The vanilloid receptor and hypertension1

Abstract

Mammalian transient receptor potential (TRP) channels consist of six related protein sub‐families that are involved in a variety of pathophysiological function, and disease development. The TRPV1 channel, a member of the TRPV sub‐family, is identified by expression cloning using the “hot” pepper‐derived vanilloid compound capsaicin as a ligand. Therefore, TRPV1 is also referred as the vanilloid receptor (VR1) or the capsaicin receptor. VR1 is mainly expressed in a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin‐sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a “sensory‐ effector” function. Regarding the latter, these neurons release stored neuropeptides through a calcium‐dependent mechanism via the binding of capsaicin to VR1. The most studied sensory neuropeptides are calcitonin gene‐related peptide (CGRP) and substance P (SP), which are potent vasodilators and natriuretic/diuretic factors. Recent evidence using the model of neonatal degeneration of capsaicin‐sensitive sensory nerves revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent 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 neurohormonal 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.

Preventive Effect of SA13353, a Novel Transient Receptor Potential Vanilloid 1 Agonist, on Ischemia/Reperfusion-Induced Renal Injury in Rats

“…Numerous attempts have been made to prevent AKI using animal models of ischemia/reperfusion-induced renal injury, and various vasodilative agents, including natriuretic peptides, adenosine antagonists, dopamine receptor agonists, calcium antagonists, endothelin receptor antagonists, and acetylcysteine, have been considered to be useful for the prevention and management of AKI [25], although it remains to be elucidated whether similar interventions are beneficial to clinical uses. TRPV1 has also been suggested to play a role in regulating vasodilatation in a variety of vascular beds [18]. The activation of TRPV1 leads to release of several neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP), and somatostatin [26].…”

“…TRPV1 expression is seen in a high percentage of primary afferent neurons that project to cardiovascular and renal tissues [18]. It has been demonstrated most recently that TRPV1 protein is highly present in the renal pelvis and exclusively regulates neuropeptide release from primary renal afferent nerves in response to mechanostimulation [19].…”

Enhanced salt sensitivity following shRNA silencing of neuronal TRPV1 in rat spinal cord

“…These data show that selective knockdown of neuronal TRPV1 enhances prohypertensive effects induced by salt loading and that pressor effects of TRPV1 shRNA may be mediated, at least in part, by enhancement of the sympatho-excitatory response. We have previously shown that neonatal degeneration of TRPV1-expressing sensory nerves increased salt sensitivity of arterial pressure as these rats grew into adulthood [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . However, the systemic sensory denervation used in these previous studies precluded us from making conclusions about whether the observed effect was due to the removal of TRPV1 or other proteins co-expressed in the same nerves innervating any specific organs or tissues [21,22] .…”

“…Thus, defining the role of TRPV1-positive sensory nerves in the regulation of blood pressure and salt sensitivity will be useful. We have shown previously that the degeneration of TRPV1-expressing sensory nerves throughout the neonatal body by subcutaneous injection of capsaicin, a selective TRPV1 agonist, leads to increased salt sensitivity of arterial pressure, indicating that TRPV1-positive sensory nerves play a counter-regulatory role against salt-induced increases in blood pressure [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] . The underlying mechanism of anti-hypertensive effects of TRPV1 may involve its counter-balancing role against the activation of the renin-angiotensin-aldosterone system [7][8][9] , sympathetic nervous system [10] , endothelin system [11,12] , superoxide generation system [13,14] , and epithelial sodium transporters [15] .…”

Diuresis and Natriuresis Caused by Activation of VR1-Positive Sensory Nerves in Renal Pelvis of Rats

“…21 Activation of the VR1 receptor by agonists opens this receptor-operated cationpermeable channel that ultimately results in an influx of sodium and calcium and a release of neuropeptides produced and stored in VR1-positive sensory neurons. CGRP is a potent vasodilator neuropeptide and intravenous bolus injection of CGRP at doses of 100 and 500 pmol/L leads to hypotension in a dose-dependent fashion.…”