Hypertensive Response Research Articles

Abstract P172: Impairment Of Estrogen Protective Effect Contributes To Maternal Gestational Hypertension-induced Sensitization Of Hypertensive Response To Post-weaning High Fat Diet In Female Adult Offspring

Obesity/high fat diet (HFD) is a risk factor for cardiovascular diseases including hypertension. Recent evidence indicates that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning HFD in both male and female offspring. However, the increase in blood pressure (BP) in female offspring is less than that in male offspring. In this study, we investigated if estrogen plays a protective role in MGHT-induced HTRS to post-weaning HFD in female offspring, and if estrogen effects are associated with regulation of brain reactivity to pressor agents and altered autonomic function. In post-weaning HFD fed intact female offspring, MGHT induced HFD-elicited HTRS (MAP, offspring of NT dams, 107.9±0.9 to 115.2±0.7 mmHg; offspring of MGHT dams, 107.3±0.8 to 120.7±1.4 mmHg, p<0.05) and enhanced pressor responses to centrally administered angiotensin (ANG) II (Δ13.7±1.1 mmHg, p<0.05 vs NFD offspring) and tumor necrosis factor α (TNF-α) (Δ13.1±0.7 mmHg, p<0.05 vs NFD offspring). Ovariectomy (OVX) significantly enhanced the HFD-induced increase in BP (115.2±0.7 to 127.1±2.2 mmHg, p<0.05) and the pressor response to central ANG II (Δ11.2±0.9 to Δ18.7±2.3 mmHg, p<0.05) or TNF-α (Δ10.0±1.0 to Δ16.5±1.6 mmHg, p<0.05) in HFD offspring of normotensive (NT) dams. However, MGHT-induced HTRS (MAP, 122.5±1.9 mmHg) and pressor responses to ANG II (Δ16.3±1.0 mmHg) or TNF-α (Δ14.9±1.0 mmHg) in HFD-fed intact offspring of MGHT dams were not potentiated further after OVX when compared to HFD-fed OVX offspring of NT dams. The resting BP and elicited pressor responses remained higher than that of NFD fed offspring of both NT and MGHT dams. Moreover, OVX induced an increase in central nervous system sympathetic drive, and HFD feeding potentiated this effect. The results indicate that estrogen normally plays a protective role in antagonizing HFD prohypertensive effects in offspring of NT dams. MGHT compromises this normal protective action of estrogen to induce HTRS elicited by HFD, which is through augmenting brain reactivity and centrally driven sympathetic activity.

Abstract P254: Sex Differences In Angiotensin Ii-induced Hypertension In Mice With Proximal Tubule-specific Deletion Of Mitochondrial Protein Sirtuin 3 In The Kidney

The development of Angiotensin II (Ang II)-induced hypertension is associated with mitochondrial dysfunction and kidney injury. Sirtuin 3 (SIRT3), a key mitochondrial protein, plays an important role in maintaining mitochondrial homeostasis. However, it remains unknown whether deletion of SIRT3 in the proximal tubules will alter the pressor and renal responses to Ang II in sex-different manners. In the present study, adult male, and female wild-type (WT) and mutant mice with proximal tubule-specific knockout of SIRT3, PT- Sirt3 -/- , were infused with or without a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail-cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP levels were lower in PT- Sirt3 -/- than in WT mice (SBP-WT: 112 ± 2 vs. SBP-PT- Sirt3 -/- : 93 ± 2 mmHg, P <0,01). The magnitude of Ang II-induced hypertension was similar between WT and PT- Sirt3 -/- mice with or without losartan treatment. Serum creatinine levels and urinary creatinine excretion were higher in PT- Sirt3 -/- mice than in WT mice ( P <0.05), but without significant sex differences in response to Ang II infusion or losartan treatment. Differences were found only in female WT and PT- Sirt3 -/- mice with lower 24 hr. urine and urinary creatinine excretion in response to Ang II infusion or losartan. Losartan significantly increased 24 hr. urinary potassium and chloride excretion in Ang II-infused male and female PT- Sirt3 -/- mice ( P <0.01). Finally, Ang II-infused PT- Sirt3 -/- mice showed significant renal cortical tubulointerstitial fibrotic responses ( P <0.05), but not glomerular fibrotic responses. We conclude that basal blood pressure is lower in male and female PT- Sirt3 -/- mice and that Ang II induces similar hypertensive and renal fibrotic responses in male and female PT- Sirt3 -/- mice without significant sex differences.

O-10 PRIMARY BILIARY CHOLANGITIS PATIENTS DIAGNOSED BY DIFFERENT COMBINATIONS OF THE DIAGNOSTIC CRITERIA PRESENT CLINICAL AND LABORATORY PECULIARITIES

Primary biliary cholangitis (PBC) diagnosis is based on international criteria, which requires two of the following: (i) elevated alkaline phosphatase (AP), (ii) anti-mitochondrial antibody (AMA) and (iii) liver biopsy (BX) suggestive of PBC. It is still unclear if patients diagnosed by different criteria combinations present peculiarities, especially in highly-admixed populations. To investigate if patients diagnosed with PBC by different combinations of validated criteria present clinical or laboratory particularities. The Brazilian Cholestasis Study Group database was reviewed to compare clinical, biochemical and histological characteristics of PBC between four groups diagnosed by: (1) AP ≥2x upper limit of normality (ULN) + presence of AMA, (2) AP ≥2x ULN + BX suggestive of PBC, (3) presence of AMA + BX suggestive of PBC and (4) all criteria. 482 patients with PBC were included (Table 1). Group-1 presented with higher levels of IgG, lower frequency of arterial hypertension (AH) and lower response to ursodeoxycholic acid (UDCA), while Group-2 had lower: age at diagnosis and HDL-C levels. Group-3 had higher: age at diagnosis, frequency of neoplasms, AH and response to UDCA; and lower: frequency of pruritus and jaundice, levels of aminotransferases, GGT and bilirubin, advanced liver disease and esophageal varices. Group-4 showed higher frequency of symptoms at presentation, especially pruritus. PBC patients diagnosed by different combinations of established criteria may present singular features that can possibly impact in disease presentation and progression.

Abstract MP46: Mutagenesis Of PRR Cleavage Site In Mice Attenuates Angiotensin II-induced Hypertension And Suppresses Renin Expression

It is well demonstrated that activation of renal (pro)renin receptor (PRR) contributes to AngII-induced hypertension. Relatively, less is known about involvement of soluble PRR (sPRR), the extracellular domain of PRR, primarily generated by site-1 protease(S1P) and furin. Moreover, the relationship between PRR/sPRR and the renin-angiotensin system (RAS) has been debated. In the present study, we used CRISPR/Cas9 strategy to generate mice with mutagenesis of the overlapping cleavage site for both proteases in PRR (termed as PRR R279V/L282V ) to examine the phenotype during angiotensin II (AngII) infusion with particular emphasis on circulating and intrarenal renin status. PRR R279V/L282V mice exhibited a reduction of sPRR level in plasma by ~53% and in the kidney by ~82%, were fertile, and had no gross developmental abnormalities. At basal condition, PRR R279V/L282V mice had drastically suppressed renin levels from plasma (plasma total prorenin/renin content [ng/ml]: 9.3 ± 0.7 in PRR R279V/L282V mice vs. 12.8 ± 0.9 in WT mice, n = 5, p < 0.05), urine (urinary total prorenin/renin excretion [ng/24h]: 0.54 ± 0.11 in PRR R279V/L282V mice vs. 1.05 ± 0.15 in WT mice, n = 5, p < 0.05), and the kidney as compared to wild-type controls (WT). By telemetry, the hypertensive response of PRR R279V/L282V to AngII infusion (300 ng/min/kg) was blunted (MAP [mmHg] in Day 10: 125.9 ± 4.6 in PRR R279V/L282V mice vs. 138.5 ± 2.8 in WT mice, n = 8 for each group, p < 0.05) in parallel with attenuated response of intrarenal renin and renal medullary α-ENaC expression. We further examined the direct role of sPRR in renin regulation in As4.1 cells, a renin-expressing cell line isolated from mouse renal tumor and M-1 cells, a mouse cell line derived from the collecting duct. The exposure to sPRR-His in both cell types consistently elevated renin activity, and renin expression at both protein and mRNA levels, all of which were sensitive to inhibition by ICG-001, a β-catenin signaling inhibitor. Together, these results represent strong evidence favoring sPRR as a mediator of AngII-induced hypertension and a master regulator of renin expression at systemic and local levels. Therefore, PRR should be considered as an integrative member of the RAS.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Abstract P209: Loss Of Rgs2 Specifically In CD4+ T Cells Decreases The Hypertensive Response To Vasopressin

Regulator of G protein Signaling (RGS) family members can modulate multiple cardiovascular hormones and are associated with hypertension and preeclampsia, a hypertensive disorder in pregnancy. We previously observed a 9-fold increase in RGS2 in CD4+ T cells isolated from women with preeclampsia compared to normotensive women. Further, in non-pregnant mice, we showed that loss of RGS2 in CD4+ T cells prevented angiotensin II-induced hypertension (measured via radiotelemetry) and resulted in increased levels of the anti-inflammatory cytokines interleukin 4 and transforming growth factor beta. We hypothesize that modulating RGS2 in CD4+ T cells may be a therapeutic strategy for hypertension. The objective of this study was to determine if loss of RGS2 specifically in CD4+ T cells protects against the development of arginine vasopressin-induced hypertension in mixed background CD4+ RGS2 knockout mice (CD4 RGS2 KO ). To generate mice wherein RGS2 is specifically knocked out in CD4+ T cells, CD4-Cre+ mice (C57BL/6J) were crossed with RGS2 flox/flox mice (B6SJLF1/J). Female 8-12 week old CD4 RGS2 KO or littermate control mice (n=5 per group) from this mixed strain were administered 24 ng/hr vasopressin for 21 days via mini-osmotic pump. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MP), and heart rate (HR) were assessed using a high throughput non-invasive blood pressure system. Prior to vasopressin infusion, KO and CTL mice showed no differences in SBP, DBP, MP, or HR. At 9-13 days of vasopressin-infusion, KO mice had a significantly lower 24-hr SBP [KO 138.7 ±4.7 vs CTL 155.9 ±3.4 mmHg, p<0.05], DBP [KO 106.9 ±4.1 vs CTL 122.8 ±2.9 mmHg, p<0.05], MP [KO 117.2 ±4.3 vs CTL 133.5 ±3.0 mmHg, p<0.05], and HR [KO 378 ±18.7 vs CTL 445 x±12.8 BPM, p<0.05] compared to CTL mice. Here, we demonstrate that in a mixed strain CD4+ RGS2 KO mouse, loss of RGS2 specifically in CD4+ T cells prevented vasopressin-induced hypertension. Therefore, RGS2 expression in CD4+ T cells may play an expanded role in the modulation of hypertension.

Abstract P194: Voluntary Exercise Eliminates Maternal Gestational Hypertension-induced Hypertensive Response Sensitization (htrs) In Post-weaning High Fat Diet Fed Male Adult Offspring

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. Our previous studies demonstrated that maternal gestational hypertension (MGHT) induces hypertensive response sensitization (HTRS) elicited by post-weaning high fat diet (HFD) in male offspring. The present study tested whether voluntary exercise would protect against MGHT-induced HTRS in HFD fed male offspring. Male offspring from both normotensive (NT) and MGHT dams were given access to either “blocked” (sedentary offspring) or functional running (exercised offspring) wheels for 10 weeks during normal fat diet (NFD) or HFD feeding. HFD feeding significantly increased resting blood pressure (BP) in sedentary offspring of both NT (112.3±0.7 to 119.9±1.2 mmHg, p<0.05) and MGHT (112.5±0.9 to 129.6±1.0 mmHg, p<0.05) dams, but the elevated BP induced by HFD was greater in sedentary offspring of MGHT dams (129.6±1.0 vs. 119.9±1.2 mmHg, p<0.05). The sedentary offspring of MGHT dams also displayed greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin (ANG) II or leptin. The running distance was comparable in four groups of exercise offspring (9.183±1.183, 9.192±1.677, 7.233±1.080, 8.482±1.455 kilometers/day, p>0.05). Voluntary exercise did not alter BP in NFD fed offspring and HFD fed offspring of NT dams, but it attenuated BP in HFD fed offspring of MGHT dams (129.6±1.0 to 121.1±0.8 mmHg, p<0.05) and body weight and heart rate in all offspring. Moreover, voluntary exercise significantly reduced sympathetic tone (Hexamethonium, ip, MAP Δ-50.6±1.0 to Δ-29.7±2.7 mmHg, p<0.05) and pressor responses to central ANG II and leptin in HFD fed offspring of both NT (ANG II: Δ16.0±0.9 to Δ7.5±1.1 mmHg; leptin: Δ11.8±0.6 to Δ5.4±0.9 mmHg, p<0.05) and MGHT (ANG II: Δ24.3±2.1 to Δ7.6±1.8 mmHg; leptin: Δ16.8±0.9 to Δ5.2±1.0 mmHg, p<0.05) dams and eliminated the differences in these responses between NFD fed offspring and HFD fed offspring. These results indicate that exercise training plays a beneficial role in preventing MGHT-induced HTRS and that this effect is associated with reduced brain reactivity to pressor stimuli and centrally driven sympathetic activity.

MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin

PurposeCardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a maladaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra- and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction. MethodsMale Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed. Results6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline. ConclusionHypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction.

Exercise blood pressure and cardiovascular disease risk: a systematic review and meta-analysis of cross-sectional studies.

A hypertensive response to exercise (HRE) is associated with cardiovascular disease and high blood pressure (BP). A poor cardiovascular risk factor profile may underlie these associations, although this has not been systematically elucidated. Via systematic review and meta-analysis, we aimed to assess the relationship between exercise BP and cardiovascular risk factors, and determine if cardiovascular risk is higher in those with an HRE vs. no-HRE across different study populations (including those with/without high BP at rest). Three online databases were searched for cross-sectional studies reporting data on exercise BP, an HRE and cardiovascular risk factors (including arterial structure, lipid, metabolic, inflammatory and kidney function markers). Random-effects meta-analyses and meta-regression were used to calculate pooled correlations between exercise BP and each risk factor and pooled mean differences between those with/without an HRE. Thirty-eight studies (38 295 participants, aged 50 ± 3years; 78% male) were included. Exercise SBP was associated with arterial, lipid and kidney function risk markers (P < 0.05). Those with an HRE had greater aortic stiffness (+0.80 ± 0.35 m/s), total (+0.14 ± 0.03 mmol/l) and low-density lipoprotein (+0.12 ± 0.03 mmol/l) cholesterol, triglycerides (+0.24 ± 0.04 mmol/l), glucose (+0.15 ± 0.05 mmol/l), white blood cell count (+0.49 ± 0.16 mmol/l) and albumin-to-creatinine ratio (standardized mean difference: +0.97 ± 0.34), and lower flow-mediated dilation (-4.13 ± 1.02%) and high-density lipoprotein cholesterol (-0.04 ± 0.01 mmol/l) vs. those with no-HRE (P < 0.05 all). Results were broadly similar across study populations. Exercise SBP is associated with multiple cardiovascular risk factors, which appear worse in those with an HRE vs. no-HRE. As results were similar across population groups, an HRE should be considered an important indicator of cardiovascular risk.

Extracellular Vesicles Correlate With Hypertensive Response To Exercise In Adults With Metabolic Syndrome

Extracellular Vesicles Correlate With Hypertensive Response To Exercise In Adults With Metabolic Syndrome

IL-10 and IL-12 (P70) Levels Predict the Risk of Covid-19 Progression in Hypertensive Patients: Insights From the BRACE-CORONA Trial.

Background: Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients.Methods: The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome.Results: During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model.Conclusions: This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.

Different volumes of repetitions and workloads in the pressor responses of hypertensive elderly: A systematic review

Objective: To synthesize the findings of chronic effects and the differences between the volume of repetitions and levels of external loads in the pressure responses of elderly hypertensive patients. Methods: The study followed the proposals of PRISMA (Preferred Reporting Items are Systematic Reviews and Metanalysis). As searches for the selected articles on the Medline, Pub Med, Cochrane, and Periodical platforms, between August and December 2020. The same studies were found using several words according to the proposed theme. ("Resistance training" and "elderly") ("Resistance training" and "blood pressure") ("Resistance training" and "cardiovascular and elderly") ("Resistance training" and "blood pressure" and "elderly") ("Resistance training" and "blood pressure" and "older"). Results: 2,698 articles were identified with these keywords. Title, abstract, duplicates excluded studies and after reading in full. Finally, ten studies were selected to read the integration, and four were selected for final analysis. Conclusion: This systematic review study uses low repetition and repetition to reduce similar magnitudes' blood pressure. The levels of external loads did not interfere in large proportions in hypertensive older adults' pressure responses. However, studies on the post-exercise resistance hypotensive effect and its variables are still scarce, making further studies on the subject necessary.

Hemiplegic migraine episode triggered by regadenoson

SPECT and PET myocardial perfusion imaging (MPI) are widely used to evaluate patients for coronary artery disease. Regadenoson (a selective A2A adenosine receptor agonist) is a commonly used vasodilator agent for stress MPI because of its safety profile and ease of use. Common adverse reactions such as headache, shortness of breath, flushing, and chest and abdominal discomfort are typically mild and can be effectively reversed using methylxanthines such as aminophylline and caffeine. Neurological adverse reactions such as seizure and stroke have rarely been reported with the use of regadenoson. The hemodynamic changes associated with regadenoson administration, such as an exaggerated hypotensive or hypertensive response, may be the cause for the reported cerebrovascular accidents. Activation of central nervous system A2A adenosine receptors is thought to be responsible for seizure episodes in patients with or without known histories of seizure. A2A adenosine receptors activation is also believed to play a role in headaches and migraine. This patient reported who has a history of hemiplegic migraine developed left side weakness and headache following the administration of regadenoson during a PET MPI study. Imaging work-up to rule out cerebrovascular accident was normal. After 1 hour from the onset of his symptoms, his weakness and headache significantly improved with complete resolution within 24 hours. We concluded that regadenoson triggered a hemiplegic migraine episode in this patient, which has not been previously reported in the literature. It may be prudent to avoid regadenoson and adenosine use in patients with a history of hemiplegic migraine.

Sex-dependent compensatory mechanisms preserve blood pressure homeostasis in prostacyclin receptor–deficient mice

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). In low-density lipoprotein receptor-deficient (Ldlr-/-) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.

Variant rs6596140 of Follistatin-like 4 Gene (FSTL4) May Be Associated with Poor Response to Angiotensin Receptor Blockers (ARBs) among Filipinos

Constituting one of the most commonly used antihypertensive drug families are the angiotensin receptor blockers (ARBs). The aim of this study was to identify the variants associated with response to ARBs that may potentially be used as markers for designing a tailor-fit treatment strategy for hypertension. An unmatched case-control study was done among adult hypertensive Filipino patients maintained on ARBs. Genotypic analysis of blood DNA was conducted. Logistic regression analyses were performed to determine association of clinical and genetic variables with ARB response. A total of 69 poor responders and 126 normal responders were included in the study. After performing univariate logistic regression, five single nucleotide polymorphisms showed association with poor response to ARBs. The genetic variant rs6596140 remained significant (dominant model; OR 2.36, p = 0.009) after adjusting for female sex and age. Variant rs6596140 was found to be associated with poor response to ARBs among Filipinos. Prior to clinical application, verification is recommended prior to clinical application. As the function of this variant is presently unknown, an investigation to elucidate its role in ARB response in hypertension is also recommended.

Pomegranate peel as a phytogenic in broiler chickens: Influence upon antioxidant, lipogenesis and hypotensive response.

The aim of this study was to evaluate antioxidant, antihyperlipidemic and hypotensive properties of pomegranate peel (PP) on antioxidant status, fat deposition, lipid peroxidation and pulmonary hypertensive response in broiler chickens. A total of 375 one‐day‐old male broilers (Cobb 500) were randomly assigned to five treatments included dietary PP levels of 0, 2.5, 5.0, 7.5 and 10 g/kg. Supplementation of PP at 7.5 and 10 g/kg resulted in significant upregulation of hepatic catalase (p < 0.004) and superoxide dismutase1 (SOD1; p < 0.05), which reflected in decreased concentration of circulatory malondialdehyde (MDA). Dietary inclusion of PP at 7.5 and 1.0 g/kg significantly decreased serum concentrations of triglycerides (p < 0.004) and cholesterol (p < 0.006) with concomitant decrease in abdominal fat deposition (p < 0.05). The antihyperlipidemic effect of PP was mediated through down‐regulation of peroxisome proliferator activated receptor alpha (PPARα). Hypotensive effect of PP was also observed at 7.5 and 10 g/kg as reduced heart weight and the right‐to‐total ventricular weight ratio (RV/TV) and decreased mortality from pulmonary hypertension. The hypotensive property of PP was associated with increased concentration of serum nitric oxide. In conclusion, this study revealed antioxidative, antihyperlipidemic and hypotensive effects of PP at 7.5 and 10 g/kg in broiler chickens exposed to hypobaric hypoxia. Health‐beneficial effects of PP suggest this product as a promising multi‐functional phytogenic feed additive for broiler chickens.

Cardiovascular risk profiles and stress echocardiography results in patients with hypertensive response to exercise

Aim. To compare markers of high cardiovascular risk and stress echocardiography results depending on the type of blood pressure (BP) response to exercise in patients without obstructive coronary artery disease.Material and methods. Our single-center cross-sectional study included 96 patients without hemodynamically significant coronary artery stenosis according to coronary angiography or multislice computed tomography angiography. All patients underwent physical examination, cardiovascular risk stratification, electrocardiography, extracranial cerebrovascular ultrasound, echocardiography, treadmill exercise stress echocardiography.Results. According to the test results, the patients were divided into groups with a hypertensive response (n=41) and a normal response to exercise (n=55). Patients with hypertensive response to exercise had significantly higher values of left ventricular mass index (100,0 (90,0; 107,0) g/m2 vs 76,0 (68,0; 91,0) g/m2, p&lt;0,0000001) and left atrial volume index (36,7 (32,0; 46,0) ml/m2 vs 29,7 (26,3; 32,0) ml/m2, p=0,000003). There was also a higher level of cardiovascular SCORE risk (5,0 (2,0; 6,0) vs 2,0 (1,0; 3,0), p=0,004); patients more often had associated clinical conditions (36,6% vs 12,7%, χ2=7,57, p=0,006) and left ventricular diastolic dysfunction (39,02% vs 78,18%, χ2=15,21, p=0,0001). Pathological BP increase during stress echocardiography was associated with worse exercise tolerance (7,4 (5,6; 10,0) METs vs 10,2 (8,4; 11,95) METs, p=0,000041) and more frequent transient regional contractility impairment (46,34% vs 1,8%, p&lt;0,00001), mainly of the lateral and inferior left ventricular walls.Conclusion. Despite the absence of coronary artery stenosis, patients with hypertensive response to exercise are significantly more likely to have markers of high cardiovascular risk and require more careful monitoring of risk factors. Also, the hypertensive response to exercise is associated with more frequent regional contractility impairment even without coronary artery stenosis.

Mutagenesis of the Cleavage Site of Pro Renin Receptor Abrogates Angiotensin II-Induced Hypertension in Mice.

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Acute Hypertensive Response in Patients With Acute Intracerebral Hemorrhage: A Narrative Review.

To review the role of the acute hypertensive response in patients with intracerebral hemorrhage, current treatment options, and areas for further research. Review of the literature to assess 1) frequency of acute hypertensive response in intracerebral hemorrhage; 2) consequences of acute hypertensive response in clinical outcomes; 3) acute hypertensive response and secondary brain injury: hematoma expansion and perihematomal edema; 4) vascular autoregulation, safety data side effects of acute antihypertensive treatment; and 5) randomized clinical trials and meta-analyses. An acute hypertensive response is frequent in patients with acute intracerebral hemorrhage and is associated with poor clinical outcomes. However, it is not clear whether high blood pressure is a cause of poor clinical outcome or solely represents a marker of severity. Although current guidelines recommend intensive blood pressure treatment (<140 mm Hg) in patients with intracerebral hemorrhage, 2 randomized clinical trials have failed to demonstrate a consistent clinical benefit from this approach, and new data suggest that intensive blood pressure treatment could be beneficial for some patients but detrimental for others. Intracerebral hemorrhage is a heterogenous disease, thus, a one-fit-all approach for blood pressure treatment may be suboptimal. Further research should concentrate on finding subgroups of patients more likely to benefit from aggressive blood pressure lowering, considering intracerebral hemorrhage etiology, ultra-early randomization, and risk markers of hematoma expansion on brain imaging.

Impact of Uncontrolled Hypertension at 3Months After Intracerebral Hemorrhage.

BackgroundSurvivors of intracerebral hemorrhage (ICH) are at high risk for recurrent stroke, which is associated with blood pressure control. Because most recurrent stroke events occur within 12 to 18 months of the index ICH, rapid blood pressure control is likely to be crucial. We investigated the frequency and prognostic impact of uncontrolled short‐term hypertension after ICH.Methods and ResultsWe analyzed data from Massachusetts General Hospital (n=1305) and the University of Hong Kong (n=523). We classified hypertension as controlled, undertreated, or treatment resistant at 3 months after ICH and determined the following: (1) the risk factors for uncontrolled hypertension and (2) whether hypertension control at 3 months is associated with stroke recurrence and mortality. We followed 1828 survivors of ICH for a median of 46.2 months. Only 9 of 234 (4%) recurrent strokes occurred before 3 months after ICH. At 3 months, 713 participants (39%) had controlled hypertension, 755 (41%) had undertreated hypertension, and 360 (20%) had treatment‐resistant hypertension. Black, Hispanic, and Asian race/ethnicity and higher blood pressure at time of ICH increased the risk of uncontrolled hypertension at 3 months (all P<0.05). Uncontrolled hypertension at 3 months was associated with recurrent stroke and mortality during long‐term follow‐up (all P<0.05).ConclusionsAmong survivors of ICH, >60% had uncontrolled hypertension at 3 months, with undertreatment accounting for the majority of cases. The 3‐month blood pressure measurements were associated with higher recurrent stroke risk and mortality. Black, Hispanic, and Asian survivors of ICH and those presenting with severe acute hypertensive response were at highest risk for uncontrolled hypertension.