Function and Regulation of Endothelin-1 and Its Receptors in Salt Sensitive Hypertension Induced by Sensory Nerve Degeneration

Abstract

Abstract-To determine the role of endothelin-1 (ET-1) and its receptors in salt-sensitive hypertension induced by sensory nerve degeneration, selective ET A antagonist (ABT-627) and ET B antagonist (A-192621) were used. Newborn Wistar rats were given vehicle or 50 mg/kg capsaicin subcutaneously on the first and second days of life. After the weaning period, male rats were divided into eight groups, and subjected to the following treatments for 2 weeks: control ϩ normal salt diet (ConϩNS, 0.5%), control ϩ high salt diet (ConϩHS, 4%), control ϩ high salt diet ϩ ABT-627 (ConϩHSϩABT-627), control ϩ high salt diet ϩ A -192621 (ConϩHSϩA-192621), capsaicin ϩ normal salt diet (CapϩNS), capsaicin ϩ high salt diet (CapϩHS), capsaicin ϩ high salt diet ϩ ABT-627 (CapϩHSϩABT-627), capsaicin ϩ high salt diet ϩ A -192621 (CapϩHSϩA-192621 Key Words: endothelin Ⅲ receptors, endothelin Ⅲ hypertension, sodium-dependent T he endothelin-1 (ET-1) belongs to a family of endothelium-derived peptides. Endogenous ET-1 is a potent vasoconstrictor and plays a fundamental physiological role in maintenance of blood pressure in human. 1 There are 2 distinct endothelin receptor subtypes, ET A and ET B.2,3 The ET A receptor has a selectively higher expression in vascular smooth muscle cells. 2 Endogenous ET-1 contributes to maintenance of the basal vascular tone and blood pressure via its action on the vascular smooth muscle ET A receptor. 4 ET B receptors are mainly expressed in endothelial cells, as well as in vascular smooth muscle cells and renal epithelium. 2,3,5,6 Endogenous ET-1 via binding to endothelial and renal ET B receptors causes vasodilation and natriuresis that result in a decrease in blood pressure. 4 The overall cardiovascular effect of endogenous ET-1 depends on the balance between ET Aand ET B -mediated effects. 4 In addition to the well-known control by sympathetic nerves, peripheral vascular resistance is regulated by sensory nerves. 7 For example, calcitonin gene-related peptide (CGRP), one of the sensory neurotransmitters, is a potent vasodilator and natriuretic factor. 7 It has been shown that CGRP-containing nerves suppress vasoconstriction mediated by sympathetic nerves. 8 It has also been suggested that the defect in sensory vasodilator function may produce an imbalance that contributes to the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). 9,10,11 In contrast to this genetic model, we have developed a novel salt-sensitive hypertensive model that is sensory nervesdependent. 12,13 We demonstrate that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant increase in blood pressure. 12,13 Moreover, we have shown that plasma renin activity is higher

The vanilloid receptor and hypertension1

“…Because we observed that plasma ET-1 levels in sensory denervated rats that were salt loaded were unaffected by blockade of the ET B clearance receptor [60] , it is clear that elevated plasma ET-1 levels are indeed the result of increased production, consistent with the possibility of increased synthesis and release of ET-1 secondary to insufficiently suppressed PRA in these capsaicin-pretreated animals [54,55] .…”

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] .…”

A Novel Mechanism Contributing to Development of Dahl Salt–Sensitive Hypertension

“…18 -21 It is conceivable that a defect in the sensory nervous system may lead to hypertension associated with reduced sodium excretion. Indeed, sodium excretion in response to sodium loading is impaired in salt-sensitive hypertension induced by sensory nerve degeneration of neonatally capsaicin-treated rats or surgically denervated rats, 3,[22][23][24] as well as in DS rats. [25][26][27] Therefore, the susceptibility of DS rats to hypertension may be attributed, at least in part, to the lack of adequate counterregulatory action of sensory nerves, and the resistance to hypertension in DR rats may be related to an enhanced function of sensory nerves.…”