TRPV1, Hypertension, and Cardiovascular Regulation

Dear Editor,We would like to highlight the further consideration of the nervous system in the mechanistic conclusions of the article “Activation of TRPV1 Dietary Capsaicin Improves Endothelium-Dependent Vasorelaxation and Prevents Hypertension” (Yang et al., 2010xYang, D.C., Luo, Z.D., Ma, S.T., Wong, W.T., Ma, L.Q., Zhong, J., He, H.B., Zhao, Z.G., Cao, T.B., Yan, Z.C. et al. Cell Metab. 2010; 12: 130–141Abstract | Full Text | Full Text PDF | PubMed | Scopus (83)See all ReferencesYang et al., 2010). While the cellular data localizing TRPV1 receptors and demonstrating direct actions of capsaicin on endothelial calcium signals is convincing, the chronic experiments critical for the authors interpretations justify further thoughts. In the first of these experiments, the authors fed rats and mice large amounts of the TRPV1 agonist capsaicin (0.01%–0.02% in chow) for 7 months and found modest reductions in systolic blood pressure in spontaneously hypertensive rats. At these levels of intake, even very conservative estimates (considering bioavailability and blood buffering capacity) of plasma circulating concentrations of capsaicin would reach into the 10–100 nM range. Unfortunately, the initial chronic experiments did not measure plasma levels, but a single dose of gastric capsaicin generated high (10 ng/ml) plasma concentrations lasting more than 1 hr—or a sustained exposure to ∼33 nM in plasma. In either case, these pharmacological concentrations of capsaicin may be sufficient to produce excitotoxic changes or widespread, sustained, functional desensitization of TRPV1. Such effects might be evident in the authors' food intake data (Figure S4, Yang et al. [2010]xYang, D.C., Luo, Z.D., Ma, S.T., Wong, W.T., Ma, L.Q., Zhong, J., He, H.B., Zhao, Z.G., Cao, T.B., Yan, Z.C. et al. Cell Metab. 2010; 12: 130–141Abstract | Full Text | Full Text PDF | PubMed | Scopus (83)See all References]Yang et al. [2010]), which shows initial aversion to the capsaicin diet followed by progressive return to normophagia consistent with a desensitization or recovery process. At a minimum these concentrations would result in strong agonism of all accessible TRPV1 receptors, including those expressed in the nervous system, and suggests a number of other pertinent considerations regarding blood pressure and long-term consequences of chronic dietary capsaicin.In interpreting the blood-pressure observations, it is worth considering the nervous system and the importance of long-recognized high-affinity TRPV1 receptors in cranial visceral afferents (Coleridge and Coleridge, 1980xColeridge, H.M. and Coleridge, J.C.G. Annu. Rev. Physiol. 1980; 42: 413–427CrossRef | PubMedSee all ReferencesColeridge and Coleridge, 1980). These cranial visceral afferents include cardiovascular and noncardiovascular primary vagal afferents that alter autonomic nervous system regulation of the cardiovascular system via the solitary tract nucleus (Andresen and Peters, 2008xAndresen, M.C. and Peters, J.H. Am. J. Physiol. Heart Circ. Physiol. 2008; 295: H2032–H2042CrossRef | PubMed | Scopus (33)See all ReferencesAndresen and Peters, 2008). Chronic activation of arterial baroreceptors produces long-term reductions in blood pressure (Lohmeier et al., 2010xLohmeier, T.E., Iliescu, R., Dwyer, T.M., Irwin, E.D., Cates, A.W., and Rossing, M.A. Am. J. Physiol. Heart Circ. Physiol. 2010; 299: H402–H409CrossRef | PubMed | Scopus (51)See all ReferencesLohmeier et al., 2010). Arterial baroreceptors express TRPV1 receptors both peripherally as well as on their central terminals (Doyle et al., 2002xDoyle, M.W., Bailey, T.W., Jin, Y.-H., and Andresen, M.C. J. Neurosci. 2002; 22: 8222–8229PubMedSee all References, Andresen and Peters, 2008xAndresen, M.C. and Peters, J.H. Am. J. Physiol. Heart Circ. Physiol. 2008; 295: H2032–H2042CrossRef | PubMed | Scopus (33)See all References, Peters et al., 2010xPeters, J.H., McDougall, S.J., Fawley, J.A., Smith, S.M., and Andresen, M.C. Neuron. 2010; 65: 657–669Abstract | Full Text | Full Text PDF | PubMed | Scopus (70)See all References) and represent a nondesensitizing target with nM affinity for capsaicin exposed through an open-blood brain barrier. Thus, chronic activation of TRPV1 receptors on arterial baroreceptors would be expected to lower blood pressure without a sustained change in heart rate (Lohmeier et al., 2010xLohmeier, T.E., Iliescu, R., Dwyer, T.M., Irwin, E.D., Cates, A.W., and Rossing, M.A. Am. J. Physiol. Heart Circ. Physiol. 2010; 299: H402–H409CrossRef | PubMed | Scopus (51)See all ReferencesLohmeier et al., 2010).Further, a number of other neural targets containing TRPV1 have the potential to alter blood pressure less directly. TRPV1 receptors contribute to thermal regulation and, through these pathways, can alter blood flow and vessel function. Gastrointestinal and other viscera provide neural signals that chronically influence feeding behaviors, nutritional balance, and homeostatic outcomes that each might contribute to blood-pressure outcomes. In the time interval of these chronic studies, potential trophic interactions between sympathetic nerves and blood-vessel function might also warrant attention. While activation of TRPV1 at vascular endothelium may critically contribute to vessel tone, a more comprehensive view of vanilloids and their multiple TRPV1 actions will be necessary to fully understand their antihypertensive potential.