Acta Pharmacologica Sinica 2005 Mar; 26 (3): 286–294 Invited review The vanilloid receptor and hypertension1 Donna H WANG2 Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48825, USA Key words Abstract TRP family; afferent neurons; capsaicin; Mammalian transient receptor potential (TRP) channels consist of six related pro- calcitonin gene-related peptide; substance P; tein sub-families that are involved in a variety of pathophysiological function, and vanilloid receptor; renin-angiotensin- aldosterone system; endothelin, sympathetic disease development. The TRPV1 channel, a member of the TRPV sub-family, is nervous system; salt-sensitive hypertension identified by expression cloning using the “hot” pepper-derived vanilloid com- pound capsaicin as a ligand. Therefore, TRPV1 is also referred as the vanilloid 1 This work was supported in part by National receptor (VR1) or the capsaicin receptor. VR1 is mainly expressed in a subpopula- Institutes of Health (grants HL-52279 and tion of primary afferent neurons that project to cardiovascular and renal tissues. HL-57853) and a grant from the Michigan These capsaicin-sensitive primary afferent neurons are not only involved in the Economic Development Corporation. 2 Correspondence to Donna H WANG, MD. perception of somatic and visceral pain, but also have a “sensory-effector” function. Phn 1-517-432-0797. Regarding the latter, these neurons release stored neuropeptides through a cal- Fax 1-517-432-1326. cium-dependent mechanism via the binding of capsaicin to VR1. The most studied E-mail [email protected] sensory neuropeptides are calcitonin gene-related peptide (CGRP) and substance Received 2004-08-10 P (SP), which are potent vasodilators and natriuretic/diuretic factors. Recent evi- Accepted 2004-12-14 dence using the model of neonatal degeneration of capsaicin-sensitive sensory nerves revealed novel mechanisms that underlie increased salt sensitivity and doi: 10.1111/j.1745-7254.2005.00057.x several experimental models of hypertension. These mechanisms include insuffi- cient suppression of plasma renin activity and plasma aldosterone levels subse- quent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neurohor- monal systems to maintain normal blood pressure when challenged with salt loading. The therapeutic utilities of vanilloid compounds, endogenous agonists, and sensory neuropeptides are also discussed. hot chilli peppers and responsible for the pungency of these Introduction spices[2]. Mammalian transient receptor potential (TRP) channels Over the last several centuries, knowledge about the consist of six related protein sub-families known as TRPV, physiological actions of capsaicin has grown and capsaicin TRPC, TRPM, TRPP, TRPML, and TRPA[1]. These channels has become a powerful tool, as will be described, for study- are widely distributed and involved in sensing local stimuli ing mechanisms underlying hypertension. Ever since its ranging from changes in hemodynamics to pH and osmo- isolation in the mid-nineteenth century, capsaicin has been larity. The TRPV1 channel, a member of the TRPV sub-family, documented to act on sensory fibers with neuroselectivity[3,4]. was identified by expression cloning using the “hot” pep- Nelson elucidated the structure of capsaicin, reporting it as per-derived vanilloid compound capsaicin as a ligand. TRPV1 8-methyl-vannillyl-6-noneamide, an acylamide derivative of is therefore referred as the vanilloid receptor (VR1) or the homovanillic acid[5]. The compound consists of three func- capsaicin receptor. Capsaicin as well as other closely re- tional moieties: vannilyl, acylamide, and alkyl[2]. Jancso later lated vanilloid substances are principal constituents in the showed that capsaicin-sensitive nerve endings could be 286 ©2005 CPS and SIMM Http://www.chinaphar.com Wang DH stimulated as well as destroyed by a sufficiently high dose stimuli that may induce neurotransmitter release are varied of capsaicin[6]. The neurotoxicity effect of capsaicin is of and include nerve growth factor[16], vascular wall tension[17], paramount importance, for reasons that will become clear, to the sympathetic nervous system[18], bradykinin[19], and neurobiologists using capsaicin sensitive-sensory nerve de- endothelin[20]. generation to study blood pressure regulation. The review that follows outlines the advances that have been made since Efferent function of VR1-positive sensory Jancso’s publications, with regard to mechanisms of neurons capsaicin’s action, cardiovascular effects of select neuropep- tides released by a subset of capsaicin-sensitive primary VR1-positive sensory neurons have a dual function: sen- afferent neurons (CSPAN) innervating cardiovascular and sory perception and sensory efferent function. Binding of renal tissues, and pathophysiologic mechanisms of hyper- capsaicin and capsaicin agonists to VR-1 leads to neuropep- tension elucidated by capsaicin sensitive sensory-nerve tide release from a subpopulation of neuropeptide-contain- [15] degeneration. Capsaicin pharmacology and the nature of ing primary afferent neurons . Binding to this receptor [21–25] capsaicin-sensitive sensory nerves are discussed in greater opens a receptor-operated permeable cation channel that detail in a number of other excellent scholarly reviews[7–9]. ultimately results in the influx of sodium and calcium ions. This review is restricted to a discussion of the effects of Sodium influx is sufficient for afferent impulse conduction. capsaicin on the cardiovascular system. Other authors have In sharp contrast, calcium influx, and thus extracellular reviewed the effects of capsaicin on the somatosensory, calcium, is prerequisite for neuropeptide release. Without respiratory, thermoregulatory, and gastrointestinal sys- extracellular calcium, sensory neuropeptides are no longer tems[10–14]. released from sensory nerve endings when these endings are depolarized[15]. Given that the neuroselectivity of capsaicin is a reflec- VR1 positive sensory neurons tion of the selective expression of the VR1 on a subpopula- VR1-positive sensory neurons refer to a subset of pri- tion of primary afferent neurons, a closer look at the VR1 is mary afferent neurons that express the VR1 receptors which warranted. Initial evidence supporting a capsaicin-binding can be activated by capsaicin. The pharmacological prop- site on a subset of primary afferent neurons came from ob- erty of sensitivity to capsaicin distinguishes these afferent servations that capsaicin analogues are able to exert similar neurons, mostly having unmyelinated (C fibers) or thinly functional changes[26,27]. Additional support came from ex- myelinated axons (Aδ fibers), from other afferent neurons[15]. perimentation with resiniferatoxin, a phorbol ester derivative Maggi[15] has described the functional anatomy of the that has been shown to exhibit structural similarity [28,29] and VR1-positive primary afferent neuron by identifying four densensitizing and excitatory properties homologous to sites from which neurotransmitter release may occur: (i) cen- those exhibited by capsaicin, albeit at 1000-fold lower tral terminals of the afferent neuron in contact with second- doses[28–30]. Definitive support for the presence of a chemi- order neurons in the CNS; (ii) terminals distributed in the cal moiety capable of binding to capsaicin and related ago- prevertebral ganglia; (iii) peripheral terminals distinct from nists came with the development of capsazepine, experimen- the terminal at which the sensory stimulus is applied; and tally shown to act as a competitive antagonist of vanilloid (iv) the same peripheral terminal at which the sensory stimu- binding and activity[31]. The VR-1 has been reviewed in lus is applied. Neurotransmitter release at sites (i) and (ii) greater detail in an authoritative review by Caterina and Julius[32]. accounts for the sensory function of CSPAN and is central Concerning the nature of transmitters released from VR1- to perception of somatic and visceral pain. In contrast, and positive sensory neurons, Maggi and Meli[15] have reported as implied by neuropeptide release from peripheral terminals that at least the following 12 different types of transmitters (iii) and (iv), CSPAN nerve endings not only serve as sen- are present in capsaicin-sensitive sensory neurons: sub- sory receptors, but also as effector sites from which neu- stance P (SP), neurokinin A, neuropeptide K, eledoisin-like rotransmitters are released. Thus, neurotransmitter release peptide, somatostatin, vasoactive intestinal polypeptide, from sites (iii) and (iv) accounts for the “sensory-efferent” cholecystokinin-octapeptide, calcitonin gene-related peptide function of CSPAN, with release from site (iv) not even re- (CGRP), galanin, corticotrophin-releasing factor, arginin quiring neuronal conduction[15]. Accordingly, Maggi and vasopressin, bombesin-like peptides. These authors also Meli[11] have termed release from site (iv) the “sensory re- report that multiple neuropeptides can be simultaneously ceptor potential-coupled efferent response.” Local sensory released from VR1-positive sensory nerve endings. However, 287 Wang DH Acta Pharmacologica Sinica ISSN 1671-4083 different neuropeptides may be preferentially released as