bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P144: DHA is a Superior Treatment Over 12/15-lipoxygenase Inhibition in LPS-induced Acute Kidney Injury via Increased Resolvin D2 and IL-10 Levels
Authors: Katary Mohamed , Elsherbini Nehal M , Ibrahim Ahmed S , Al-Shabrawey Mohamed , Elmarakby Ahmed A
Published: June 2021

Acute kidney injury (AKI) is characterized by loss of kidney function and is often associated with high mortality rate. The polyunsaturated, omega-3 fatty acid, docosahexaenoic acid (DHA), has a promising role in preventing AKI; however; DHA reno-protective mechanism remains unclear. Our aim is to investigate whether and how DHA attenuates lipopolysaccharide (LPS)-induced AKI. Four groups of wild type C57BL/6 (WT) mice were used; control, LPS injected (4 mg/kg i.p), LPS treated with the 12/15-lipoxygenase (12/15-LO) inhibitor baicalein (20 mg/kg i.p for 6 days) and LPS treated with DHA (50 mg/kg i.p for 6 days). LPS-injected mice showed significant elevation in markers of renal injury as urinary excretion levels of protein, podocalyxin and albumin were elevated compared to WT untreated mice (albuminuria was 112±4 vs. 8±1 μg/day and podocalyxin was 3.5±0.6 vs. 0.6±0.1 μg/day in LPS injected mice vs. control WT, P< 0.05). The elevation in renal injury markers were also associated with increases in urinary excretion of thiobarbituric acid reactive substance (TBARs), as a marker of oxidative stress and monocyte chemoattractant protein-1 (MCP-1), as a marker of inflammation, in LPS injected mice. Treatment of LPS injected mice with either DHA or baicalein significantly reduced markers of renal injury, inflammation and oxidative stress. DHA or baicalein treatment also significantly reduced the elevation in renal mRNA expression levels of intercellular adhesion molecule 1 (ICAM-1) and tumor necrosis factor-α (TNF-α) in LPS injected mice. DHA was superior over baicalein in reducing renal expression of Interleukin-6 (IL-6) and IL-1β and in increasing the renal expression of the anti-inflammatory cytokine IL-10 in LPS injected mice. DHA reduced renal tubular necrosis and vaculated cells and lowered renal expression of CD45, a marker of leucocyte adhesion, in LPS injected mice. DHA also restored the decrease in plasma resolvin D2 (RvD2) in LPS injected mice. In conclusion, our data suggest that 12/15-LO activation is involved in LPS-induced acute kidney injury and DHA is a superior treatment over 12/15-LO inhibitor in preventing LPS-induced kidney injury, at least in part, via 12/15-LO-induced resolvin D2.
Abstract P161: Inspiratory Muscle Training and Aerobic Training in the Treatment of Hypertension: Baroreflex Sensitivity, Sympathetic Activity and Endothelial Function Responses
Authors: Ferreira Janaina B , Hong Valéria , Coelho Otávio , Cavasin Silvia , Santos Fernando , Consolim-Colombo Fernanda , Irigoyen Maria Cláudia C
Published: June 2021

Arterial hypertension is associated to sympathetic hyperactivity and endothelial dysfunction. Aerobic training (AT) is highly recommended to improve vascular function minimizing complications and Inspiratory muscle training (IMT) has demonstrated beneficial effects in this population, especially improving cardiovascular autonomic control. We sought to observe the effects of both training modalities on baroreflex sensitivity, sympathetic activity and endothelial function, in patients with controlled arterial hypertension. 10 patients (55±4 years old, both genders) were included and allocated into two groups: IMT (n=5, 7days/week, 30min/day, load=30%PImax) and AT (n=5, 2days/week, 1hour/day, load=70%HRmax). Both training protocols were performed during 12 weeks. Blood pressure (BP) and heart rate (HR) signals were recorded before and after protocols, as well as the other evaluations, by pulse telemetry (Finometer®PRO) and ECG (PowerLab®). Arterial baroreflex sensitivity was analysed by sequence method. Sympathetic activity was evaluated by microneurography (PowerLab®) and the endothelial function was evaluated by flow mediated dilation (EnVisor CHD, Philips, Bothell, WA, USA). After 12 weeks treatment IMT improved baroreflex sensitvity to both tachycardic and bradycardic responses respectively (BRR Down Gain (mean): IMT=26.51(±1.7)vs15.57(±6.7), AT=13.94(±5.5)vs17.92(±1.6); BRR Up Gain (mean): IMT=17.16(±1.2)vs16.28(±1.1), AT=12.39(±5)vs12.69(±3.3)). Additionally, we observed reduction of sympathetic activity in both groups (IMT:33.23±11.79vs25.07±13.28; AT:29.88±7.07vs24.09±6.37) and improvement of endothelial function independent of the treatment (IMT:6.4±2.18vs7.22±2.08; AT:5.49±7.43vs7.06±3.12). Regarding the responses to inspiratory muscle training and aerobic training on autonomic cardiovascular control and endothelial function in Hypertension, we demonstrated for the first time that IMT and AT present quite similar effects in patients with controlled blood pressure.
Abstract P163: Effects of Erythropoietin and Erythropoietin-receptor Materials in Blood Pressure, Hematocrit and Body- Spleen Weight Variability
Authors: Lee Mary S , Lee John S , Lee Jong Y , Halberg Franz
Published: June 2021

Adversity with erythropoietin (Epo) treatment (Epo-Rx) is grim in the cardio-cerebrovascular system. Because circadian rhythmic variability is an important aspect of cardiovascular function, we evaluated circadian blood pressure (BP), hematocrit (Hct), body and spleen weight (BW, SW) variability immediately before and after 4-week, twice-weekly course of Epo-Rx (50 U/kg) along with physiological saline (control), pure human Epo-receptor protein (Epo-bp) and anti-Epo-bp antibody (αEpo-bp) groups at midnight, 4 AM, 8 AM, noon, 4 PM and 8 PM in Sprague-Dawley rats.

In our earlier report, Epo-Rx increased BP, Hct and SW markedly overall compared with saline, Epo-bp, and αEpo-bp groups (Hypertension 2007;50:439-45). In this current report, variability (%) of BP, Hct, BW and SW are compared. Epo-bp treated BP Variability (BPV) was lower than others (9.5 vs. 15.5 control and others in similar values). Phase changes were noticed when exposed to Epo (daytime peaks in Epo, Epo+Epo-bp and Epo+αEpo-bp). Hct variability (HctV) in Epo and Epo-bp treated groups shows somewhat lower than in control group (18.3 in C vs. 13.3, 12.9, and 19.4 in Epo, Epo-bp and αEpo-bp, respectively). However, Epo effect was additive to HctV when Epo was added to Epo-bp or αEpo-bp (32.0 and 30.4, respectively). All 5-study groups showed phase changes, although Epo-exposed groups had a much greater magnitude with markedly increased Hct (peak at 19:00 in control and 5 study groups during the daytime through noon-hour peaks). BW variability is similar in each group (except lower BW in the Epo-group) with various peak hours but SW variability (SWV) showed a similar pattern as shown in HctV. Best treatment times for Epo, Epo+Epo-bp and Epo+αEpo-bp were estimated: BP at 4 PM, 4 AM and 4 AM, respectively; Hct at 4 AM and both at midnight, respectively; SW at midnight, 8 PM and noon, respectively. Thus, significantly increased BPV, HctV and SWV in Epo-Rx than those of other groups and extremely increased Hct resulted in splenomegaly.
Abstract P174: 17-hydroxyprogesterone Caproate Improves Blood Pressures and Placental Cytolytic Nk Cells in Response to Placental Ischemia During Pregnancy
Authors: Amaral Lorena M , Elfarra Jamil , Cornelius Denise C , Cunningham Mark W , Ibrahim Tarek , LaMarca Babbette
Published: June 2021

Preeclampsia (PE), new onset hypertension, is characterized by decreased fetal weight, elevated cytolytic natural killer (NK) cells and placental ischemia during pregnancy. Cytolytic NK are thought to play a role in fetal demise as they have also been shown to be increased in patients suffering from miscarriage.Currently, there is no effective treatment for PE except for early delivery, making PE the leading cause for premature births worldwide. Multiple injections of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of preterm labor, but not for management of PE. We have shown that injections of 17-OHPC to the RUPP rat model of PE improves some but not all facets of PE observed in this model. Therefore this study was designed to test the hypothesis that injections of 17-OHPC on both day 15 (GD15) and GD (18) improve outcomes of hypertension in response to placental ischemia. To do so, 17-OHPC (3.32mg/kg) was administered intraperitoneally on GD 15 and 18 to reduced uterine perfusion pressure (RUPP) rats, carotid catheters were inserted on GD 18 and blood pressure (MAP) andplacental cytolytic NK cells were measured on GD 19. MAP in normal pregnant (NP) rats (n=8) was 104±4,119±
5
in RUPP rats (n=5) and 102±5 mmHgin RUPP+17-OHPC GD15 &18 (n=4), p <0.05.Total number of placental NK cells was 8.5± 3 in NP, 20±2 in RUPP rats, which decreased to 4.7± 3 % in RUPP+17-OHPC GD15 &18, p<0.05. Activated placental NK cells was 3.4± 1.6 in NP, 10.5±2.3 in RUPP, which improved to 2.7± 2.7 % in RUPP+17-OHPCGD15 & 18, p <0.05.In conclusion, administration of 17-OHPC on days 15 and 18 decreased hypertension and NK cells that are associated with PE in the RUPP ratand should be considered for addition to the management of PE.
Abstract P178: Vasopressin Induces Discrete Symptoms of Preeclampsia Through Receptor- and Gestational Age-specific Mechanisms
Authors: Sandgren Jeremy A , Linggonegoro Danny W , Pearson Nicole A , Perschbacher Katherine J , Santillan Donna A , Scroggins Sabrina M , Gibson-Corley Katherine N , Pierce Gary L , Santillan Mark K , Grobe Justin L
Published: June 2021

Preeclampsia (PE) is a common late-gestational disorder characterized by
de novo pregnancy specific
hypertension, proteinuria, and renal glomerular endotheliosis (RGE). Arginine vasopressin (AVP) secretion (as measured by copeptin) is elevated as early as 6 weeks gestation in pregnancies which later develop PE, and chronic low-dose AVP infusion is sufficient to phenocopy PE in pregnant mice. However, the identity and timeframe of involvement of specific AVP receptors initiating discrete symptoms of PE in this model remain unclear. Wildtype C57BL/6J mice were instrumented with subcutaneous osmotic minipumps to infuse AVP (24 ng/hr) and/or inhibitors during gestation. To clarify the involvement of AVP V
1A
and V
2
receptors, one cohort of saline- or AVP-infused pregnant mice was simultaneously infused with the combined V
1A
+V
2
antagonist, conivaptan (22 ng/hr). Conivaptan co-treatment ameliorated the hypertension phenotype (SBP on gestational day (GD)15: saline 108.3±2.1, n=24; AVP 120.5±2.1, n=17; conivaptan 112.8±4.1, n=8; AVP+conivaptan 109.8±3.5 mmHg, n=11) but did not prevent proteinuria (on GD17: saline 46.4±6.4, n=15; AVP 79.3±8.5, n=15; conivaptan 64.6±6.7, n=7; AVP+conivaptan 72.9±12.3 mg/mL, n=11) or RGE. To clarify the important timeframes of involvement of AVP for discrete symptoms, subsets of mice were infused with AVP throughout gestation or to only GD10. Continuous infusion of AVP was required to maintain the hypertensive phenotype, as infusion to only GD10 initially elevated blood pressure (SBP at GD10: saline 103.7±1.3, n=26; AVP to GD10 111.5±1.6 mmHg, n=19) but failed to sustain hypertension for the remainder of gestation (SBP at GD15: 112.2±1.3 mmHg, n=19). In contrast, infusion of AVP only to GD10 caused a sustained proteinuria (at GD17: 88.2±9.2 mg/mL, n=19). Infusion of AVP only to GD3 had no effect on any examined endpoint. These data support a specific role for AVP V
1A
/V
2
receptors throughout gestation for the hypertension but not proteinuria or RGE phenotypes of PE. Our results therefore indirectly support an early-gestational role for other receptors (perhaps V
1B
, cullin-5, or the oxytocin receptor) in the proteinuria and RGE phenotypes of this disorder.
Abstract P179: Neonatal Outcomes in Normal and Preeclamptic Pregnancies: A retrospective Comparative Study
Authors: Vora Niraj , Kalagiri Ram R , Raju Venkata N , Drever Nathan , Beeram Madhava R , Mallett Lea , Uddin Mohammad N
Published: June 2021

Background:
Preeclampsia (PreE), a de novo development of Hypertension in consort with proteinuria after 20 weeks of gestation is the leading cause of morbidity and mortality in mother and the offspring. It affects approximately 3-8% of overall pregnancies. Although, specific etiologies remain unknown, it has been supported by various studies that PreE is not just a single disorder, but a syndrome of pertinent multiple pathophysiological factors.

Methods:
An IRB approved retrospective chart review over a year (January 2014 to December 2014) was conducted of all pregnancies occurred at Baylor Scott and White Health System, Temple, Texas (N = 3704). We divided all pregnancies into two separate groups: PreE (N = 299) vs. Non PreE (N = 3405). We compared the neonatal outcomes between two groups including their offspring’s gestational age, birth weight, admission rate to Neonatal Intensive Care Unit (NICU), occurrence of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), hypoglycemia, thrombocytopenia, intraventricular hemorrhage (IVH) and length of hospital stay (LOS).

Results:
We found amongst these two groups, infants born to PreE mothers have significantly lower birthweight (Mean = 2807 grams, SD = 841 grams) compared to Non PreE mothers (Mean = 3383 grams, SD = 619 grams) (P<0.05), significantly lower GA (Mean = 36.7 weeks, SD = 3.25 weeks) compared to Non PreE group (Mean = 38.7 weeks, SD = 2.1 weeks) (P<0.05), significantly higher rate of BPD (11%) compared to Non PreE group (6.9%)(P<0.05), significantly higher occurrence of hypoglycemia (26%) compared to non PreE group (20%) (P<0.05), significantly higher rate of thrombocytopenia (28%) compared to Non PreE group (17%) (P<0.05) and significantly higher length of hospital stay (Mean = 19 days, SD = 20 days) compared to Non PreE group (Mean = 14 days, SD = 20 days) (P<0.05).

Conclusion:
We can conclude from this retrospective analysis that infants born to PreE mothers have lower birth weight indicating the intrauterine growth restriction and the lower gestational age indicating preterm birth. Moreover, the data indicate the higher rate of BPD, hypoglycemia, thrombocytopenia and requirement of increased length of hospital stay in infants born to PreE mothers compared to Non PreE mothers.
Abstract P192: AT1R Blockade Increases the Depressor Effect of Alamandine in Normotensive SD Rats
Authors: Canta Giovanni , Lautner Roberto , Santos Robson
Published: June 2021

The renin–angiotensin system (RAS) plays a critical role in blood pressure control and electrolyte homeostasis. It has been established that Ang II is not the only active peptide of the RAS. Recently, new active fragments formed through metabolism of the classical axis peptides have been identified and their biological effects characterized. One of these peptides, is Alamandine, which was described by our group. Here we investigate the effect of Alamandine on blood pressure in non-anesthetized SD rats. To study the
in vivo
effects of this peptide, we used 12 weeks old SD rats (300-400 g). Administration of drugs and the blood pressure measurement were performed with a cannula inserted through the femoral vein and artery, respectively. We administered Alamandine with bolus injections (0.02, 0.2 ,1 ,5, 20 and 80 ng). A biphasic effect of alamandine was observed. The greatest depressor effect of Alamandine was observed at a lower dose, 1 ng. (Δ MAP: - 10.33±0.85 mmHg
p
<0.05). On the other hand, the highest dose, 80 ng, did not change significantly the blood pressure. Interestingly, when Losartan (5mg/kg) was administered 30min before the injection of alamandine, the depressor effect of this peptide was increased, mainly at 0.2 ng (Δ MAP: - 6±1.05 mmHg Alamandine vs. Δ MAP: - 20.33 ± 2,34 mmHg Alamandine after Losartan
p
<0.05). In losartan treated rats only depressor response were observed with all doses. In conclusion, our data show that Alamandine has a biphasic effects on blood pressure and seems to interact whith AT1 receptor in a dose - dependent manner.
Abstract P195: Prorenin Receptor Activation Increases Profibrotic Markers and Fibroblast Like Phenotype Through MAPK-dependent ROS Formation in Mouse Renal Collecting Duct Cells
Authors: Gonzalez Alexis A , Reyes-Martinez Cristian , Zamora Leonardo , Prieto Minolfa C
Published: June 2021

Binding of prorenin or renin to (pro)renin receptor (PRR) activates mitogen activated protein kinases (MAPK)/extracellular regulated kinases 1/2 (ERK 1/2), which have been proposed as mediators in tissue damage. Prorenin, renin, and PRR are overexpressed in the collecting duct (CD) in diabetes and hypertension. Activation of the PRR upregulates profibrotic markers through reactive oxygen species (ROS) formation; however, the exact mechanisms have not been established. We hypothesized that the activation of PRR increases the expression of profibrotic markers through MAPK-dependent ROS formation in CD cells. To address this hypothesis, a mouse renal CD cell line (M-1) was treated with recombinant prorenin plus ROS or MAPK inhibitor to evaluate their effect on the expression of profibrotic markers. Recombinant prorenin increased ROS formation and expression of alpha smooth muscle actin (α-SMA), connecting tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1). Induction of profibrotic factors was blunted by antioxidant p-coumaric acid, and partially prevented by lyophilic antioxidant trolox C or ascorbic acid. Inhibition of MAPK pathway (PD98059) prevented the prorenin-dependent ROS formation and augmentation of profibrotic factors, as well as fibroblast-like phenotype. Knockdown of PRR did not show effects on cell viability in M-1 cells and partially reduced the augmentation of fibronectin, collagen I and fibroblast-like phenotype induced by prorenin treatment. These results suggest that the activation of CD-derived PRR plays a role in the development of tubular damage.
Abstract P208: N-acetyl-seryl-aspartyl-lysyl-proline Prevents Renal Fibrosis in Dahl Salt-sensitive Rats by an Early Upregulation of miR Let-7b
Authors: Worou Morel E , Kumar Nitin , Rhaleb Nour-Eddine , Peterson Edward L , Carretero Oscar A
Published: June 2021

We recently showed that N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a natural tetrapeptide with antifibrotic properties prevented high salt-induced albuminuria and renal damage including fibrosis in Dahl Salt-Sensitive (SS) rats and their consomic SS13BN controls. However, the mechanism of this antifibrotic effect is unknown. MicroRNAs (miRNAs) have been shown to be important endogenous regulators of several physiological and pathophysiological conditions. The miRNA let-7 family has been suggested as a negative regulator of profibrotic processes in many diseases and its downregulation has been associated with renal fibrosis. Here, we hypothesized that in SS rats, the antifibrotic effect of Ac-SDKP on high salt-induced renal fibrosis is due to an upregulation of miRNA let-7b expression. Dahl SS and consomic SS13BN rats were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with vehicle (Veh) or Ac-SDKP (1.6 mg/kg/day) subcutaneously
via
osmotic minipump for 1 week. Animals were divided into the following groups: LS + Veh, HS + Veh and HS + Ac-SDKP. HS increased the systolic blood pressure (SBP) in SS rats, but not in SS13BN rats. Ac-SDKP did not affect SBP. In both strains, one week of HS diet increased albuminuria. Ac-SDKP prevented HS-induced albuminuria. In SS rats, HS-induced a significant downregulation of the renal cortex miR-let 7b expression measured by quantitative RT-PCR (HS + Veh 0.27±0.16 vs. LS + Veh 1.00±0.09; P=0.005), whereas a treatment with Ac-SDKP significantly upregulated the miR-let 7b expression (HS + Ac-SDKP 2.80±0.11; P=0.002). No miR-let 7b expression difference was observed in SS13BN rats. The overexpression of miR-let 7b by Ac-SDKP is associated with a significant decrease in collagen1 mRNA expression (HS + Veh 3.89±0.74 vs. HS + Ac-SDKP 1.25±0.13; P=0.005). One week on HS diet was not sufficient to cause measurable changes in renal collagen protein. In summary, Ac-SDKP prevented albuminuria and renal cortex collagen1 mRNA expression in SS rats fed HS diet for 1 week, and this was associated with an upregulation of miRNA let-7b expression. The antifibrotic effect of Ac-SDKP on HS-induced renal fibrosis in SS rats may be in part due to preceded upregulation of miRNA let-7b expression.
Abstract P209: Activation of Renal (Pro)Renin Receptor Contributes to High Fuctose-induced Salt Sensitivity
Authors: Xu Chuanming , Lu Aihua , Fang Hui , Zhou Li , Yang Tianxin
Published: June 2021

A high-fructose (HF) diet is shown to induce salt-sensitive hypertension but the underlying mechanism remains unclear. The major goal of the present study was to test the role of renal (pro)renin receptor (PRR) in this model. Male Sprague-Dawley rats were randomly divided into the following 4 groups: 1) Control, 2) Fructose, 3) Fructose + PRO20, and 4) Fructose + allopurinol, and the treatments lasted for 3 months. Fructose was added to drinking water (as 20% solution) so was allopurinol (at 30 mg/kg/d). PRO20, an antagonist of (pro)renin receptor, was administered at 700 μg/kg/day via i.p. injections. High fructose (HF) intake induced a 150% increase in renal protein expression of full-length PRR (fPRR), which were attenuated by allopurinol. HF intake also upregulated renal mRNA and protein expression of NHE3 (206% for protein) and NKCC2 (169% for protein) as well as
in vivo
NKCC2 activity (2-fold increases in 1-h urine volume and UNaV), all of which were nearly completely blocked by PRO20 or allopurinol treatment. HF intake induced >5-fold increases in urinary renin activity, renin content, and total renin content, and a 2-fold increase in urinary AngII, which were suppressed by 60-70% with PRO20 or allopurinol, contrasting to relatively consistent values of these parameters in the plasma, evidence of involvement of intrarenal RAS . At the last week of the experimental period, radiotelemetry was performed to monitor blood pressure during one-week high salt (HS) diet (8% NaCl). The 3-mo HF intake or a 1-wk HS diet alone did not affect mean arterial pressure (MAP), but the combination of the two maneuvers induced a ~10 mm Hg increase of MAP, which was abolished by PRO20 or allopurinol treatment. In cultured human kidney 2 cells, both fructose and uric acid (UA) increased protein expression of soluble PRR (sPRR) in a time- and dose-dependent manner; fructose-induced PRR upregulation was inhibited by allopurinol. Taken together, our data suggest that fructose via UA stimulates renal expression of PRR/sPRR that stimulate NHE3 and NKCC2 expression and intrarenal RAS to induce salt-sensitive hypertension.
Abstract P212: Sphingolipid De Novo Pathway is a Novel Regulator of Blood Pressure Homeostasis
Authors: Cantalupo Anna , Zhang Yi , Jiang Xian-Cheng , Di Lorenzo Annarita
Published: June 2021

Background and objectives:
Sphingolipids, particularly sphingosine 1-phosphate (S1P), play an important role in the cardiovascular homeostasis. Recently, we revealed that endothelial
de novo
biosynthesis of sphingolipids is very important to control vascular functions and blood pressure. We discovered that in blood vessels, particularly in endothelial cells, Nogo-B, a membrane protein of the endoplasmic reticulum, inhibits serine palmitoyltransferase (SPT), the first and rate-limiting enzyme of
de novo
production of sphingolipids, to impact vascular tone and blood pressure. Indeed, mice lacking Nogo-B are protected from angiotensin II-induced hypertension, and pharmacological inhibition of SPT by myriocin reinstates high blood pressure in absence of Nogo-B, suggesting that the upregulation of SPT activity exerts anti-hypertensive functions. Thus,
the goal of this study is to investigate the role of SPT in vascular functions and blood pressure regulation
by using novel genetic mouse models.

Methods:
The SBP was evaluated in 14 weeks old mice heterozygous for Sptlc2 (

Sptlc2
+/-

) or lacking Sptlc2 specifically in endothelial cells (ECKO
Sptlc2
) and smooth muscle cells (SMCKO
Sptlc2
) by using tail-cuff system. Vascular reactivity of isolated mesenteric arteries was assessed
ex-vivo
by using the pressure myograph system.

Results:

Sptlc2
+/-

, ECKO
Sptlc2
and SMCKO
Sptlc2
mice were hypertensive compared to their respective controls (

Sptlc2
+/-

128.9±2.6 vs. WT 112.1±2.6 mmHg; ECKO
Sptlc2
125.5±1.8, SMCKO
Sptlc2
127.2±0.6 vs.

Sptlc2
f/f

106±0.84 mmHg) and developed endothelial dysfunction as shown by the impaired vasodilation in response to acetylcholine (EC
50

Sptlc2
+/-

1.48x10
-6
M vs. WT 4.46x10
-7
M; Emax ECKO
Sptlc2
73.2±3.3% vs.

Sptlc2
f/f

95.3±1.1%), as well as to flow (Emax:

Sptlc2
+/-

23.3±1.4 μm vs. WT 42.9±4.4 μm; ECKO
Sptlc2
19.9±0.9 μm vs.

Sptlc2
f/f

41.3±3.1 μm).

Conclusion:
This study demonstrates the important role of SPT, thus the
de novo
production of sphingolipids, in controlling blood flow and pressure homeostasis, and provides the ground for the development of alternative therapeutic strategies to manage high blood pressure.
Abstract P214: The Non-canonical Stress Tolerance Cascade for Toll-like Receptor 9 in the Vasculature Signals Through Liver Kinase B1
Authors: McCarthy Cameron G , Wenceslau Camilla F , Ogbi Safia , Szasz Theodora , Webb R.Clinton
Published: June 2021

Toll-like receptor (TLR)9 is a pattern recognition receptor of the innate immune system. Recently, a non-canonical stress tolerance pathway has been reported for TLR9 in non-immune cells (cardiomyocytes and neurons), independent of inflammatory signaling. It was observed that TLR9 inhibited sarco/endoplasmic reticulum Ca
2+
-ATPase (SERCA)2, increasing cytosolic calcium, and resulting in 5’ AMP-activated protein kinase (AMPK)α activation. In our laboratory, we have reported that TLR9 treatment
in vivo
causes arterial dysfunction that contributes to the pathogenesis of hypertension and that these phenotypes occurred in conjunction with vascular AMPKα phosphorylation (Thr172). However, whether a dysregulation in calcium homeostasis via the non-canonical stress tolerance cascade underlies the impaired vascular function after TLR9 stimulation needs to be clarified. We hypothesized that TLR9 activation would inhibit SERCA2 activity in the vasculature. SERCA2 activity was assessed using a luciferase-based ATP quantification kit. Microsomes were isolated from pooled aortae of Sprague-Dawley rats and subjected to treatment with either Vehicle (Veh) or ODN2395 (2 μM), with or without a SERCA2 inhibitor (thapsigargin; 1 μM). The presence of thapsigargin increased ATP concentrations similarly in both Veh and ODN2395 [ATP (μM), Veh: 19±3 vs. Veh+thapsigargin: 140±35; ODN2395: 22±9 vs. ODN2395+thapsigargin: 129±12, both p<0.05], suggesting TLR9 activation did not inhibit SERCA2 activity. Next, MRA from Sprague-Dawley rats were divided into three sections for Western blot analysis of AMPKα-activating kinases, specifically calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and liver kinase B1 (LKB1). ODN2395 alone did not increase protein expression of phospho-CaMKK2
Ser511
(p>0.05), again suggesting calcium-independent activation of AMPKα. However, ODN2395 did increase phospho-LKB1
Ser428
(3.8 fold vs. Veh, p<0.05), and this increase in expression was inhibited by pre-incubation with TLR9 antagonist ODN2088 (20 μM) (p>0.05). These results suggest that the TLR9 non-canonical stress tolerance pathway in the vasculature is mediated by LKB1, and not SERCA2 inhibition.
Abstract P221: Vascular Smooth Muscle-Specific Overexpression of Cyp4a12-20-HETE Synthase Causes Hypertension and Vascular Remodeling
Authors: Hutcheson Rebecca , Zhang Frank , Gotlinger Katherine , Schwartzman Michal
Published: June 2021

20-Hydroxyeicosatetraenoic acid (20-HETE) is a potent vasoactive eicosanoid of the microcirculation exhibiting effects on vascular smooth muscle (VSM) function that include stimulation of contractility, migration and growth. We have previously demonstrated in mice which globally overexpress 20-HETE that hypertension as well as vascular remodeling is not fully prevented by pharmacological normalization of blood pressure. However, both hypertension and vascular remodeling are prevented by antagonism of 20-HETE, suggesting that 20-HETE exerts vascular effects independent of hypertension. To examine the contribution of VSM-derived 20-HETE to hypertension and vascular remodeling, we have developed a transgenic mouse model that overexpresses the primary mouse 20-HETE synthase, Cyp4a12, specifically in VSM by crossbreeding floxed Cyp4a12 with Myh11-Cre mice. All mice carry the floxed Cyp4a12 gene and express a GFP protein under control of a modified CMV promoter. Cre-recombination excises the GFP cDNA and inserts the Cyp4a12 cDNA.

Three to four month old male Cyp4a12-floxed mice carrying the Myh11-Cre gene (Cyp4a12
fl/fl
Myh11
Cre+/-
) exhibited higher systolic blood pressure than control mice Cyp4a12
fl/fl
Myh11
Cr-/-
(WT) mice (135 vs. 115 mmHg, n=4, *p<0.05). 20-HETE production in Cyp4a12
fl/fl
Myh11
Cre+/-
mice were higher than in WT in mesenteric (3333±891 vs. 545± 196 ng/mg/h) and renal interlobar arteries (RIA; 1859±376 vs. 242±62 ng/mg/h). Plasma levels of 20-HETE were also elevated (324±61 vs. 185±34 pg/mL) while urinary levels were not significantly different (146±26 vs. 117±29 pg/mL). We also observed increased medial thickness and decreased lumen area of blood vessels by Myh11 immunofluorescence in heart and kidney sections. RIA from male Myh11-Cyp4a12 mice displayed higher constrictor sensitivity to phenylephrine and impaired relaxation to acetylcholine compared to WT.

Taken together, these data suggest that this model displays hypertension and pathological hypertrophic vascular remodeling. We therefore conclude that the Cyp4a12
fl/fl
Myh11
Cre/-
is a promising and unique transgenic mouse model to examine the contribution of smooth muscle-derived 20-HETE to hypertension and hypertrophic vascular remodeling.
Abstract P246: Targeting 20-Hydroxyeicosatetraenoic Acid in Rofecoxib-induced Cerebrovascular Damage
Authors: Wang Mong-Heng , Weng Jing , Ergul Adviye
Published: June 2021

Background:
Coxibs, selective cyclooxygenase-2 (COX-2) inhibitors, significantly improved the quality of life of millions of individuals affected by pain and inflammation. Unfortunately, increased risk of stroke with the use of coxibs limited their clinical usefulness. The
goal
of this study is to investigate the role of 20-hydroxyeicosatetraenoic acid (20-HETE) metabolism by COX-2 in rofecoxib-induced cerebrovascular damage. We treated MC38 mice (1.4 x 10
6
MC38 cells/mouse) with rofecoxib (50 mg/L) + HET0016 (20-HETE blocker; 5 mg/kg/day, i.p.), rofecoxib, or vehicle for 3 weeks. We then subjected these MC38 and control mice to thromboembolic stroke. Finally, we treated B6 mice with 20-OH PGE
2
(250 ng/h; osmotic pump) and vehicle for 7 days, and then subjected them to ischemic stroke.

Results:
1
). Rofecoxib significantly reduced MC38 tumor size (from 693 ± 106 to 329 ± 40 mm
3
,
P
< 0.05). Within its therapeutic dose, rofecoxib selectively increased circulating 20-HETE levels (100 ± 18 vs. 150 ± 11%,
P
< 0.05), which was reversed by HET0016 (150 ± 11 vs. 100 ± 16%,
P
< 0.05). We did not find significant change on cyp4a (20-HETE synthesizing enzymes) expression in the brain microvessels after rofecoxib treatment.
2
). A major prostaglandin (PG) metabolite, which is 20-OH PGE
2
, was generated when we incubated purified COX-2 with 20-HETE (5 uM). Strikingly, rofecoxib (1 uM) inhibited 20-OH PGE
2
synthesis by 71% (from 100 ± 16 to 29 ± 8%,
P
< 0.05).
3
). Hemorrhagic transformation (HT) was greater in rofecoxib group (4/5 mice showing bleeding), a vascular injury that was prevented by co-treatment with HET0016 (0/6 mice showing bleeding).
4
). 20-OH PGE
2
supplementation reduced both infarct size (45 ± 10 vs. 17 ± 8% contralateral hemisphere,
P
< 0.05) and neurological deficits (3.6 ± 0.5 vs. 2 ± 1,
P
< 0.05).

Conclusion:
1
) Rofecoxib increases circulating levels of 20-HETE, which exacerbates stroke damage.
2
) COX-2 is the key player in regulating 20-HETE metabolism.
3
) 20-HETE blockade prevents HT induced by rofecoxib.
4
) 20-OH PGE
2
exerts cerebroprotective after ischemic stroke.
In summary
, these results suggest that both 20-HETE blockade and 20-OH PGE
2
supplementation are new approaches to ameliorate coxib-induced cerebrovascular damage and adverse stroke outcomes.
Abstract P249: Melanocortin-4 Receptors in Cholinergic Preganglionic Neurons of the Hindbrain and Spinal Cord are Important in Mediating Cardiovascular Responses to Acute Stress
Authors: do Carmo Jussara M , Fang Taoling , Moak Sydney P , Browing Jackson R , Hall John E
Published: June 2021

Previous studies suggest that melanocortin-4 receptor (MC4R) activation in areas outside of the hypothalamus may regulate appetite but the role of MC4R in specific neuronal populations of the hindbrain in regulating cardiovascular function are still unknown. We examined the impact of total body MC4R deficiency (LoxTB-MC4R mice) and restoration of MC4R specifically in the brainstem and/or spinal cord on blood pressure (BP) response to acute stress. We selectively rescued MC4R only in preganglionic parasympathetic neurons of the dorsal motor of the vagus (DMV) and in the nucleus tractus solitarius (NTS) (LoxTB-MC4R/Phox2B-cre mice, n=5) or in cholinergic preganglionic neurons of the hindbrain and spinal cord (LoxTB-MC4R/Chat-cre mice, n=4). Mice were implanted with telemetry probes for measurement of mean arterial pressure (MAP) and heart rate (HR). After a 10-day recovery period, MAP and HR were continuously measured for 30 minutes before, during and 30 minutes after an air jet stress test. Acute air jet stress significantly increased MAP by 33±3 in WT mice and 31±2 in LoxTB-MC4R/Chat-cre mice compared to only 18±4 or 20±3 mmHg in LoxTB-MC4R/Phox2B-cre mice and LoxTB-MC4R mice, respectively. HR was increased by 180±20, 110±20, 100±23, and 127±15 bpm in response to air jet stress in WT, LoxTB-MC4R, LoxTB-MC4R/Phox2B and LoxTB-MC4R/Chat-cre mice, respectively. These results indicate that MC4Rs in cholinergic preganglionic neurons of the hindbrain and spinal cord play a key role in the BP responses to acute stress. (NHLBI-PO1HL51971, NIGMS- P20GM104357, and AHA-SDG5680016)
Abstract P251: Association of Microvascular Measures with Brachial and Central Pressures in Young Non-hypertensive Adults
Authors: Cheng Cynthia , Townsend Raymond , Chirinos Julio , Keith Scott
Published: June 2021

Microvascular rarefaction (reduced capillary density) is associated with hypertension. Little is known about capillary rarefaction in young individuals, in whom brachial and central blood pressure (BP) may be quite divergent. Thus, we compared capillary density in young subjects with their office and central BP profiles.

We measured central BP using the SphygmoCor XCEL device, and office BP in 102 healthy young participants (
Table 1
). Capillary density was measured progressively in the nailbed at baseline rest, following ischemic stimulus, and using passive venous congestion. All capillary densities were significantly associated with central DBP and MAP (
Table 2
). Only post-ischemic capillary density was significantly associated with office brachial SBP and MAP (rest and venous densities were marginally associated).

In conclusion, capillary density is consistently and significantly associated with central MAP in young, non-hypertensive individuals. Since MAP is a key determinant of systemic vascular resistance, capillary rarefaction may lead to the future development of hypertension.
Abstract P252: Hypertension Educator: Evidence for an Interdisciplinary Approach
Authors: Doyle-Campbell Courtney
Published: June 2021

Purpose:
Certified Diabetes educators have long been utilized to educate patients with diabetes on effective lifestyle changes and to assist in optimizing evidence based medication. Using the same interprofessional prospective to target HTN would be an effective tool in decreasing CV risk. This study demonstrates the efficacy of a clinical pharmacist in controlling BP through patient education and medication intervention within a level 3 medical home.

Methods:
This is a retrospective analysis of patients seen by a clinical pharmacist from 2013 to 2015 in a HTN clinic located in a level 3 medical home. Patients are referred to the clinic by primary care physicians. During the one hour initial consultation the clinical pharmacist reviews the patient’s prescription and over-the-counter medications, recommends medication optimization, and educates the patient on medication, lifestyle and HTN. Recommended medication changes, lab requests and specialty referrals are pended to the physician for approval. The patient has the opportunity to follow-up in the HTN clinic until BP is controlled. Impact of pharmacist intervention was assessed based on number of follow-ups to the clinic.

Results:
A significant change was noted in the SBP and DBP in patients seen within the HTN Clinic within the 1st, 2nd and 3rd follow-ups (p<0.05) (table 1). There were 312 medication changes recommended by the pharmacist and approved by the PCP during the study period.

Conclusion:
This study provides evidence that incorporating pharmacists into medical homes can provide BP lowering benefits for patients and provide important preventative care.
Abstract P253: Carvedilol Benefits in Hypertensive Cardiomyopathy
Authors: Dominguez Renata , Costa-Hong Valeria , Consolim-Colombo Fernanda , Ferretti Luan , Bortolotto Luiz , Egan Brent , Lopes Heno F
Published: June 2021

Left ventricle remodeling is a common consequence of uncontrolled hypertension. Hypertension treatment including renin-angiotensin-aldosterone system inhibition and beta-blockers offers cardiac protection. Carvedilol uses in cardiomyopathy from different etiology have shown good results in left ventricle reverse remodeling. There is a lack of information regarding carvedilol use in hypertensive cardiomyopathy. The main objective in this study was to evaluate the use of carvedilol in hypertensive patients with reduced left ventricle ejection fraction. We evaluate 98 subjects with reduced left ventricle ejection fraction (55 years age, 59 males, 64 white, 34 nonwhite) before and after at least six months of carvedilol use. Clinical data, laboratory tests, and echocardiogram were evaluated at least 6 months before and after carvedilol was added to the treatment. Other causes of cardiomyopathy, including coronary artery disease, were excluded. A hundred percent of patients was taking diuretic and renin-angiotensin-aldosterone system inhibitors. Twenty eight percent were using statins, 19% were using antidiabetic drugs, and 29% were taking digoxin. Blood pressure and heart rate (144/92 mmHg, 84 bpm) decreased significantly after (130/82 mmHg, 70 bpm) carvedilol treatment. Ejection fraction improved in 68.5% patients. Let ventricle diastolic diameter decreased from 62 to 56 mm, left ventricle systolic diameter decreased from 53 to 42 mm, left ventricle mass index decreased from 145 to 129 g/m
2
, left ventricle relative posterior wall increased from 0.32 to 0.36. Carvedilol, in addition to antihypertensive drugs, showed improvement in hemodynamic parameters, and in echocardiographic structural and functional parameters in hypertensive cardiomyopathy patients.
Abstract P258: Antihypertensive Medication Nonadherence Among Hispanic Adults by Healthcare Access and Acculturation Characteristics - Estilos Survey, 2015
Authors: Ayala Carma , Tong Xin (Cindy) , Ochoa Carol , Mercado Carla , Fang Jing
Published: June 2021

Medication adherence for hypertensive adults (HTNs) is an important factor in achieving and maintaining blood pressure control, as it has been associated with better health outcomes and lower costs of medical care. We assessed the differences in the prevalence of self-reported antihypertensive medication use and adherence among Hispanic HTNs by selected characteristics.

Methods:
ESTILOS is an online panel for health survey data of Hispanic adults in the USA. In 2015, 1,000 adults completed the survey with a response rate of 29%. The resulting data were weighted using 8 factors: gender, age, household income, household size, education, census region, country of origin, and acculturation (based on years living in the USA, language spoken at home, cultural self-identification, and use of Spanish language). The differences among characteristics for prevalence ± standard error of medication use and adherence were compared by using χ
2
statistics.

Results:
The prevalence of hypertension was 27.5±2.7%. The prevalence of antihypertensive medication use in HTNs was 67.9±4.6%) overall and was higher among those ≥55 years of age (95.2±2.1%;
P
=<0.0001), retirees (92.3±4.0%;
P
=0.0002), who had healthcare coverage (72.5±4.8%;
P
=0.02) and had a primary care physician (PCP) (71.9±4.9%;
P
=0.03), did not have any reported cost barriers to seeing their PCP within past 12 months (71.9±5.3%;
P
=0.001), and took 3-4 lifestyle actions (79.7±5.4%;
P
=0.015) than <3 lifestyle actions). Among HTNs taking antihypertensives, 24.0±7.0% reported missing or skipping medication doses. HTNs aged <55 years or who could not see a PCP within the past year due to cost barriers, were more likely to miss or skip doses of antihypertensive medication (<55=54.1±13.4%) vs >55=11.5±5.3%;
P
=0.03 and could not see PCP=45.2±12.1% vs 12.0±5.2%; 0.01, respectively).

Conclusion:
Poor antihypertensive medication adherence among Hispanics with hypertension was associated with younger age groups and those who reported barriers to engaging with a PCP. Public health practitioners and clinicians can utilize this information to support their programs and can tailor strategies for improved outcomes.
Abstract P261: Intensive Systolic Blood Pressure Lowering Will Prevent Over 100,000 Deaths Annually
Authors: Kramer Holly , Bress Adam , Beddhu Srinivasan , Muntner Paul , Cooper Richard S
Published: June 2021

Background:
The Systolic Blood Pressure Intervention Trial (SPRINT) trial randomized 9,361 adults aged ≥50 years at high cardiovascular disease (CVD) risk without diabetes or stroke to intensive systolic blood pressure (SBP) lowering (≤120 mmHg) or standard SBP lowering (≤140 mmHg). After a median follow up of 3.26 years, all-cause mortality was 27% (95% CI 40%, 10%) lower with intensive SBP lowering. We estimated the potential number of prevented deaths with intensive SBP lowering in the U.S. population meeting SPRINT criteria.

Methods:
SPRINT eligibility criteria were applied to the National Health and Nutrition Examination Survey 1999-2006, a representative survey of the U.S. population, linked with the mortality data through December 2011. Eligibility included (1) age ≥50 years with (2) SBP 130-180 mmHg depending on number of antihypertensive classes being taken, and (3) presence of ≥1 CVD risk conditions (history of coronary heart disease, estimated glomerular filtration rate (eGFR) 20 to 59 ml/min/1.73 m
2
, 10-year Framingham risk score ≥15%, or age ≥75 years). Adults with diabetes, stroke history, >1 g/day proteinuria, heart failure, on dialysis, or eGFR<20 ml/min/1.73m
2
were excluded. Annual mortality rates for adults meeting SPRINT criteria were calculated using Kaplan-Meier methods and the expected reduction in mortality rates with intensive SBP lowering in SPRINT was used to determine the number of potential deaths prevented. Analyses accounted for the complex survey design.

Results:
An estimated 18.1 million U.S. adults met SPRINT criteria with 7.4 million taking blood pressure lowering medications. The mean age was 68.6 years and 83.2% and 7.4% were non-Hispanic white and non-Hispanic black, respectively. The annual mortality rate was 2.2% (95% CI 1.9%, 2.5%) and intensive SBP lowering was projected to prevent 107,453 deaths per year (95% CI 45,374 to 139,490). Among adults with SBP ≥145 mmHg, the annual mortality rate was 2.5% (95% CI 2.1%, 3.0%) and intensive SBP lowering was projected to prevent 60,908 deaths per year (95% CI 26, 455 to 76, 792).

Conclusions:
We project intensive SBP lowering could prevent over 100,000 deaths per year of intensive treatment.
Abstract P263: Identification and Analyses of Mirnas And Lncrnas Influencing Hypertension in Dahl Salt-sensitive Rats
Authors: Endo Kosuke , Iwai Naoharu
Published: June 2021

Background:
Noncoding RNAs (ncRNAs), including microRNA (miRNA) and long noncoding RNA (lncRNA), are functional and non-protein coding RNA molecules. miRNAs are small ncRNAs of 18-23 nucleotides, whereas LncRNAs are longer than 200 nucleotides and were recently recognized as a class of genomic regulatory molecules and reported in various species. Nonetheless, their physiological functions have not been elucidated.

Methods:
In order to investigate a possible involvement of ncRNAs in salt-sensitive hypertension, we performed ncRNA sequencing and transcriptome analysis in Dahl salt-sensitive rats and Lewis rats. The pathway analysis were used to understand the biological roles of differently expressed ncRNAs.

Results:
Following ncRNA sequencing, 591 transcripts were defined as mature miRNAs and 2636 transcripts as lncRNAs. Of these, 9 miRNA were mapped to candidate chromosomal regions (chromosome 1, 10, and 12), previously reported to be involved in salt-sensitive hypertension. Differential expression was detected for 3 of these miRNAs (miR-150-5p, miR-7a-5p, miR-21-5p) (fold up/down ≥ 1.2, q < 0.05). However, only one lncRNA (XLOC_081666) encoded by the candidate region of chromosome 1 showed no difference. In contrast, 10 miRNAs (miR-1b, miR-221-3p, miR-300-3p, miR-411-5p, miR-184, miR-205, miR-129-5p, miR-741-3p, miR-379-5p, miR-138-5p) and 5 lncRNAs (XLOC_102471, XLOC_047839, XLOC_253638, XLOC_778532, XLOC_1029112), located in other regions, showed significant differential expression (fold up/down ≥ 2.0, q < 0.05). The pathway analysis showed that Wnt and MAPK signaling pathways are associated with the targets of detected miRNAs and metabolic pathways are associated with the possible targets of detected lncRNAs. Although expression levels of target mRNAs in these pathways showed no differences between Dahl salt-sensitive and Lewis rats, it is likely that effects of a single ncRNA on mRNA expression are subtle and may exhibit different response to salt intake.

Conclusions:
Our results demonstrate the probable implication of miRNAs and lncRNAs in salt-sensitive hypertension. This new finding may contribute to the exploration of candidate factors involved in the hypertension mechanism.
Abstract P266: Thromboxane-prostanoid Receptors (tp-rs) Mediate Hypertension, H2o2 Generation and Impaired Renal Afferent Arteriolar Myogenic Responses Leading to Nephropathy in Doca/salt Mice
Authors: Wilcox Christopher S , Li Lingli , Lai En Yin , Hosszu Adam , Welch William J
Published: June 2021

Background:
DOCA/uninephrectomy/high salt (DOCA) is a model of hypertensive nephropathy. Afferent arteriolar myogenic responses prevent hypertensive renal barotrauma but myogenic tone is blocked by vascular generation of H
2
O
2
. Since thromboxane-prostanoid receptors (TP-Rs) generate H
2
O
2
, we tested the hypothesis that they mediate hypertensive nephropathy.

Methods:
DOCA and Sham TP-R +/+ and -/- mice (n=6/group) were studied at 2 weeks and myogenic responses recorded from the diameter of perfused single afferent arterioles studied in a bath preparation during increased perfusion pressure (40 to 80 mmHg).

Results:
DOCA treatment in TP-R +/+ mice increased (p<0.001) 24-hour excretion of H
2
O
2
(45 ± 3 vs 220 + 15 nmol)
,
TxB
2
(4 ± 2 vs 29 ± 4 pmol) and albumin (20 ± 5 vs 270 ± 20 mg) and increased MAP by 35 ± 5 mmHg. However, all effects of DOCA were prevented in TP-R -/- mice. Sham treatment had no effect in TPR +/+ or -/- mice. Myogenic responses were severely impaired in DOCA vs sham WT mice (Δ diameter: -4 ± 1 vs -8 ± 1%; p< 0.005). Myogenic responses also were reduced by incubation of arterioles with 10
-10
mol·l
-1
of the TP-R mimetic, U-46,619 vs vehicle added to the bath for 10 minutes (Δ diameter: -7 ± 1 vs -10 ± 1%; p<0.01) and in WT mice infused for 3 days with U-46,619 (500 ng·kg
-1
·d
-1
x 3) vs vehicle (Δ diameter: -3 ± 1 vs -10 ± 1%; p<0.005).

Conclusion:
Hypertensive nephropathy is dependent on TP-Rs that mediate the increase in H
2
O
2
and blood pressure and likely the impaired myogenic responses that expose the kidney to barotrauma