scholarly journals Differential Expression of Sphingolipid Metabolizing Enzymes in Spontaneously Hypertensive Rats: A Possible Substrate for Susceptibility to Brain and Kidney Damage

2021 ◽  
Vol 22 (7) ◽  
pp. 3796
Author(s):  
Giuseppe Pepe ◽  
Maria Cotugno ◽  
Federico Marracino ◽  
Susy Giova ◽  
Luca Capocci ◽  
...  
Keyword(s):  
De Novo ◽  
Spontaneously Hypertensive Rat ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Biologically Active ◽  
Sphingolipid Metabolism ◽  
Spontaneously Hypertensive ◽  
Sphingosine 1 Phosphate ◽  
Rat Strain ◽  
Wistar Kyoto

Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis of hypertension-related cerebrovascular and renal damage. In this study, we evaluated the existence of possible abnormalities related to the sphingolipid metabolism in the brain and kidneys of two well validated spontaneously hypertensive rat strains, the stroke-prone (SHRSP) and the stroke-resistant (SHRSR) models, as compared to the normotensive Wistar Kyoto (WKY) rat strain. Our results showed a global alteration in the metabolism of sphingolipids in both cerebral and renal tissues of both hypertensive strains as compared to the normotensive rat. However, few defects, such as reduced expression of enzymes involved in the metabolism/catabolism of sphingosine-1-phosphate and in the de novo biosynthetic pathways, were exclusively detected in the SHRSP. Although further studies are necessary to fully understand the significance of these findings, they suggest that defects in specific lipid molecules and/or their related metabolic pathways may likely contribute to the pathogenesis of hypertensive target organ damage and may eventually serve as future therapeutic targets to reduce the vascular consequences of hypertension.

Cardiomyocyte function associated with hyperactivity and/or hypertension in genetic models of LV hypertrophy

2006 ◽  
Vol 290 (1) ◽  
pp. H463-H473 ◽  
Author(s):  
Bradley M. Palmer ◽  
Zengyi Chen ◽  
Richard R. Lachapelle ◽  
Edith D. Hendley ◽  
Martin M. LeWinter
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Left Ventricular ◽  
Adult Males ◽  
Compensatory Response ◽  
Spontaneously Hypertensive ◽  
Hypertrophic Response ◽  
Rat Strain ◽  
Males And Females ◽  
Sarcomere Dynamics ◽  
Wistar Kyoto

We examined cardiomyocyte intracellular calcium ([Ca2+]i) dynamics and sarcomere shortening dynamics in genetic rat models of left ventricular (LV) hypertrophy associated with or without hypertension (HT) and with or without hyperactive (HA) behavior. Previous selective breeding of the spontaneously hypertensive rat (SHR) strain, which is HA and HT, with the Wistar-Kyoto (WKY) rat strain, which is not hyperactive (NA) and not hypertensive (NT), has led to two unique strains: the WKHA strain, selected for HA and NT, and the WKHT strain, selected for NA and HT. Cardiomyocytes were isolated from young adult males and females of each strain, paced at 2, 3, and 4 Hz in 1.2 mM external Ca2+ concentration at 37°C, and cardiomyocyte [Ca2+]i and sarcomere dynamics were recorded simultaneously. Under these conditions, LV cardiomyocyte systolic and diastolic [Ca2+]i dynamics and diastolic sarcomere dynamics in the WKHT were significantly enhanced compared with WKY controls, suggesting an underlying LV hypertrophic response that successfully compensated for HT in the absence of HA. LV cardiomyocyte [Ca2+]i dynamics in the WKHA and SHR were strikingly similar to each other and only slightly reduced compared with WKY. LV cardiomyocyte systolic and diastolic sarcomere dynamics, on the other hand, were significantly reduced in the SHR compare with WKHA and more so in male than in female SHR. We conclude from these data that HT alone is an insufficient descriptor of the cause of LV hypertrophy and diminished LV cardiomyocyte function in the SHR rat. These data further suggest that HA (augmented by male sex) in the SHR may interact with the HT state to initiate impaired cardiomyocyte function and thereby inhibit or undermine an otherwise compensatory response that may occur with HT in the absence of HA.

Transport of calcium by duodenum of spontaneously hypertensive rat

1981 ◽  
Vol 241 (4) ◽  
pp. G344-G347 ◽  
Author(s):  
M. A. Toraason ◽  
G. L. Wright
Keyword(s):  
Calcium Transport ◽  
Spontaneously Hypertensive Rat ◽  
Detectable Effect ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Before And After ◽  
Rat Strain ◽  
Wistar Kyoto

The absorption of calcium by segments of duodenum obtained from spontaneously hypertensive (SH) rats and normotensive Wistar-Kyoto (WKy) rats was measured before and after the development of hypertension. The systolic blood pressure (SBP) of 5-wk-old SH rats (116 +/- 4 Torr) was significantly elevated above that of age-matched WKy rats (103 +/- 3 Torr) but was not at a level generally considered to be hypertensive. Values obtained for calcium transport [ratio of serosal-to-mucosal fluid 45Ca2+ concn (S/M ratio)] from everted duodenal sacs were similar between the two groups at this age. At 12 wk of age, SH rats exhibited a SBP (153 +/- 4 Torr) well above that of WKy controls (127 +/- 3 Torr), and calcium S/M ratios for duodenal sacs were significantly greater than the WKy control values. Similarly, the in vivo uptake of calcium in duodenal segments was significantly elevated in 12-wk-old SH rats compared with WKy controls. The administration of vitamin D3 or its metabolite, 25-hydroxycholecalciferol, had no detectable effect on duodenal transport of calcium in 12-wk-old SH or WKy rats. By comparison, 1,25-dihydroxycholecalciferol produced a significant increase in duodenal calcium transport both in vitro and in vivo in WKy but not in SH rats. The results indicate a distinct abnormality in the transport of calcium in the duodenum of SH rats, suggesting that the decrease in duodenal uptake of calcium that normally occurs with maturation is slow to develop in this rat strain.

scholarly journals Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats

2011 ◽  
Vol 300 (6) ◽  
pp. H1990-H1996 ◽  
Author(s):  
Houli Jiang ◽  
John Quilley ◽  
Anabel B. Doumad ◽  
Angela G. Zhu ◽  
John R. Falck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Blood Pressure Reduction ◽  
Maximal Velocity ◽  
Spontaneously Hypertensive ◽  
Cis And Trans Isomers ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto ◽  
Cis And Trans ◽  
Cis Isomer

Epoxyeicosatrienoic acids (EETs) are vasodilator, natriuretic, and antiinflammatory lipid mediators. Both cis- and trans-EETs are stored in phospholipids and in red blood cells (RBCs) in the circulation; the maximal velocity ( Vmax) of trans-EET hydrolysis by soluble epoxide hydrolase (sEH) is threefold that of cis-EETs. Because RBCs of the spontaneously hypertensive rat (SHR) exhibit increased sEH activity, a deficiency of trans-EETs in the SHR was hypothesized to increase blood pressure (BP). This prediction was fulfilled, since sEH inhibition with cis-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (AUCB; 2 mg·kg−1·day−1 for 7 days) in the SHR reduced mean BP from 176 ± 8 to 153 ± 5 mmHg ( P < 0.05), whereas BP in the control Wistar-Kyoto rat (WKY) was unaffected. Plasma levels of EETs in the SHR were lower than in the age-matched control WKY (16.4 ± 1.6 vs. 26.1 ± 1.8 ng/ml; P < 0.05). The decrease in BP in the SHR treated with AUCB was associated with an increase in plasma EETs, which was mostly accounted for by increasing trans-EET from 4.1 ± 0.2 to 7.9 ± 1.5 ng/ml ( P < 0.05). Consistent with the effect of increased plasma trans-EETs and reduced BP in the SHR, the 14,15- trans-EET was more potent (ED50 10−10 M; maximum dilation 59 ± 15 μm) than the cis-isomer (ED50 10−9 M; maximum dilation 30 ± 11 μm) in relaxing rat preconstricted arcuate arteries. The 11,12-EET cis- and trans-isomers were equipotent dilators as were the 8,9-EET isomers. In summary, inhibition of sEH resulted in a twofold increase in plasma trans-EETs and reduced mean BP in the SHR. The greater vasodilator potency of trans- vs. cis-EETs may contribute to the antihypertensive effects of sEH inhibitors.

Enhanced renal sensitivity of the spontaneously hypertensive rat to urotensin II

2008 ◽  
Vol 295 (4) ◽  
pp. F1239-F1247 ◽  
Author(s):  
Alaa E. S. Abdel-Razik ◽  
Richard J. Balment ◽  
Nick Ashton
Keyword(s):  
Renal Function ◽  
Spontaneously Hypertensive Rat ◽  
Renal Medulla ◽  
Fractional Excretion ◽  
Urotensin Ii ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Hypertensive Rat ◽  
Fractional Excretion Of Sodium ◽  
Wistar Kyoto

Urotensin II (UII) has been implicated widely in cardiovascular disease. The mechanism(s) through which it contributes to elevated blood pressure is unknown, but its emerging role as a regulator of mammalian renal function suggests that the kidney might be involved. The aim of this study was to determine the effect of UII on renal function in the spontaneously hypertensive rat (SHR). UII infusion (6 pmol·min−1·100 g body wt−1) in anesthetized SHR and control Wistar-Kyoto (WKY) rats produced marked reductions in glomerular filtration rate (ΔGFR WKY, n = 7, −0.3 ± 0.1 vs. SHR, n = 7, −0.6 ± 0.1 ml·min−1·100 g body wt−1, P = 0.03), urine flow, and sodium excretion rates, which were greater in SHR by comparison with WKY rats. WKY rats also showed an increase in fractional excretion of sodium (ΔFENa; +0.6 ± 0.1%, P = 0.02) in contrast to SHR in which no such change was observed (ΔFENa −0.6 ± 0.2%). Blockade of the UII receptor (UT), and thus endogenous UII activity, with urantide evoked an increase in GFR which was greater in SHR (+0.3 ± 0.1) compared with WKY rats (+0.1 ± 0.1 ml·min−1·100 g body wt−1, P = 0.04) and was accompanied by a diuresis and natriuresis. UII and UT mRNA expression were greater in the renal medulla than the cortex of both strains; however, expression levels were up to threefold higher in SHR tissue. SHR are more sensitive than WKY to UII, which acts primarily to lower GFR thus favoring salt retention in this model of hypertension.

Role of adenosine in noradrenergic neurotransmission in spontaneously hypertensive rats

1987 ◽  
Vol 253 (4) ◽  
pp. H909-H918 ◽  
Author(s):  
E. K. Jackson
Keyword(s):  
Plasma Levels ◽  
Spontaneously Hypertensive Rat ◽  
Base Line ◽  
Inhibitory Effects ◽  
Spontaneously Hypertensive ◽  
Vascular Responses ◽  
Rat Mesentery ◽  
Wistar Kyoto

The purpose of this study was to compare the in vivo role of adenosine as a modulator of noradrenergic neurotransmission in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto control rat (WKY). In the in situ blood-perfused rat mesentery, vascular responses to periarterial (sympathetic) nerve stimulation (PNS) and to exogenous norepinephrine (NE) were enhanced in SHR compared with WKY. In both SHR and WKY, vascular responses to PNS were more sensitive to inhibition by adenosine than were responses to NE. At matched base-line vascular responses, compared with WKY, SHR were less sensitive to the inhibitory effects of adenosine on vascular responses to PNS, but SHR and WKY were equally sensitive with respect to adenosine-induced inhibition of responses to NE. Antagonism of adenosine receptors with 1,3-dipropyl-8-p-sulfophenylxanthine shifted the dose-response curve to exogenous adenosine sixfold to the right yet did not influence vascular responses to PNS or NE in either SHR or WKY. Furthermore, PNS did not alter either arterial or mesenteric venous plasma levels of adenosine in SHR or WKY, and plasma levels of adenosine in both strains were always lower than the calculated threshold level required to attenuate neurotransmission. It is concluded that in vivo 1) exogenous adenosine interferes with noradrenergic neurotransmission in both SHR and WKY; 2) SHR are less sensitive to the inhibitory effects of exogenous adenosine on noradrenergic neurotransmission than are WKY; 3) endogenous adenosine does not play a role in modulating neurotransmission in either strain under the conditions of this study; and 4) enhanced noradrenergic neurotransmission in the SHR is not due to defective modulation of neurotransmission by adenosine.

Hypoxic moderation of systemic hypertension in the spontaneously hypertensive rat

1987 ◽  
Vol 252 (3) ◽  
pp. R554-R561 ◽  
Author(s):  
W. N. Henley ◽  
A. Tucker
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rat ◽  
Metabolic Adaptation ◽  
Systemic Hypertension ◽  
Thyroid Status ◽  
Blood Pressure Elevation ◽  
Spontaneously Hypertensive ◽  
Moderate Hypobaric Hypoxia ◽  
Hypertensive Rat ◽  
Wistar Kyoto

The mechanism by which chronic, moderate, hypobaric hypoxia attenuates systemic systolic blood pressure (SBP) in the spontaneously hypertensive rat (SHR) was investigated in a three-part study. In experiment 1, 10 wk of hypoxia (3,658 m altitude) commencing in 7-wk-old rats was partially effective in preventing the rise in SBP [hypoxic SHR (SHR-H) 154 mmHg vs. normoxic SHR (SHR-N) 180 mmHg; P less than 0.01]. When hypoxia was initiated in 5-wk-old SHR (experiments 2 and 3), protection against hypertension was nearly complete (experiment 2: SHR-H 122 mmHg vs. SHR-N 175 mmHg; P less than 0.001; experiment 3: 135 vs. 152 mmHg, respectively; P less than 0.05). Elevations in O2 consumption (VO2) and rectal temperature (Tre) in SHR vs. normotensive [Wistar-Kyoto (WKY)] rats provided evidence that the SHR is a hypermetabolic animal. Thyroid hormonal indices suggested that SHR changed from a low to high thyroid status at a time that rapid blood pressure elevation occurred; however, hypoxia did not influence thyroid status. Acute, significant decrements in VO2 and Tre in SHR-H (experiments 2 and 3) accompanied the attenuation of SBP by hypoxia, whereas large decrements in VO2 and SBP did not occur in hypoxic WKY. Timely administration of moderate hypoxia protects against the development of hypertension in the SHR. This protection may relate to a metabolic adaptation made by the hypoxic SHR.

Reciprocal rat chromosome 2 congenic strains reveal contrasting blood pressure and heart rate QTL

2002 ◽  
Vol 10 (3) ◽  
pp. 199-210 ◽  
Author(s):  
Adamu Alemayehu ◽  
Laura Breen ◽  
Drahomira Krenova ◽  
Morton P. Printz
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Spontaneously Hypertensive Rat ◽  
Cardiovascular Responses ◽  
Chromosome 2 ◽  
Spontaneously Hypertensive ◽  
Congenic Strains ◽  
Multiple Blood ◽  
Wistar Kyoto ◽  
Chromosome Segments

Evidence exists implying multiple blood pressure quantitative trait loci (QTL) on rat chromosome 2. To examine this possibility, four congenic strains and nine substrains were developed with varying size chromosome segments introgressed from the spontaneously hypertensive rat (SHR/lj) and normotensive Wistar-Kyoto rat (WKY/lj) onto the reciprocal genetic background. Cardiovascular phenotyping was conducted with telemetry over extended periods during standard salt (0.7%) and high-salt (8%) diets. Our results are consistent with at least three independent pressor QTL: transfer of SHR/lj alleles to WKY/lj reveals pressor QTL within D2Rat21-D2Rat27 and D2Mgh10-D2Rat62, whereas transfer of WKY/lj D2Rat161-D2Mit8 to SHR/lj reveals a depressor locus. Our results also suggest a depressor QTL in SHR/lj located within D2Rat161-D2Mgh10. Introgressed WKY/lj segments also reveal a heart rate QTL within D2Rat40-D2Rat50 which abolished salt-induced bradycardia, dependent upon adjoining SHR/lj alleles. This study confirms the presence of multiple blood pressure QTL on chromosome 2. Taken together with our other studies, we conclude that rat chromosome 2 is rich in alleles for cardiovascular and behavioral traits and for coordinated coupling between behavior and cardiovascular responses.

Altered norepinephrine uptake in neuronal cultures from spontaneously hypertensive rat brain

1985 ◽  
Vol 248 (5) ◽  
pp. C488-C497 ◽  
Author(s):  
C. Sumners ◽  
T. F. Muther ◽  
M. K. Raizada
Keyword(s):  
Spontaneously Hypertensive Rat ◽  
Neuronal Cell ◽  
Neuronal Cultures ◽  
Maximal Velocity ◽  
Spontaneously Hypertensive ◽  
Lower Affinity ◽  
Neuronal Cell Bodies ◽  
Sodium Dependent ◽  
Uptake Sites ◽  
Wistar Kyoto

Uptake of [3H]norepinephrine (NE) has been characterized and compared in neuronal cultures prepared from the brains of 1-day-old normotensive (Wistar-Kyoto, WKY) and spontaneously hypertensive (SH) rats. In cultures from both strains total [3H]NE uptake consisted of a sodium-dependent portion and a sodium-independent portion. The sodium-dependent [3H]NE uptake was inhibited by NE uptake blockers such as maprotiline or desmethylimipramine (both at 0.5-100 microM). This sodium-dependent, NE uptake blocker-sensitive portion of the uptake was also stereospecific, preferring the l-isomer of NE. In contrast, the sodium-independent uptake was not sensitive to maprotiline or desmethylimipramine. Autoradiograms of cultures incubated with [3H]NE showed label concentrated in certain, but not all, neurites and in a few neuronal cell bodies. Cultures incubated with label in sodium-free buffer did not show any such localization of grains but instead showed a diffuse pattern. Incubation of neuronal WKY or SH brain cultures with various concentrations of l-[3H]NE and unlabeled l-NE in the presence or absence of sodium enabled the construction of saturation curves for sodium-dependent uptake in each culture type. In WKY cultures, Km and maximal velocity of uptake (Vmax) values of 0.37-0.45 microM and 0.58-0.69 pmol X mg protein-1 X min-1, respectively, were obtained for sodium-dependent uptake. In contrast, the Km and Vmax values for [3H]NE uptake in SH neuronal cultures were 1.4 microM and 1.31 pmol X mg protein-1 X min-1, respectively. Kinetic analyses of the results show that in SH neuronal cultures the [3H]NE uptake sites are of lower affinity but higher capacity compared with those in WKY neuronal cultures.

scholarly journals Feeding Stimulates Sphingosine-1-Phosphate Mobilization in Mouse Hypothalamus

2019 ◽  
Vol 20 (16) ◽  
pp. 4008
Author(s):  
Valentina Vozella ◽  
Natalia Realini ◽  
Alessandra Misto ◽  
Daniele Piomelli
Keyword(s):  
De Novo ◽  
Sphingolipid Metabolism ◽  
Rt Pcr ◽  
Liquid Chromatography Tandem Mass ◽  
Sphingosine 1 Phosphate ◽  
Phosphate Mobilization ◽  
S1p Receptor ◽  
Free Feeding ◽  
G Protein Coupled ◽  
Sphingolipid Biosynthesis

Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the hypothalamus of C57Bl6/J male mice subjected to one of four conditions: free feeding, 12 h fasting, and 1 h or 6 h refeeding. Liquid chromatography/tandem mass spectrometry was used to quantify various sphingolipid species, including sphinganine (SA), sphingosine (SO), and their bioactive derivatives SA-1-phosphate (SA1P) and S1P. In parallel experiments, transcription of S1PR1 (encoded in mice by the S1pr1 gene) and of key genes of sphingolipid metabolism (Sptlc2, Lass1, Sphk1, Sphk2) was measured by RT-PCR. Feeding increased levels of S1P (in pmol-mg−1 of wet tissue) and SA1P. This response was accompanied by parallel changes in SA and dihydroceramide (d18:0/18:0), and was partially (SA1P) or completely (S1P) reversed by fasting. No such effects were observed with other sphingolipid species targeted by our analysis. Feeding also increased transcription of Sptlc2, Lass1, Sphk2, and S1pr1. Feeding stimulates mobilization of endogenous S1PR1 agonists S1P and SA1P in mouse hypothalamus, via a mechanism that involves transcriptional up-regulation of de novo sphingolipid biosynthesis. The results support a role for sphingolipid-mediated signaling in the central control of energy balance.

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