Anandamide (AEA), a cannabinoid 1 receptor (CB1) agonist, has been suggested to be involved in the pathogenesis of hypertension (Lake et al, 1997) and cardiogenic shock (Wagner et al, 2001). AEA also binds to transient receptor potential vanilloid 1 (TRPV1) channels (Zygmunt et al, 1999), which are expressed on pulmonary C-fibers (Michael & Priestley, 1999). The latter are believed to be involved in the sensation of inflammation during lung disease (Lee & Widdicombe, 2001), and dyspnea during exercise (Paintal, 1973). In rats, intravenous injection of AEA elicits the pulmonary chemoreflex (apnea, bradycardia and hypotension; Lin & Lee, 2002), which is a C-fiber mediated reflex (Coleridge & Coleridge, 1984). However, the role of the transient receptor potential vanilloid 1 (TRPV1) receptor in this cardiopulmonary response remains unknown.
We measured the responses to AEA in anesthetized spontaneously breathing TRPV1+/+ (wildtype - WT) and TRPV1-/- (knockout - KO) mice. We also measured the response to aerosolized AEA in conscious, chronically instrumented WT and KO mice. Respiratory frequency (f) and heart rate (HR) were measured using a whole body plethysmograph and telemetry respectively. Vehicle, and AEA (9mM) were aerosolized at 350ml/min.
In anesthetized animals, the reflex pulmonary response to AEA was abolished in TRPV1 KO mice. In conscious mice, a significant bradycardia was observed during nebulization of AEA in the WT mice that was abolished in the TRPV1 KOs.
We conclude that TRPV1 plays a critical role in the cardiopulmonary reflex response to AEA.
We speculate that the TRPV1 protein is a primary molecular mechanism mediating C-fiber reflexes and may represent a therapeutic target for respiratory sensations involving bronchopulmonary C-fiber afferents.
Steven Smith, None.