore, we hypothesized that the function of CB1 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 CB1 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 CB1 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 CB1 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 CB1 receptor sensitivity in this disease.

Original languageEnglish (US)
Pages (from-to)835-845
Number of pages11
JournalJournal of Physiology
Volume586
Issue number3
DOIs
StatePublished - Feb 1 2008

Fingerprint

Afferent Neurons
Cannabinoids
Cardiomyopathies
Cannabinoid Receptors
Reflex
Blood Pressure
Capsaicin
Cell Death
Intra-Arterial Injections
DNA Nucleotidylexotransferase
Spinal Ganglia
Hindlimb
Muscle Contraction
Cations
Heart Failure
Heart Rate

ASJC Scopus subject areas

  • Physiology

Cite this

The group IV afferent neuron expresses multiple receptor alterations in cardiomyopathyic rats : Evidence at the cannabinoid CB 1 receptor. / Williams, Maurice A.; Smith, Scott A.; O'brien, Daniel E.; Mitchell, Jere H.; Garry, Mary G.

In: Journal of Physiology, Vol. 586, No. 3, 01.02.2008, p. 835-845.

Research output: Contribution to journalArticle

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AB - 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 (CB1) receptor on group IV afferent neurons. Therefore, we hypothesized that the function of CB1 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 CB1 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 CB1 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 CB1 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 CB1 receptor sensitivity in this disease.

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