Abstract 064: 20-HETE Contributes to Vasoconstriction of Renal Microvessels and Sodium Retention in Cyp4a14-/- Mice, a Model of 20-HETE Dependent Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Ankit Gilani ◽  
Varunkumar Pandey ◽  
Joseph Zullo ◽  
Priyanka Mishra ◽  
John R Falck ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Isotonic Saline ◽  
Urinary Sodium Excretion ◽  
Water Soluble ◽  
Arachidonic Acid Metabolite ◽  
Male Mice ◽  
Kidney Weight ◽  
Doppler Flowmetry ◽  
In The Wild

20-HETE (20-Hydroxyeicosatetraenoic acid), is a cytochrome P450 (CYP) 4A-derived arachidonic acid metabolite. 20-HETE has been linked to both pro-hypertensive (via increased vasoconstriction, vascular remodeling and vascular injury of renal microvessels) and anti-hypertensive (inhibiting ion transport in the distal nephron) functions. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water soluble antagonist of the actions of 20-HETE on renal hemodynamics and sodium (Na) excretion in Cyp4a14 knockout (CYP4a14-/-) male mice. The CYP4a14-/- male mice display hypertension accompanied by increased vascular 20-HETE levels. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized blood pressure (BP) in male Cyp4a14-/- mice at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male Cyp4a14-/- mice; p<0.05). The normalization of blood pressure was accompanied by transient increase in the urinary sodium excretion in the Cyp4a14-/- male mice (8.3±0.7 vs. 5.8±0.5 μmol/g body weight/day; p<0.05). Importantly, 20-SOLA increased glomerular filtration rate (GFR) of Cyp4a14-/- mice (2.38±0.05 vs. 1.88±0.18 μL/min/mg kidney weight, p<0.05) as opposed to no changes observed in the wild type (WT: (2.26±0.18 vs. 2.33±0.20μL/min/mg kidney weight). Evaluation of the renal blood flow (RBF) by laser Doppler flowmetry showed that treatment with 20-SOLA increased the RBF in Cyp4a14-/- mice by 12.3±4%, which remained unaltered in the WT. Additionally, the pressure-induced myogenic tone of isolated preglomerular microvessels was significantly elevated in Cyp4a14-/- mice; 20-SOLA treatment prevented the increase in myogenic responses. The natriuretic response to an isotonic saline loading challenge (10% of body weight, IP) was significantly attenuated in the Cyp4a14-/- mice as compared to the WT (35.5±2.8 vs. 57.4±8.3 percentage of Na load, p<0.05); this was corrected by 20-SOLA (61.7±5.7 percentage of Na load, p<0.05). These results confirm that 20-SOLA normalizes blood pressure of Cyp4a14-/- male mice and demonstrates that this is associated with increases in GFR, RBF and natriuresis.

Abstract 047: 20-SOLA, A Novel Water-soluble 20-HETE Antagonist, Elicits Natriuresis And Abrogates Hypertension In Cyp4a14 Knockout Mice.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Varunkumar G Pandey ◽  
Victor Garcia ◽  
Gregory Joseph ◽  
Frank F Zhang ◽  
Brian Shkolnik ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Urine Output ◽  
Vascular Reactivity ◽  
Urinary Sodium Excretion ◽  
Smooth Muscle Contraction ◽  
Water Soluble ◽  
Renal Tubules ◽  
Male Mice ◽  
Natriuretic Effect ◽  
Arachidonate Metabolite

20-HETE (20-hydroxyeicosatetraenoic acid) is a cytochrome P450 (CYP) 4A-derived arachidonate metabolite. In the vasculature, 20-HETE increases smooth muscle contraction, endothelial dysfunction/activation and sensitivity to constrictor stimuli; all of which contribute to hypertension. In renal tubules, 20-HETE inhibits ion transport and has pro-natriuretic functions in salt-sensitive models of hypertension. The pro-natriuretic effect of 20-HETE has not been reported in mouse models of 20-HETE-dependent hypertension. The CYP4a14 knockout (KO) male mice exhibit androgen-dependent upregulation of Cyp4a12, the sole 20-HETE synthase in mice, and display 20-HETE-dependent hypertension; female KO mice show no increase in Cyp412-20-HETE and are normotensive. We examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water-soluble 20-HETE antagonist, and determined its effect on blood pressure (BP) and natriuresis in the KO mice. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized BP in male KO mice; a significant reduction was observed on day 4 (146±1 vs153±2 mmHg in untreated littermates) reaching BP of the normotensive female KO mice (124±1 and 126±1 mmHg for treated and untreated, respectively) at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male KO; p<0.05). 20-SOLA decreased vascular reactivity to phenylephrine in male KO renal microvessels by 7-fold (EC50: 1.58±0.23 vs 0.22±0.03 μM). Moreover, treatment with 20-SOLA increased urine output in KO male mice as compared to untreated littermates (1.25±0.04 vs. 1.06±0.04 mL; p<0.05). The urine output to water intake ratio was significantly elevated in 20-SOLA-treated KO vs. untreated (0.25±0.01 vs. 0.19±0.01, p<0.05). Importantly, treatment with 20-SOLA increased urinary sodium excretion in the KO male mice (12.33±0.44 vs. 8.33±0.63 μmol/gr BW/24Hrs; p<0.05). These results suggest that 20-HETE has an anti-natriuretic effect in the kidneys of KO mice and that antagonism of 20-HETE’s action using 20-SOLA elicited natriuresis concurrent with reduction in blood pressure. The potential vascular and tubular mechanisms underlying 20-HETE anti-natriuretic action are being currently explored.

Abstract P276: A High Sodium Diet Reduces Cutaneous Microvascular Function In Normotensive Individuals With Salt Sensitive Blood Pressure

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jordan C Patik ◽  
Joseph M Stock ◽  
Nathan T Romberger ◽  
Shannon L Lennon ◽  
William B Farquhar ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Sodium Intake ◽  
Local Heating ◽  
Urinary Sodium Excretion ◽  
Microvascular Function ◽  
Dietary Sodium ◽  
Heating Unit ◽  
Doppler Flowmetry ◽  
High Sodium

Impaired vascular function likely contributes to the association between dietary sodium intake and the development of cardiovascular disease. Using the cutaneous microvasculature as a model, we have previously shown that a high sodium (HS) diet blunts local heating-induced vasodilation in normotensive individuals with salt resistant (SR) blood pressure (BP). However, the effect of a HS diet on the cutaneous microvasculature in normotensive salt sensitive (SS) individuals remains unclear. Therefore, we tested the hypothesis that cutaneous microvascular function is reduced by a HS diet to a greater degree in SS compared to SR individuals. After each 7-day controlled feeding diet (low sodium (LS) = 20 mmol/day; HS = 300 mmol/day), an intradermal microdialysis fiber was inserted in the ventral forearm and perfused with Ringer’s solution. Skin blood flow (SkBF) was continuously monitored via laser Doppler flowmetry and a local heating unit was placed over the fiber and heated to 42°C until SkBF reached a stable plateau. Site-specific maximal SkBF was determined by perfusing 28mM sodium nitroprusside and heating to 43°C. Mean arterial pressure (MAP) was assessed at regular intervals on the contralateral arm and was used to calculate cutaneous vascular conductance (CVC = SkBF / MAP). Subjects wore a 24-hr ambulatory BP monitor and collected their urine on the final day of each diet. Fourteen subjects (9W / 5M, 42 ± 14 yr) whose MAP increased >5 mmHg (Δ8 ± 1 mmHg) on the HS diet were defined as SS and were compared to 14 age- (43± 14 yr) and sex-matched SR subjects (Δ1 ± 3 mmHg). SS and SR had similar MAP at baseline (88 ± 9 vs. 90 ± 8 mmHg, P = 0.88) and urinary sodium excretion was increased similarly across groups by the HS diet (Δ239 ± 104 vs. Δ220 ± 66 mmol / 24 hr, P = 0.20). Cutaneous vasodilation in response to local heating was decreased on the HS diet relative to the LS diet in both SS (Δ-9 ± 9 %CVCmax, P = 0.005) and SR (Δ-9 ± 9 %CVCmax, P=0.005); however, there was not a group x diet interaction (P = 0.99). In contrast to our hypothesis, these results suggest that the deleterious effects of high sodium diets on cutaneous microvascular function are similar in normotensive salt sensitive and salt resistant individuals.

Failure of renal denervation to attenuate hypertension in Dahl NaCl-sensitive rats

1987 ◽  
Vol 65 (12) ◽  
pp. 2428-2432 ◽  
Author(s):  
J. Michael Wyss ◽  
Wanida Sripairojthikoon ◽  
Suzanne Oparil
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Creatinine Clearance ◽  
Sodium Excretion ◽  
Renal Denervation ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Renal Nerves ◽  
Urinary Volume ◽  
Volume Output

In previous experiments we have demonstrated that the renal nerves play a significant role in all genetic and (or) induced models of hypertension that we have studied. The current experiments extended this research by investigating the contribution of the renal nerves to hypertension in the Dahl NaCl-sensitive rat. This was investigated by assessing the effect of bilateral phenol renal denervation carried out prior to initiation of a high NaCl (8% NaCl) diet. In two separate studies, renal denervation did not affect systolic blood pressure in either Dahl NaCl-sensitive rats or their normotensive counterparts, Dahl NaCl-resistant rats. Further, denervation did not increase absolute urinary sodium excretion, percent urinary sodium excretion, urinary volume output, or food or water intake; nor did it differentially alter creatinine clearance or body weight. Denervation was verified at the termination of each study by a greater than 80% depletion of renal noradrenaline stores. These results indicate that the renal nerves do not provide a major contribution to hypertension in the Dahl NaCl-sensitive rat.

Duodenal mucosal alkaline secretion, permeability, and blood flow

1993 ◽  
Vol 265 (6) ◽  
pp. G1029-G1038 ◽  
Author(s):  
O. Nylander ◽  
A. Hallgren ◽  
L. Holm
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Arterial Blood Pressure ◽  
Fluid Secretion ◽  
Duodenal Mucosa ◽  
Water Soluble ◽  
Mucosal Permeability ◽  
Doppler Flowmetry ◽  
Arterial Blood ◽  
Alkaline Secretion

The relationship between duodenal mucosal alkaline secretion, permeability, and blood flow was examined in anesthetized rats. Duodenum was perfused with saline, and rate of luminal alkalinization (LA), mucosal permeability (clearance of 51Cr-EDTA from blood to lumen), effluent volume, mean arterial blood pressure (MABP), and blood flow (laser-Doppler flowmetry) were determined. Infusion of vasoactive intestinal polypeptide (VIP, 13.5 micrograms.kg-1 x h-1 i.v.) increased LA and fluid secretion but decreased MABP and mucosal permeability. The concentration of base in the secreted fluid was 45 mM. Systemic infusion of VIP (2.5 micrograms.kg-1 x h-1) increased LA and fluid secretion; the HCO3- concentration in secreted fluid was 86 mM. The lower VIP dose affected neither blood flow nor mucosal permeability. Both intravenous (10 mg/kg + 3 mg.kg-1 x h-1) and intraluminal (3 x 10(-3) M) N omega-nitro-L-arginine (L-NNA) increased LA and effluent volume; the HCO3- concentration in the secreted fluid was 38 and 44 mM, respectively. Intravenous, but not intraluminal, L-NNA increased mucosal permeability and decreased blood flow. Reduction of arterial blood pressure by blood withdrawal or by injection of prazosin (50 micrograms/kg i.v.) or hexamethonium (20 mg/kg i.v.) decreased LA and mucosal permeability. Prazosin decreased blood flow, whereas hexamethonium slightly increased blood flow. We conclude that NO may be an inhibitory regulator of LA and that both L-NNA and VIP increase LA via stimulation of active HCO3- transport. VIP probably increases HCO3- and fluid secretion by two separate ion transport mechanisms. No causal relationship exists between LA and blood flow, between LA and mucosal permeability, or between mucosal permeability and blood flow. A positive linear correlation exists between MABP and mucosal permeability, suggesting that marked changes of MABP may influence permeation of small water-soluble solutes across duodenal mucosa.

scholarly journals Sex-Specific Difference in Adipose Tissue and Blood Pressure in a New Mouse Model Expressing Human Soluble Prorenin Receptor in Adipocytes

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 56-56
Author(s):  
Kellea Nichols ◽  
Audrey Poupeau ◽  
Eva Gatineau ◽  
Gertrude Arthur ◽  
Ming Gong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Mouse Model ◽  
Fat Mass ◽  
Lean Mass ◽  
Soluble Form ◽  
Male Mice ◽  
Female Mice ◽  
Prorenin Receptor ◽  
Body Weights

Abstract Objectives Sex differences exist in obesity associated with cardiovascular disease; however, underlying mechanisms are not completely understood. Previous studies from our laboratory demonstrated that the prorenin receptor (PRR) and its soluble form (sPRR) contribute to adipogenesis and blood pressure control. The present study aimed to determine whether adipose-sPRR stimulated obesity is associated with hypertension and whether it is sex-dependent. Methods Transgenic mice on the C57BL/6 J background were generated expressing the human form of the soluble prorenin receptor (HsPRR) in a Cre-inducible manner. Male mice expressing Cre recombinase under the control of the adiponectin promotor were bred to heterozygote HsPRR/+ female mice to generate mice over-secreting sPRR (adi-HsPRR) and control littermate mice (CTL). The secretion of sPRR in the media doubled in primary adipocytes of adi-HsPRR mice compared to control mice (sPRR. CTL: 3729 ± 805 pg/ml; adi-HsPRR: 6170 ± 1237 pg/ml, P &lt; 0.05) validating the mouse model. Male (CTL = 4; adi-HsPRR = 8) and female mice (CTL = 10; adi-HsPRR = 10) were fed a low-fat (LF) diet or a high-fat diet (HF) for 20 weeks. Body weight was assessed weekly and EchoMRI was examined monthly. Results After 20 weeks on LF diet, adi-HsPRR male mice gained significantly more weight than CTL male mice (CTL: 25.1 ± 0.8 g; adi-HsPRR: 29.0 ± 0.8 g P &lt; 0.05), whereas no significant differences in body weights were observed in female mice. The body composition revealed a significant increase of fat mass, specifically in the epidydimal fat (CTL: 0.35 ± 0.04 g; adi-HsPRR: 0.61 ± 0.07 g, P &lt; 0.05), and lean mass of HsPRR male mice compared to CTL male mice. In contrast, female mice exhibited similar body weights (CTL: 20.6 ± 0.3 g; adi-HsPRR: 20.4 ± 0.4 g) and there was no differences of fat mass or lean mass between CTL and adi-HsPRR female mice. The sex-specific mechanism of sPRR on adipogenesis and blood pressure (by radiotelemetry) with LF and HF diet is currently under investigation. Conclusions Overall, sPRR stimulated body weight gain and fat mass expansion in male mice but not in female mice suggesting that female mice are protected from sPRR induced-hypertrophic effect. Funding Sources R01_HL142969–01 Yiannikouris, PI 07/15/2018–06/30/2022 NIH/NHLBI Title: The role of soluble prorenin receptor in hypertension associated with obesity Role: Ph.D Graduate Student.

Abstract MP34: Collecting Duct Cells-derived Human Sprr Impairs The Antihypertensive Effects Of Losartan And Upregulates Erk1/2 And Aqp2 Expression

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Gertrude Arthur ◽  
Audrey Poupeau ◽  
Kellea Nichols ◽  
Jacqueline Leachman ◽  
Analia S Loria ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Water Balance ◽  
Collecting Duct ◽  
Urine Volume ◽  
Plasma Osmolality ◽  
Standard Diet ◽  
Male Mice ◽  
Humanized Mouse Model ◽  
Prorenin Receptor

Recent studies showed that soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation and in water balance. In rodent models, sPRR contributes to AngII production by increasing renin activity, systolic blood pressure (SBP) and aquaporin2 (AQP2)-dependent antidiuretic action. However, there is a gap of knowledge concerning the functional role of locally produced sPRR from the kidney. Therefore, we evaluated the kidney-derived human sPRR role in SBP control and fluid homeostasis. Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male mice were fed a standard diet for 10 months (n=8-11/group). Body weight and urine volume were examined and SBP measured by radiotelemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice validating the humanized mouse model. Body weight did not change and 24hr-SBP was similar between CLT and RHsPRR mice (128±2 and 122±5 mmHg, respectively). However, the chronic response to losartan treatment was reduced in RHsPRR compared to CTL (ΔSBP: CTL: -9±3; RHsPRR: -5±1 mmHg, P<0.05). Kidney-derived human sPRR did not change GFR (838±75 vs 1088±163 μl/min/100g BW) and urinary vasopressin (0.62±0.21; 0.72±0.20 ng/mg creatinine), while modestly decreasing urine excretion rate by ~40% (CTL: 1.04±0.20; RHsPRR: 0.57±0.25 ml/day). Furthermore, RHsPRR mice had higher AQP2 protein expression in renal cortex (CTL: 0.24±0.07; RHsPRR: 4.11±0.70 AU, P<0.05) and medulla (CTL: 0.11±0.04; RHsPRR: 4.03±1.74 AU, P<0.05) than CTL mice. Kidney-derived human sPRR significantly increased phosphorylation of ERK 1/2 in the cortex compared to CTL (CTL: 5.4±1.0; RHsPRR: 9.2±1.4 AU, P<0.05), an MAPK involved in the regulation of water balance. In addition, RHsPRR mice showed increased plasma osmolality compared to CTL mice (CTL: 349±2; RHsPRR: 357±2 mOsm/kg, P<0.05). Overall, our data suggest that renal human sPRR could contribute to the increase in plasma tonicity by promoting the activation of ERK1/2-AQP2 pathway. Whether this signaling is associated with impaired antihypertensive effects of AT1R blockage remains under investigation.

scholarly journals THE INTRARENAL PRESSURE

1950 ◽  
Vol 92 (6) ◽  
pp. 637-642 ◽  
Author(s):  
A. V. Montgomery ◽  
John C. Davis ◽  
J. M. Prine ◽  
H. G. Swann
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Kidney Weight ◽  
Positive Correlation ◽  
Intrarenal Pressure

1. The intrarenal pressure of dogs anesthetized with pentobarbital averages 26 mm. Hg, and ranges from 10 to 58 mm.; that of decerebrate dogs is 25 mm., and that of unanesthetized dogs with explanted kidneys is 25 mm. Tests of a few cats and rabbits indicate that their intrarenal pressure has about the same magnitude. 2. There is a slight positive correlation between intrarenal pressure and both body weight and kidney weight, but intrarenal pressure is not related to sex, blood pressure, or age.

Efficacy and safety of drospirenone-containing microdosage combined oral contraceptive use with starting contraception

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (2) ◽  
pp. 9-13
Author(s):  
A R Khachaturian ◽  
E V Misharina ◽  
M I Yarmolinskaya
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Oral Contraceptive ◽  
Waist Circumference ◽  
Young Women ◽  
Iron Metabolism ◽  
Serum Iron ◽  
The Body ◽  
Menstrual Bleeding ◽  
Combined Oral Contraceptive

Androgen-dependent dermopathy, as well as premenstrual syndrome of varying severity in young women, can cause emotional depression, difficulties in social adaptation and even depressive disorders. The aim of the study was to study the safety and efficacy of using a combined oral contraceptive (COC) Dimia® containing 20 μg ethinyl estradiol and 3 mg drospirenone in young women, as well as its therapeutic effects in androgen-dependent dermopathy. Materials and methods. The study included 57 young women aged 23.1±2.2 years with signs of androgen-dependent dermopathy. The evaluation of the change in the character of menstrual bleeding, the anthropometric parameters (body weight, waist circumference and hips), the therapeutic effect of the drug on the symptoms of androgen-dependent dermopathy, as well as the dynamics of arterial pressure, hemoglobin level, serum iron have been studied. The psycho-emotional state was assessed using the SAN questionnaire (well-being-activity-mood). Results. During 6 months of observation, there was no significant change in the body mass index, waist circumference, and hips, and the drug did not affect the blood pressure numbers. Against the background of taking the drug, there was an increase in the parameters of iron metabolism (hemoglobin content, serum iron). After 3 months of taking the contraceptive with drospirenone, the number of patients with a complaint about the abundance of menstruation decreased more than twofold (from 22.8 to 10.5%), and after 6 months of taking the drug no patient noted the profuse nature of menstruation. Before the start of taking COC with drospirenone, 57.9% of women reported painful menstrual bleeding. Against the background of taking the contraceptive within 3 months, this complaint was stopped in all patients. Sufficient efficacy of treatment of androgen dependent dermopathy in young women with the help of a microdosed drospirenone-containing combined oral contraceptive is estimated from the dermatological acne index. The analysis of the SAN questionnaire made it possible to reveal the improvement in the psychoemotional state of patients on the background of taking the drug. The conclusion. The results obtained proved the effectiveness and safety of the microclinized COC Dimia®. The drug has no significant effect on body weight, blood pressure, provides reliable control of the cycle and a decrease in menstrual bleeding, which results in stabilization of iron metabolism in the body. Dimia® is effective in the treatment of androgen-dependent dermopathy and can be recommended to young women for starting contraception.

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