Substance P in Subtotal Nephrectomy-Salt Hypertension

Abstract

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...

Role of sensory nervous system vasoactive peptides in hypertension

“…Our studies also suggested that the depressor effect of SP is mediated, at least in part, through the interaction of SP with vascular NK-1 receptors. Quantification of DRG SP mRNA and peptide levels revealed no significant increase in SP mRNA or protein in the SN-salt rats (N = 8) compared to two groups (N = 8/group) of controls (sham operated with either tap water or saline drinking water) (43). This is similar to what was found for CGRP expression in this setting.…”

“…In DOC-salt rats iv Span-II caused a rapid increase in MAP compared to controls (9.3 ± 1.5 vs 0.9 ± 2.2 mmHg) (42). In SN-salt rats, iv Span-II also significantly elevated MAP (13.9 ± 0.8 vs 1.7 ± 1.7 mmHg) (43). Our studies also suggested that the depressor effect of SP is mediated, at least in part, through the interaction of SP with vascular NK-1 receptors.…”

Benidipine Suppresses in situ Proliferation of Leukocytes and Slows the Progression of Renal Fibrosis in Rat Kidneys with Advanced Chronic Renal Failure

“…Therefore, the lack of a subsequent decrease in blood pressure despite the use of benidipine paradoxically indicated that the drug could not exert an antihypertensive effect at this advanced stage of CRF. According to previous studies, the pathophysiological mechanisms that contribute to the maintenance of severe hypertension in end-stage renal disease include sodium and volume overload, inappropriate renin secretion, sympathetic nervous system activity, electrolyte disturbances, and alterations in endothelin and nitric oxide [27,28,29]. In the present study, the administration of 5 mg/kg benidipine alone was unlikely to be sufficient to overcome these mechanisms and decrease the severely elevated blood pressure in rat models with advanced CRF.…”

Calcitonin gene-related peptide and substance P contribute to reduced blood pressure in sympathectomized rats

“…Hemodynamic studies were then performed ϳ3 h after surgery with the animals in a fully awake and unrestrained state. Our laboratory (29,50) has previously validated the use of the CGRP and NK1 receptor antagonists by showing that CGRP8-37 (50 and 200 g) and spantide II (350 g) could completely block the hypotensive effects of exogenously administered CGRP and SP, respectively. These same doses were used in the current study.…”