Antihypertensive Mechanisms Underlying a Novel Salt-Sensitive Hypertensive Model Induced by Sensory Denervation

Abstract

Abstract-A novel model of hypertension recently developed in our laboratory shows that neonatal degeneration of capsaicin-sensitive sensory nerves renders a rat responsive to a salt load with a significant rise in blood pressure. To determine the role of the renin-angiotensin system and the sympathetic nervous system in the development of hypertension in this model, newborn Wistar rats were given capsaicin 50 mg/kg SC on the first and second days of life. Control rats were treated with vehicle. After they were weaned, male rats were divided into 6 groups and subjected to the following treatments for 2 weeks: controlϩhigh sodium diet (4%) (CON-HS), capsaicinϩnormal sodium diet (0.5%) (CAP-NS), capsaicinϩhigh sodium diet (CAP-HS), capsaicinϩhigh sodium dietϩlosartan (10 mg/kg per day) (CAP-HS-LO), capsaicinϩhigh sodium dietϩprazosin (3 mg/kg per day) (CAP-HS-PR), and capsaicinϩhigh sodium dietϩhydralazine (10 mg/kg per day) (CAP-HS-HY). Levels of calcitonin gene-related peptide in dorsal root ganglia were decreased by capsaicin treatment (PϽ0.05). Both tail-cuff systolic blood pressure and mean arterial pressure were higher in CAP-HS and CAP-HS-PR than in CON-HS, CAP-NS, CAP-HS-LO, and CAP-HS-HY (PϽ0.05). The 24-hour urinary volume and sodium excretion were increased when a high sodium diet was given (PϽ0.05), but they were lower in CAP-HS, CAP-HS-LO, CAP-HS-PR, and CAP-HS-HY than in CON-HS (PϽ0.05). Urinary potassium excretion was not different among all 6 groups. We conclude that blockade of the angiotensin type 1 receptor with losartan but not antagonism of the ␣ 1 -adrenoreceptor with prazosin prevents the development of salt-sensitive hypertension induced by sensory denervation. Sensory denervation impairs urinary sodium and water excretion in response to a high sodium intake, regardless of blood pressure, suggesting that sensory innervation plays a direct role in regulating the natriuretic response to sodium loading. Key Words: capsaicin Ⅲ sodium, dietary Ⅲ innervation, sensory Ⅲ hypertension, salt-sensitive Ⅲ renal circulation I t is well established that in a considerable number of essential hypertensive patients and patients with glomerulonephritis, primary aldosteronism, and diabetes mellitus, blood pressure is sodium sensitive. 1 Despite intensive research in this area, the cellular and molecular mechanisms underlying salt-sensitive hypertension are not well defined, and no pharmacological approaches have been developed that directly target the defect in salt handling. The existing genetic and experimental animal models of salt-sensitive hypertension, eg, Dahl salt-sensitive rats, Milan hypertensive rats, and deoxycorticosterone-salt hypertensive rats, have been widely used to explore underlying mechanisms linked to saltsensitive hypertension. 1 Recently, we developed a novel salt-sensitive hypertensive model that is sensory nerve dependent. We found that capsaicin-induced degeneration of sensory nerves in rats impairs normal increase in urinary sodium and water excretion when a high sodium diet is give...

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] .…”

Development of salt-sensitive hypertension in a sensory denervated model: the underlying mechanisms

“…On the first and second days of life, neonatal rats received capsaicin, 50 mg/kg s.c., as described. 1,2,7,8 Control rats were treated with equal volumes of vehicle solution (5% ethanol, 5% Tewwn 80 in saline). After three weeks, male rats were divided into four groups, pair-fed different sodium diets, and subjected to following treatments for three weeks: control + high sodium diet (4%, CON-HS), capsaicin pretreatment + normal sodium diet (0.5%, CAP-NS), capsaicin pretreatment + high sodium diet (CAP-HS), capsaicin pretreatment + high sodium diet + candesartan cilexetil (10 mg/kg/per day by oral gavage) (CAP-HS-CAN).…”

“…Furthermore, we have previously shown that development of salt-sensitive hypertension induced by sensory denervation can be prevented by the AT 1 -receptor antagonist losartan. 2 However, the molecular basis for the antihypertensive effect of losartan in this model is unknown. The goal of the current study is to test the hypothesis that the circulating and/or tissue renin angiotensin systems are activated in response to a high-salt intake and contribute to the elevation of BP induced by salt load in this model.…”

“…We found that capsaicin-induced degeneration of sensory nerves renders a rat responsive to a salt load with a significant and sustained rise in BP. 1,2 These studies provide decisive evidence that sensory innervation plays a significant functional role in antagonising the development of salt-induced hypertension and provide a novel experimental paradigm for exploring underlying mechanisms linked with salt-sensitive hypertension and sensory nerve function.…”