Role Of Calcitonin Gene-Related Peptide and Substance P in Dahl-Salt Hypertension

Katki, Khurshed A.; Supowit, Scott C.; DiPette, Donald J.

doi:10.1161/hy09t1.095761

Cited by 20 publications

(13 citation statements)

References 19 publications

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“…In addition to TRPV1 impairment, CGRP levels in DRG are similarly decreased, and CGRP-positive sensory nerves innervating mesenteric resistance arteries are remarkably reduced in DS rats fed an HS diet. This is in an agreement with a previous report from Katki et al, 15 which indicates that CGRP expression is reduced in DRG in DS rats. Given that the same reduction in CGRP-positive sensory nerve fibers is not observed in deoxycorticosterone acetate-salt-hypertensive rats that have similarly high blood pressure, the finding suggests that elevation in blood pressure may not be the cause of sensory nerve impairment.…”

Section: Discussionsupporting

confidence: 94%

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

Wang

2006

Hypertension

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Abstract-To determine the role of the transient receptor potential vanilloid type 1 (TRPV1) channels in development of hypertension in Dahl salt-sensitive (DS) rats fed a high-salt diet (HS), male DS and Dahl salt-resistant (DR) rats were maintained on a low-salt diet (LS) or HS for 3 weeks. HS significantly increased systolic blood pressure in DSϩHS rats compared with DSϩLS, DRϩHS, and DRϩLS rats. Intravenous bolus injection of capsazepine (3 mg/kg), a selective TRPV1 antagonist, significantly increased mean arterial pressure in conscious DRϩHS rats compared with DRϩLS, DSϮHS, and DSϮLS rats. In contrast, capsaicin (10 or 30 g/kg), a selective TRPV1 agonist, dose-dependently decreased mean arterial pressure in all of the groups with the most profound magnitude in DRϩHS rats compared with the other 3 groups. TRPV1 expression in mesenteric resistance arteries and the renal cortex and medulla, calcitonin gene-related peptide levels in dorsal root ganglia, and calcitonin gene-related peptide-positive sensory nerve density in mesenteric resistance arteries were significantly decreased in DSϩHS rats compared with DSϩLS, DRϩHS, and DRϩLS rats. Taken together, our data indicate that the TRPV1 receptor is activated and its expression upregulated during HS intake in DR rats, which acts to prevent salt-induced increases in blood pressure. In contrast, TRPV1 expression and function are impaired in DS rats, which renders DS rats sensitive to salt load in terms of blood pressure regulation. Key Words: peptides Ⅲ rats, Dahl Ⅲ hypertension, sodium-dependent Ⅲ blood pressure B oth clinical and experimental studies have shown a correlation of dietary salt intake and the prevalence and progression of hypertension. 1 Salt-sensitive hypertension is more prevalent in blacks and the elderly, who are accompanied by a decrease in sensory nerve function. 2 Studies in animals provide compelling evidence showing that sensory nerves play a key role in preventing salt-induced elevation in blood pressure, 3 suggesting that a defect in sensory nerve function may contribute to increased salt sensitivity in humans. Dahl salt-sensitive (DS) rats have been used as a model of human salt-sensitive hypertension given that salt load exaggerates the development of hypertension in this strain that is genetically predisposed to hypertension 4,5 and that these rats exhibit elevated insulin resistance, which mimics the black hypertensive population. 6 Thus, studies of DS rats may provide valuable clues to the pathogenesis of salt-sensitive hypertension and related traits in black patients.The transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated nonselective ion channel expressed primarily in sensory nerves of unmyelinated C-fibers or thinly myelinated A␦-fibers innervating cardiovascular tissues including the heart, kidney, and blood vessels. 2,7,8 The TRPV1 functions as a molecular integrator of multiple chemical and physical stimuli including capsaicin, lipid metabolites, proton, and noxious heat. 9 -12 Activation of the TRPV1...

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Section: Discussionsupporting

confidence: 94%

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

Wang

2006

Hypertension

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“…We have since extended these results to the DOC-salt model of hypertension, in which the neuronal expression and release of SP is increased as a compensatory mechanism to the elevated BP, 15 and in the DAHL-salt model (a genetic and salt-independent model of hypertension), in which SP does not seem to play a compensatory vasodilator role. 11 In addition, these data are in keeping with reports from the literature, which indicate reduced plasma levels of SP observed in the SHR and human essential hypertension 10 and the elevation of BP in these models could be due, at least in part, to the insufficient synthesis and release of endogenous SP.…”

Section: Discussionsupporting

confidence: 85%

“…Span-II has been previously shown to block the hypotensive effects of exogenously administered SP in normal rats. 11 For the present studies, each animal was anesthetized as described above. The left carotid artery was cannulated for continuous monitoring of mean arterial pressure (MAP) using a pressure transducer coupled to a recorder (Gould Instruments).…”

Section: Sp Receptor Agonist/antagonist Administration and Mean Artermentioning

confidence: 99%

Substance P in Subtotal Nephrectomy-Salt Hypertension

2002

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Abstract-We have previously demonstrated that calcitonin gene-related peptide (CGRP) plays a counterregulatory role in subtotal nephrectomy-salt (SN-salt) hypertension through an increase in vascular responsiveness to the dilator activity of this neuropeptide. Substance P (SP) is often co-localized with CGRP in perivascular sensory nerves. To determine the role and mechanism of action of SP in SN-salt hypertension, we induced hypertension in 4-to 6-week-old male Sprague-Dawley rats (nϭ8) by subtotal nephrectomy and 1% saline drinking water. Sham-operated rats were given either tap water (nϭ9) or 1% saline to drink (nϭ9). Eleven to 13 days after each protocol, all rats had intravenous (for drug administration) and arterial (for continuous monitoring of mean arterial pressure [MAP]) catheters surgically implanted and were studied in the conscious and unrestrained state. Baseline MAP was significantly elevated in the SN-salt rats (157Ϯ6 mm Hg) compared with tap water-fed controls (128Ϯ3 mm Hg) and 1% saline-fed controls (132Ϯ5 mm Hg). Vehicle administration did not alter the MAP in any group. In contrast, administration of spantide-II (0.2 mol/L in saline), an SP receptor antagonist, significantly elevated the MAP in SN-salt rats (13.9Ϯ0.8 mm Hg) compared with the tap water (1.7Ϯ1.7 mm Hg) and 1% saline controls (2.0Ϯ1.9 mm Hg). SP mRNA and peptide levels in dorsal root ganglia were not significantly different between the 3 groups. Administration of exogenous SP (12 and 24 nmol · L Ϫ1 · kg Ϫ1 intravenously) resulted in a significantly greater decrease in MAP in the SN-salt rats compared with both control groups. Taken together, these data suggest that in SN-salt hypertension, SP plays a counterregulatory role in the absence of an increase in its neuronal expression, thereby suggesting that one possible mechanism of this compensatory vasodilator response is enhanced vascular reactivity to SP. Key Words: rats Ⅲ neuropeptides Ⅲ renal disease Ⅲ blood pressure Ⅲ RNA Ⅲ radioimmunoassay S ubstance P (SP), an 11-amino acid neuropeptide, is a member of the tachykinin family that also includes neurokinin A (NK-A), neurokinin B (NK-B), neuropeptide K (NP-K), and neuropeptide-␥ (NP-␥). 1,2 SP is derived from tissue-specific alternative splicing of the preprotachykinin I gene and is produced almost exclusively in neuronal tissues. 2 A prominent site for SP synthesis is the dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons that terminate centrally in the spinal cord and peripherally on blood vessels. 3 SP and its receptor (NK-1 receptor) are widely distributed in the central and peripheral nervous system. Immunoreactive substance P (iSP) containing nerve fibers are widely distributed in the brain as well as peripheral sensory nerve endings, where it is often co-localized and co-released with calcitonin gene-related peptide (CGRP). 4 SP is involved in various physiological activities such as neuromodulation, smooth muscle contraction, and the modulation of vascular tone. 5,6 A role for CGRP in experiment...

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“…However, the mechanisms responsible for the activation of the ET system remain to be elucidated. There is accumulating evidence showing that a defect in the sensory nervous system exists in spontaneously hypertensive rats and Dahl-salt sensitive hypertensive rats (33,17). Given the fact that ET-1 and the activation of ET A receptors contribute to the development of hypertension and renal dysfunction in sensory nerve-degenerated rats fed a HS diet, it is conceivable that sensory nerve dysfunction may contribute to the activation of the ET system in these models of hypertension.…”

Section: Discussionmentioning

confidence: 99%

ET_A receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

Wang¹,

Chen²,

Wang³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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To test the hypothesis that activation of the endothelin type A (ET(A)) receptor contributes to decreased renal excretory function and increased blood pressure in sensory nerve-degenerated rats fed a high-salt diet, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg s.c.) on the first and second day of life. After being weaned, vehicle or CAP-treated rats were fed a normal (NS, 0.5%) or a high- (HS, 4%) sodium diet for 2 wk with or without ABT-627 (5 mg x kg(-1) x day(-1), a selective ET(A) receptor antagonist). Systolic blood pressure increased in CAP-treated rats fed a HS diet (CAP-HS) compared with vehicle-treated rats fed a HS diet (CON-HS, 145 +/- 7 vs. 89 +/- 5 mmHg, P < 0.05). Creatinine clearance and fractional sodium excretion (FE(Na)) decreased in CAP-HS rats compared with CON-HS rats (creatinine clearance, 0.54 +/- 0.05 vs. 0.81 +/- 0.09 ml x min(-1) x 100 g body wt(-1); FE(Na), 8.68 +/- 0.99 vs. 12.53 +/- 1.47%, respectively; P < 0.05). Water and sodium balance increased in CAP-HS rats compared with CON-HS (water balance, 20.2 +/- 1.5 vs. 15.5 +/- 1.9 ml/day; sodium balance, 11.9 +/- 3.1 vs. 2.4 +/- 0.3 meq/day, respectively; P < 0.05). The endothelin (ET)-1 levels in plasma and isolated glomeruli increased by about twofold in CAP-HS rats compared with CON-HS rats (P < 0.05). ABT-627 prevented the decrease in creatinine clearance and FE(Na), the increase in water and sodium balance, and the increase in blood pressure in CAP-HS rats (P < 0.05). Therefore, the blockade of the ET(A) receptor ameliorates the impairment of renal excretory function and prevents the elevation in blood pressure in salt-sensitive hypertension induced by degeneration of sensory nerves, indicating that the activation of the ET(A) receptor impairs renal function and contributes to the development of a salt-induced increase in blood pressure in this model.

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Role Of Calcitonin Gene-Related Peptide and Substance P in Dahl-Salt Hypertension

Cited by 20 publications

References 19 publications

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

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

Substance P in Subtotal Nephrectomy-Salt Hypertension

ET_A receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

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Role Of Calcitonin Gene-Related Peptide and Substance P in Dahl-Salt Hypertension

Cited by 20 publications

References 19 publications

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

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

Substance P in Subtotal Nephrectomy-Salt Hypertension

ETA receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

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Product

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ET_A receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation