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Objective: 2017 blood pressure (BP) categories focus on cardiac risk. We hypothesize that studying the balance between mechanisms that increase or decrease BP across the medical phenome will lead to new insights. We devised a classifier that uses BP measures to assign individuals to mutually exclusive categories centered in the upper (Htn), lower (Hotn) and middle (Naf) zones of the BP spectrum; and examined the epidemiologic and phenotypic patterns of these BP-categories., Methods: We classified a cohort of 832,560 deidentified electronic health records by BP-category; compared the frequency of BP-categories and four subtypes of Htn and Hotn by sex and age-decade; visualized the distributions of systolic, diastolic, mean arterial and pulse pressures stratified by BP-category; and ran Phenome-wide Association Studies (PheWAS) for Htn and Hotn. We paired knowledgebases for hypertension and hypotension and computed aggregate knowledgebase status (KB-status) indicating known associations. We assessed alignment of PheWAS results with KB-status for phecodes in the knowledgebase, and paired PheWAS correlations with KB-status to surface phenotypic patterns., Results: BP-categories represent distinct distributions within the multimodal distributions of systolic and diastolic pressure. They are centered in the upper, lower, and middle zones of mean arterial pressure and provide a different signal than pulse pressure. For phecodes in the knowledgebase, 85% of positive correlations align with KB-status. Phenotypic patterns for Htn and Hotn overlap for several phecodes and are separate for others. Our analysis suggests five candidates for hypothesis testing research, two where the prevalence of the association with Htn or Hotn may be under appreciated, three where mechanisms that increase and decrease blood pressure may be affecting one another's expression., Conclusion: PairedPheWAS methods may open a phenome-wide path to disentangling hypertension and chronic hypotension. Our classifier provides a starting point for assigning individuals to BP-categories representing the upper, lower, and middle zones of the BP spectrum. 4.7 % of individuals matching 2017 BP categories for normal, elevated BP or isolated hypertension, have diastolic pressure < 60. Research is needed to fine-tune the classifier, provide external validation, evaluate the clinical significance of diastolic pressure < 60, and test the candidate hypotheses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: William Stead and Lisa Bastarache report financial support was provided by National Center for Advancing Translational Sciences. Lisa Bastarache reports financial support was provided by National Library of Medicine. William Stead reports a relationship with National Heart Lung and Blood Institute that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

In the proximal tubules of the kidney, angiotensin II (ANG II) binds and activates ANG II type 1 (AT 1a ) receptors to stimulate proximal tubule Na + reabsorption, whereas atrial natriuretic peptide (ANP) binds and activates natriuretic peptide receptors (NPR A ) to inhibit ANG II-induced proximal tubule Na + reabsorption. These two vasoactive systems play important counteracting roles to control Na + reabsorption in the proximal tubules and help maintain blood pressure homeostasis. However, how AT 1a and NPR A receptors interact in the proximal tubules and whether natriuretic effects of NPR A receptor activation by ANP may be potentiated by deletion of AT 1 (AT 1a ) receptors selectively in the proximal tubules have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors, PT- Agtr1a -/- , to test the hypothesis that deletion of AT 1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower ( P < 0.01), fractional proximal tubule Na + reabsorption was significantly lower ( P < 0.05), whereas 24-h urinary Na + excretion was significantly higher, in PT- Agtr1a -/- mice than in wild-type mice ( P < 0.01). Infusion of ANP via osmotic minipump for 2 wk (0.5 mg/kg/day ip) further significantly decreased blood pressure and increased the natriuretic response in PT- Agtr1a -/- mice by inhibiting proximal tubule Na + reabsorption compared with wild-type mice ( P < 0.01). These augmented hypotensive and natriuretic responses to ANP in PT- Agtr1a -/- mice were associated with increased plasma and kidney cGMP levels ( P < 0.01), kidney cortical NPR A and NPR C mRNA expression ( P < 0.05), endothelial nitric oxide (NO) synthase (eNOS) and phosphorylated eNOS proteins ( P < 0.01), and urinary NO excretion ( P < 0.01). Taken together, the results of the present study provide further evidence for important physiological roles of intratubular ANG II/AT 1a and ANP/NPR A signaling pathways in the proximal tubules to regulate proximal tubule Na + reabsorption and maintain blood pressure homeostasis. NEW & NOTEWORTHY This study used a mutant mouse model with proximal tubule-selective deletion of angiotensin II (ANG II) type 1 (AT 1a ) receptors to study, for the first time, important interactions between ANG II/AT 1 (AT 1a ) receptor/Na + /H + exchanger 3 and atrial natriuretic peptide (ANP)/natriuretic peptide receptor (NPR A )/cGMP/nitric oxide signaling pathways in the proximal tubules. The results of the present study provide further evidence for important physiological roles of proximal tubule ANG II/AT 1a and ANP/NPR A signaling pathways in the regulation of proximal tubule Na + reabsorption and blood pressure homeostasis.

Background: Renal tubular dysgenesis (RTD) is a severe disorder with poor prognosis significantly impacting the proximal tubules of the kidney while maintaining an anatomically normal gross structure. The genetic origin of RTD, involving variants in the ACE, REN, AGT, and AGTR1 genes, affects various enzymes or receptors within the Renin angiotensin system (RAS). This condition manifests prenatally with oligohydramninos and postnatally with persistent anuria, severe refractory hypotension, and defects in skull ossification., Case Presentation: In this report, we describe a case of a female patient who, despite receiving multi vasopressor treatment, experienced persistent hypotension, ultimately resulting in early death at five days of age. While there was a history of parental consanguinity, no reported family history of renal disease existed. Blood samples from the parents and the remaining DNA sample of the patient underwent Whole Genome Sequencing (WGS). The genetic analysis revealed a rare homozygous loss of function variant (NM&#95;000685.5; c.415C > T; p.Arg139*) in the Angiotensin II Receptor Type 1 (AGTR1) gene., Conclusion: This case highlights the consequence of loss-of-function variants in AGTR1 gene leading to RTD, which is characterized by high mortality rate at birth or during the neonatal period. Furthermore, we provide a comprehensive review of previously reported variants in the AGTR1 gene, which is the least encountered genetic cause of RTD, along with their associated clinical features., (© 2024. The Author(s).)

Objective: Sacubitril/valsartan is a commonly used medicine for treating heart failure (HF) patients, but the treatment effects significantly vary. Neprilysin (NEP) and carboxylesterase 1 (CES1) play an important role in the efficacy of sacubitril/valsartan. The purpose of this study was to explore the relationship between NEP and CES1 gene polymorphisms and the efficacy and safety of sacubitril/valsartan treatment in HF patients., Methods: Genotyping of 10 single nucleotide polymorphisms (SNPs) of the NEP and CES1 genes in 116 HF patients was performed by the Sequenom MassARRAY method, and logistic regression and haplotype analysis were used to evaluate the associations between SNPs and the clinical efficacy and safety of sacubitril/valsartan in HF patients., Results: A total of 116 Chinese patients with HF completed the whole trial, and T variations in rs701109 in NEP gene were an independent risk factor (P = 0.013, OR = 3.292, 95% CI:1.287-8.422) for the clinical efficacy of sacubitril/valsartan. Furthermore, haplotype analysis of 6 NEP SNPs (including rs701109) was performed and showed that the CGTACC and TGTACC haplotypes were significantly associated with clinical efficacy (OR = 0.095, 95%CI: 0.012-0.723, P = 0.003; OR = 5.586, 95% CI: 1.621-19.248, P = 0.005). Moreover, no association was found between SNPs of other selected genes in terms of efficacy in HF patients, and no association was observed between SNPs and symptomatic hypotension., Conclusion: Our results suggest an association between rs701109 and sacubitril/valsartan response in HF patients. Symptomatic hypotension is not associated with the presence of NEP polymorphisms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hypertension or hypotension prevails as a comorbidity in patients with heart failure (HF). Although blood pressure (BP) is an important factor in managing the mortality of HF, the molecular mechanisms of changes in BP have not been clearly understood in cases of HF. We and others have demonstrated that a loss in PRDM16 causes hypertrophic cardiomyopathy, leading to HF. We aimed to determine whether BP is altered in mice that experience cardiac loss of Prdm16 and identify the underlying mechanism of BP-associated changes. BP decreased significantly only in female mice with a cardiac-null mutation of Prdm16 compared with controls, by an invasive protocol under anesthesia and by telemetric method during conscious, unrestrained status. Mice with a cardiac loss of Prdm16 had higher heart-to-body weight ratios and upregulated atrial natriuretic peptide, suggesting cardiac hypertrophy. Plasma aldosterone-to-renin activity ratios and plasma sodium levels decreased in Prdm16-deficient mice versus control. By RNA-seq and in subsequent functional analyses, Prdm16-null hearts were enriched in factors that regulate BP, including Adra1a, Nos1, Nppa, and Nppb. The inhibition of nitric oxide synthase 1 (NOS1) reverted the decrease in BP in cardiac-specific Prdm16 knockout mice. Mice with cardiac deficiency of Prdm16 present with hypotension and cardiac hypertrophy. Further, our findings suggest that the increased expression of NOS1 causes hypotension in mice with a cardiac-null mutation of Prdm16. These results provide novel insights into the molecular mechanisms of hypotension in subjects with HF and contribute to our understanding of how hypotension develops in patients with HF., Competing Interests: The authors have declared that no competing interests exist.

Anaesthesia with propofol is frequently associated with hypotension, which is at least partially attributable to increased nitric oxide (NO) formation derived from the activation of protein kinase C (PKC)/endothelial NO synthase (NOS3) axis. In this cross-sectional study, we tested whether PRKCA (which encodes PKCα) polymorphisms, or haplotypes, and interactions among PRKCA and NOS3 polymorphisms affect the hypotensive responses to propofol. We collected venous blood samples from 164 patients before and 10 min after propofol administration. Genotypes were determined by PCR and haplotype frequencies were estimated. Nitrite and NO x (nitrites+nitrates) levels were measured by using an ozone-based chemiluminescence assay and the Griess reaction, respectively. We used multifactor dimensionality reduction to test interactions among PRKCA and NOS3 polymorphisms. Propofol promoted enhanced blood pressure-lowering effects and increased nitrite levels in subjects carrying GA + AA genotypes for the rs16960228 and TC + CC genotypes for the rs1010544 PRKCA polymorphisms, and the CCG haplotype. Moreover, genotypes for the rs1010544 PRKCA polymorphism were associated with higher or lower blood pressure decreases in response to propofol depending on the genotypes for the rs2070744 NOS3 polymorphism. Our findings suggest that PRKCA genotypes and haplotypes impact the hypotensive responses to propofol, possibly by modifying NO bioavailability, and that PRKCA-NOS3 interactions modify the blood pressure-lowering effects of propofol., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 ( Panx1 -/- ) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1 -/- erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1 -/- ( n = 6) and WT ( n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1 -/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1 -/- ( n = 6) vs. WT ( n = 6) basally, and increased in WT but not Panx1 -/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1 -/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1 -/- ( n = 6) vs. WT mice ( n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1 -/- mice ( n = 8) was 82% lower than that from WT ( n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood. NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.

Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.

Background: Unless prevented, hypotension occurs in up to 80% of normotensive women undergoing spinal anaesthesia for caesarean delivery. Renin-angiotensin-aldosterone system genetic polymorphisms have been associated with hypertensive disease, but few studies investigated effects on blood pressure regulation under spinal anaesthesia. We postulated that these polymorphisms increased vasodilation and maternal hypotension during spinal anaesthesia., Methods: A retrospective secondary analysis of data from four prospective trials with similar inclusion/exclusion criteria evaluating phenylephrine/ephedrine delivery systems during spinal anaesthesia for elective caesarean delivery. Angiotensin type-1 receptor (AT1R) (A1166C), angiotensin-converting enzyme (ACE) (I/D), and aldosterone synthase CYP11B2 (C344T) polymorphisms were identified from stored specimens. The associations between the polymorphisms and hypotension (systolic blood pressure <80% of baseline), and vasopressor use, were determined by univariable and multivariable regression., Results: Of 556 patients, 378 (68.0%) had hypotension. The AC/CC genotypes of AT1R (A1166C) were associated with hypotension by univariable analysis (OR 2.70, 95% CI 1.38 to 5.28, P=0.004]) and multivariable analysis (OR 3.65, [95% CI 1.68 to 7.94, P=0.004]) after adjustment for age, race, intravenous fluid volume, and block height. No difference in vasopressor use or adverse maternal or fetal outcomes were noted. Baseline characteristics were similar, with the exception of higher baseline blood pressure, block height, and intravenous fluid volume in the hypotensive group. There was no significant association between ACE and CYP11B2 polymorphisms and hypotension., Conclusion: AC/CC genotypes of AT1R (A1166C) polymorphism were associated with maternal hypotension under spinal anaesthesia for caesarean delivery. An association with cardiovascular indices and high-risk parturients should be examined., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The zinc-finger protein ZBTB20 regulates development and metabolism in multiple systems, and is essential for postnatal survival in mice. However, its potential role in the cardiovascular system remains undefined. Here, we demonstrate that ZBTB20 is critically involved in the regulation of cardiac contractility and blood pressure in mice. At the age of 16 days, the relatively healthy Zbtb20-null mice exhibited hypotension without obvious change of heart rate or other evidence for heart failure. Moreover, Zbtb20 deletion led to a marked reduction in heart size, left ventricular wall thickness, and cell size of cardiomyocytes, which was largely proportional to the decreased body growth. Notably, echocardiographic and hemodynamic analyses showed that cardiac contractility was greatly impaired in the absence of ZBTB20. Mechanistically, ZBTB20 deficiency decreased cardiac ATP contents, and compromised the enzyme activity of mitochondrial complex I in heart as well as L-type calcium current density in cardiomyocytes. Furthermore, the developmental activation of some mitochondrial function-related genes was significantly attenuated in Zbtb20-null myocardium, which included Hspb8, Ckmt2, Cox7a1, Tfrc, and Ogdhl. Put together, these results suggest that ZBTB20 plays a crucial role in the regulation of heart development, energy metabolism, and contractility., (© 2020 Federation of American Societies for Experimental Biology.)

Autosomal recessively inherited pathogenic variants in genes associated with the renin-angiotensin-aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal., (© 2020 Wiley Periodicals LLC.)

Background: Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. Severe and ultimately lethal, DMD progresses relatively slowly in that patients become wheelchair bound only around age twelve with a survival expectancy reaching the third decade of life., Methods: The mildly-affected mdx mouse model of DMD, and transgenic DysΔMTB-mdx and Fiona-mdx mice expressing dystrophin or utrophin, respectively, were exposed to either mild (scruffing) or severe (subordination stress) stress paradigms and profiled for their behavioral and physiological responses. A subgroup of mdx mice exposed to subordination stress were pretreated with the beta-blocker metoprolol., Findings: Subordination stress caused lethality in ∼30% of mdx mice within 24 h and ∼70% lethality within 48 h, which was not rescued by metoprolol. Lethality was associated with heart damage, waddling gait and hypo-locomotion, as well as marked up-regulation of the hypothalamus-pituitary-adrenocortical axis. A novel cardiovascular phenotype emerged in mdx mice, in that scruffing caused a transient drop in arterial pressure, while subordination stress caused severe and sustained hypotension with concurrent tachycardia. Transgenic expression of dystrophin or utrophin in skeletal muscle protected mdx mice from scruffing and social stress-induced responses including mortality., Interpretation: We have identified a robust new stress phenotype in the otherwise mildly affected mdx mouse that suggests relatively benign handling may impact the outcome of behavioural experiments, but which should also expedite the knowledge-based therapy development for DMD., Funding: Greg Marzolf Jr. Foundation, Summer's Wish Fund, NIAMS, Muscular Dystrophy Association, University of Minnesota and John and Cheri Gunvalson Trust., Competing Interests: Declaration of Competing Interest The authors who have taken part in this study declare that they do not have anything to disclose regarding conflicts of interest concerning this manuscript., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute lung injury is a major complication of hemorrhagic shock and the required resuscitation with large volumes of crystalloid fluids and blood products. We previously identified a role of macrophage-derived chemokine (CCL22/MDC) pulmonary inflammation following hemorrhage and resuscitation. However, further details regarding the induction of CCL22/MDC and its precise role in pulmonary inflammation after trauma remain unknown. In the current study we used in vitro experiments with a murine alveolar macrophage cell line, as well as an in vivo mouse model of hemorrhage and resuscitation, to identify key regulators in CCL22/MDC production. We show that trauma induces expression of IFNγ, which leads to production of CCL22/MDC through a signaling mechanism involving p38 MAPK, NF-κB, JAK, and STAT-1. IFNγ also activates TNFα production by alveolar macrophages, potentiating CCL22/MDC production via an autocrine mechanism. Neutralization of IFNγ or TNFα with specific antibodies reduced histological signs of pulmonary injury after hemorrhage and reduced inflammatory cell infiltration into the lungs.

Cadmium (Cd) is a toxic heavy metal ubiquitous in the environment. Maternal exposure to Cd is associated with fetal growth restriction, trace element deficiencies, and congenital malformations. Cd exposure during adulthood is associated with cardiovascular disease (CVD); however, the effects of maternal Cd exposure on offspring cardiovascular development and disease are not well-understood. Utilizing a mouse model of maternal Cd exposure, we show that offspring born to Cd-exposed mothers have increased heart weights at birth and susceptibility to hypertension during adulthood. Despite inefficient maternal-fetal transfer of Cd, maternal Cd alters fetal levels of essential trace elements including a deficiency in iron, which is required for cardiovascular system development, oxygen homeostasis, and cellular metabolism. RNA-seq on newborn hearts identifies differentially expressed genes associated with maternal Cd exposure that are enriched for functions in CVD, hypertension, enlarged hearts, cellular energy, and hypoxic stress. We propose that a maternal Cd exposure-induced iron deficiency leads to altered cellular metabolic pathways and hypoxic conditions during fetal development; this stress may contribute to increased heart weight at birth and the programming of susceptibility to hypertension in adulthood. These studies will give insights into potential mechanisms through which maternal Cd exposure impacts cardiovascular development and disease.

Background: The alpha-adrenergic agonist phenylephrine is often used to treat hypotension during anesthesia. In clinical situations, low blood pressure may require prompt intervention by intravenous bolus or infusion. Differences in responsiveness to phenylephrine treatment are commonly observed in clinical practice. Candidate gene studies indicate genetic variants may contribute to this variable response., Methods: Pharmacological and physiological data were retrospectively extracted from routine clinical anesthetic records. Response to phenylephrine boluses could not be reliably assessed, so infusion rates were used for analysis. Unsupervised k-means clustering was conducted on clean data containing 4130 patients based on phenylephrine infusion rate and blood pressure parameters, to identify potential phenotypic subtypes. Genome-wide association studies (GWAS) were performed against average infusion rates in two cohorts: phase I (n = 1205) and phase II (n = 329). Top genetic variants identified from the meta-analysis were further examined to see if they could differentiate subgroups identified by k-means clustering., Results: Three subgroups of patients with different response to phenylephrine were clustered and characterized: resistant (high infusion rate yet low mean systolic blood pressure (SBP)), intermediate (low infusion rate and low SBP), and sensitive (low infusion rate with high SBP). Differences among clusters were tabulated to assess for possible confounding influences. Comorbidity hierarchical clustering showed the resistant group had a higher prevalence of confounding factors than the intermediate and sensitive groups although overall prevalence is below 6%. Three loci with P < 1 × 10 -6 were associated with phenylephrine infusion rate. Only rs11572377 with P = 6.09 × 10 -7 , a 3'UTR variant of EDN2, encoding a secretory vasoconstricting peptide, could significantly differentiate resistant from sensitive groups (P = 0.015 and 0.018 for phase I and phase II) or resistant from pooled sensitive and intermediate groups (P = 0.047 and 0.018)., Conclusions: Retrospective analysis of electronic anesthetic records data coupled with the genetic data identified genetic variants contributing to variable sensitivity to phenylephrine infusion during anesthesia. Although the identified top gene, EDN2, has robust biological relevance to vasoconstriction by binding to endothelin type A (ET A ) receptors on arterial smooth muscle cells, further functional as well as replication studies are necessary to confirm this association.

Objectives: Phenylephrine and salbutamol are drugs that are used widely to treat diseases/disorders, such as nasal congestion, hypotension, and asthma, in individuals of different age groups. Human cytosolic sulfotransferase (SULT) SULT1A3 has been shown to be critically involved in the metabolism of these therapeutic agents. This study was carried out to investigate the effects of single nucleotide polymorphisms of human SULT1A3 and SULT1A4 genes on the sulfation of phenylephrine and salbutamol by SULT1A3 allozymes., Materials and Methods: Wild-type and SULT1A3 allozymes, prepared previously by site-directed mutagenesis in conjunction with bacterial expression and affinity purification, were analyzed for sulfating activity using an established assay procedure., Results: Purified SULT1A3 allozymes, in comparison with the wild-type enzyme, showed differential sulfating activities toward phenylephrine and salbutamol. Kinetic studies showed further significant variations in their substrate-binding affinity and catalytic activity toward phenylephrine and salbutamol., Conclusion: The results obtained showed clearly the differential enzymatic characteristics of SULT1A3 allozymes in mediating the sulfation of phenylephrine and salbutamol. This information may contribute toward a better understanding of the pharmacokinetics of these two drugs in individuals with distinct SULT1A3 and/or SULT1A4 genotypes.

Vasodilatory shock in sepsis is caused by the failure of the vasculature to respond to vasopressors, which results in hypotension, multiorgan failure, and ultimately patient death. Recently, it was reported that CPI-17, a key player in the regulation of smooth muscle contraction, was downregulated by lipopolysaccharide (LPS) in mesenteric arteries concordant with vascular hypocontractilty. While Sp1 has been shown to activate CPI-17 transcription, it is unknown whether Sp1 is involved in LPS-induced smooth muscle CPI-17 downregulation. Here we report that tumor necrosis factor (TNF) was critical for LPS-induced smooth muscle CPI-17 downregulation. Mechanistically, we identified two GC boxes as a key TNF response element in the CPI-17 promoter and demonstrated that KLF4 was upregulated by TNF, competed with Sp1 for the binding to the GC boxes in the CPI-17 promoter, and repressed CPI-17 transcription through histone deacetylases (HDACs). Moreover, genetic deletion of TNF or pharmacological inhibition of HDACs protected mice from LPS-induced smooth muscle CPI-17 downregulation, vascular hypocontractility, hypotension, and mortality. In summary, these data provide a novel mechanism of the transcriptional control of CPI-17 in vascular smooth muscle cells under inflammatory conditions and suggest a new potential therapeutic strategy for the treatment of vasodilatory shock in sepsis., (Copyright © 2019 Zhao et al.)

Background: Postprandial hypotension (PPH) is a serious condition that has been shown to be an independent risk factor for falls, fractures and death., Purpose: The prevalence of this problem in older adults with a past history of falls has shown a wide variability in the literature; the present study seeks to examine how the frequency with which blood pressure is measured impacts the prevalence and severity of PPH., Methods: Older adults were recruited sequentially from a geriatric medicine falls clinic for meal testing (n=95). All subjects (mean age 77.5±0.7 years, 61±5% female) were fasting prior to each 90 min standardized meal test. A Finometer (Finapres Medical Systems BV) was used to monitor blood pressure. Beat-by-beat systolic (SBP) measures were averaged for 0.5, 1, 2, 3, 5, 6, 9, 10, 15, 18, 30, 45 and 90 min respectively during the meal test., Results: Using the original diagnostic method of checking mean blood pressure every 10 min resulted in a PPH prevalence of 42.1±5.1% in our population, with an overall range from 81.1±4.0% to 11.6±3.3% depending on the frequency of calculating SBP. The maximal observed postprandial decrease in SBP also showed a significant difference with blood pressure measurement frequency (p.

FURIN is a proprotein convertase subtilisin/kexin enzyme important in pro-renin receptor processing, and FURIN (furin, paired basic amino acid cleaving enzyme) variants are involved in multiple aspects of blood pressure (BP) regulation. Therefore, we examined associations among FURIN variants and the immediate blood pressure (BP) response to bouts of aerobic exercise, termed postexercise hypotension (PEH). Obese (30.9 ± 3.6 kg   m -2 ) Black- (n = 14) and White- (n = 9) adults 42.0 ± 9.8 year with hypertension (139.8 ± 10.4/84.6 ± 6.2 mmHg) performed three random experiments: bouts of vigorous (VIGOROUS) and moderate (MODERATE) intensity cycling and control. Subjects were then attached to an ambulatory BP monitor for 19 h. We performed deep-targeted exon sequencing with the Illumina TruSeq Custom Amplicon kit. FURIN genotypes were coded as the number of minor alleles (#MA) and selected for additional statistical analysis based upon Bonferonni or Benjamini-Yekutieli multiple testing corrected P-values under time-adjusted linear models for 19 hourly BP measurements. After VIGOROUS over 19 h, as FURIN #MA increased in rs12917264 (P = 2.4E-04) and rs75493298 (P = 6.4E-04), systolic BP (SBP) decreased 30.4-33.7 mmHg; and in rs12917264 (P = 1.6E-03) and rs75493298 (P = 9.7E-05), diastolic BP (DBP) decreased 17.6-20.3 mmHg among Blacks only. In addition, after MODERATE over 19 h in FURIN rs74037507 (P = 8.0E-04), as #MA increased, SBP increased 20.8 mmHg among Blacks only. Whereas, after MODERATE over the awake hours in FURIN rs1573644 (P = 6.2E-04), as #MA increased, DBP decreased 12.5 mmHg among Whites only. FURIN appears to exhibit intensity and race-dependent associations with PEH that merit further exploration among a larger, ethnically diverse sample of adults with hypertension., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

SPAK (Ste20/SPS1-related proline/alanine-rich kinase) has been recently identified as a protein kinase which targets the electroneutral cation-coupled chloride cotransporters and it stands out as a target for inhibition in novel anti-hypertensive agents. From this prospective, any information about physiological consequences of SPAK inhibition would be useful to better understand the efficacy and potential adverse effects of the SPAK-based anti-hypertensive therapy. Radiotelemetry was employed to continuously measure the parameters of blood pressure (mean arterial blood pressure, systolic blood pressure, and diastolic blood pressure), heart rate, and physical activity in SPAK knock-in (KI) mice and littermate controls for 24 h. For each parameter, the area under the curve (AUC) was calculated and compared between the SPAK KI mice and wild type mice. There was no statistically significant difference in the AUC of blood pressure parameters between SPAK KI and littermate mice. When mice were physically inactive, the AUCs for blood pressures were significantly lower in SPAK KI than in littermates. When physically active, blood pressures were significantly higher in SPAK KI than in littermates. The heart rate followed a similar pattern. The AUC of physical activity was significantly increased in SPAK KI mice when compared to littermates and the SPAK KI mice spent significantly less time in an inactive state and significantly more time in active states. Comparison between SPAK KI mice and unrelated wild type mice yielded similar results to the comparison between SPAK KI mice and littermates. We conclude that SPAK inhibition increases spontaneous locomotor activity, which has a significant effect on blood pressure., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Intake of ethanol (alcohol) affects cardiovascular function. Acute ethanol intake has been shown to lower blood pressure (BP) in hypertensive patients. The present study was undertaken to examine the effects and mechanisms of acute administration of ethanol on BP in hypertensive and normotensive rats. Ethanol was given by intraperitoneal (i.p.) injection in male spontaneously hypertensive rats (SHRs) and the normotensive Wistar-Kyoto rats (WKYs). BP responses were measured in free-moving conscious rats or in urethane-anesthetized rats. Inhibitors were applied by bilateral microinjection into the rostral ventrolateral medulla (RVLM). Nitric oxide (NO•) levels and glutamate levels were determined by nitrate and nitrite (NOx) analyzer and HPLC-ECD, respectively. Intraperitoneal (i.p.) injection of ethanol (1.6 g/kg) caused a significant decrease in BP in free-moving or in anesthetized SHRs but not in WKYs. A higher dose (3.2 g/kg) of ethanol decreased BP in both SHRs and WKYs, although the depressor responses in SHRs occurred significantly earlier than those in WKYs. The blood ethanol concentrations 60 min after injection were similar in SHRs and WKYs. Bilateral microinjection of nitric oxide synthase (NOS) inhibitors or glutamatergic NMDA receptor antagonists into the RVLM 5 min after administration of ethanol significantly inhibited the ethanol-induced depressor effects in SHRs. The levels of NOx and glutamate release in the RVLM following ethanol administration and the NOx content in the RVLM areas 30 min after administration were significantly increased in SHRs, but not in WKYs. Our results showed that SHRs were more sensitive to ethanol-induced hypotensive effects than WKYs because of augmentation of ethanol-induced expression of the glutamatergic NMDA receptor/NO• signal in the RVLM of SHRs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

STX1B is a gene that encodes syntaxin-1B. STX1B mutations have recently been implicated in fever-associated epilepsy syndromes. However, these have not previously been reported in sleep-related hypermotor epilepsy. A 20-year-old man with a strong family history of epilepsy was investigated in our epilepsy monitoring unit due to uncontrolled epilepsy, compatible with sleep-related hypermotor epilepsy. Electroclinical and polygraphic physiological recordings revealed left frontal epileptiform discharges and prominent peri-ictal hypotension. Normal MRI using an epilepsy protocol prompted a search for a genetic epilepsy, which revealed a likely pathogenic mutation in the STX1B gene. The patient remained seizure-free after treatment optimization with carbamazepine. This case suggests that a sleep-related hypermotor epilepsy phenotype can be associated with syntaxin-1B gene mutation, and testing for this gene should be considered in such patients. Furthermore, it may also be concluded that autonomic dysfunction, characterized by peri-ictal hypotension, can also occur in this discorder. [Published with video sequences on www.epilepticdisorders.com].

Rare variants, in particular renal salt handling genes, contribute to monogenic forms of hypertension and hypotension syndromes with electrolyte abnormalities. A study by Ji et al (2008) demonstrated this effect for rare loss-of-function coding variants in SLC12A3 (NCCT), SLC12A1 (NKCC2), and KCNJ1 (ROMK) that led to reduction of ∼6 mm Hg for SBP and ∼3 mm Hg for DBP among carriers in 2492 European ancestry Framingham Heart Study (FHS) subjects. These findings support a potentially large role for these variants in interindividual variation in systolic and diastolic blood pressure (SBP, DBP) in the population. The present study focuses on replicating the analyses completed by Ji et al to identify effects of rare variants in the population-based Atherosclerosis Risk in Communities (ARIC) study.We attempted to replicate the findings by Ji et al by applying their criteria to identify putative loss-of-function variants with allele frequency <0.001 and complete conservation across a set of orthologs, to exome sequencing data from 7444 European ancestry participants of the ARIC study.Although we failed to replicate the previous findings when applying their methods to the ARIC study data, we observed a similar effect when we restricted analyses to the subset of variants they observed.These results simultaneously support the utility of exome sequencing data for studying extremely rare coding variants in hypertension and underscore the need for improved filtering methods for identifying functional variants in human sequences.

Background: Glucocorticoids play an important role in endocrine control. The association of glucocorticoid receptor (GR) gene polymorphisms with altered sensitivity to glucocorticoid therapy has been reported in adults. However, there are few such reports in infants. The present study analyzed the prevalence of four GR polymorphisms in preterm infants born before 30 weeks of gestation and determined the associations between these polymorphisms and clinical outcomes in the infants., Methods: Totally, 41 preterm infants born at two hospitals in Fukushima were retrospectively screened for the presence of four GR gene polymorphisms, using a TaqMan single-nucleotide polymorphism genotyping assay. The effect of GR gene polymorphisms on clinical outcomes during hospitalization was evaluated. The following primary clinical outcomes were assessed: refractory hypotension in the acute phase and/or severe bronchopulmonary dysplasia, maximum dopamine and dobutamine doses administered, and total hydrocortisone dose administered in the first 48 h of life. Multivariate analysis with logistic regression was used to assess the association between clinical factors and refractory hypotension., Results: Of the four GR polymorphisms, only the BclI polymorphism was detected. The genotype distribution was as follows: C/C, 33; C/G, 8; and G/G, 0 infants. Significant differences were observed between the C/C and C/G genotypes with respect to the following variables: refractory hypotension (6% vs. 50%), dopamine dose [3.0 (2.0-4.0) vs. 4.8 (4.0-7.5) μg/kg/min], dobutamine dose [2.4 (0.0-3.6) vs. 4.0 (0-10.0) μg/kg/min], and total hydrocortisone dose administered in the first 48 h of life [2.0 (0-10.0) vs. 6.0 (0-12.0) mg/kg]. Multivariate analysis showed that the BclI genotype (C/C) was significantly less associated with refractory hypotension in the acute phase (odds ratio, 0.008; 95% confidence interval, 0.000-0.371; p = 0.013)., Conclusion: The incidence of refractory hypotension in infants with the C/C genotype was initially expected to be higher than that in infants with the C/G genotype. However, the results of this study were rather different from what we originally expected. The suppressive effect of antenatal steroid use on the HPA axis of the preterm infants with the BclI variant may be associated with refractory hypotension in the acute phase., (Copyright © 2017. Published by Elsevier B.V.)

Aim: Protein kinase Cα (PKCα) is a critical regulator of multiple cell signaling pathways including gene transcription, posttranslation modifications and activation/inhibition of many signaling kinases. In regards to the control of blood pressure, PKCα causes increased vascular smooth muscle contractility, while reducing cardiac contractility. In addition, PKCα has been shown to modulate nephron ion transport. However, the role of PKCα in modulating mean arterial pressure (MAP) has not been investigated. In this study, we used a whole animal PKCα knock out (PKC KO) to test the hypothesis that global PKCα deficiency would reduce MAP, by a reduction in vascular contractility., Methods: Radiotelemetry measurements of ambulatory blood pressure (day/night) were obtained for 18 h/day during both normal chow and high-salt (4%) diet feedings. PKCα mice had a reduced MAP, as compared with control, which was not normalized with high-salt diet (14 days). Metabolic cage studies were performed to determine urinary sodium excretion., Results: PKC KO mice had a significantly lower diastolic, systolic and MAP as compared with control. No significant differences in urinary sodium excretion were observed between the PKC KO and control mice, whether fed normal chow or high-salt diet. Western blot analysis showed a compensatory increase in renal sodium chloride cotransporter expression. Both aorta and mesenteric vessels were removed for vascular reactivity studies. Aorta and mesenteric arteries from PKC KO mice had a reduced receptor-independent relaxation response, as compared with vessels from control. Vessels from PKC KO mice exhibited a decrease in maximal contraction, compared with controls., Conclusion: Together, these data suggest that global deletion of PKCα results in reduced MAP due to decreased vascular contractility.

Objectives: The prevalence of responsiveness to initial fluid challenge among hypotensive sepsis patients is unclear. To avoid fluid overload, and unnecessary treatment, it is important to differentiate these phenotypes. We aimed to 1) determine the proportion of hypotensive sepsis patients sustaining favorable hemodynamic response after initial fluid challenge, 2) determine demographic and clinical risk factors that predicted refractory hypotension, and 3) assess the association between timeliness of fluid resuscitation and refractoriness., Design: Secondary analysis of a prospective, multisite, observational, consecutive-sample cohort., Setting: Nine tertiary and community hospitals over 1.5 years., Patients: Inclusion criteria 1) suspected or confirmed infection, 2) greater than or equal to two systemic inflammatory response syndrome criteria, 3) systolic blood pressure less than 90 mm Hg, greater than 40% decrease from baseline, or mean arterial pressure less than 65 mm Hg., Measurements and Main Results: Sex, age, heart failure, renal failure, immunocompromise, source of infection, initial lactate, coagulopathy, temperature, altered mentation, altered gas exchange, and acute kidney injury were used to generate a risk score. The primary outcome was sustained normotension after fluid challenge without vasopressor titration. Among 3,686 patients, 2,350 (64%) were fluid responsive. Six candidate risk factors significantly predicted refractoriness in multivariable analysis: heart failure (odds ratio, 1.43; CI, 1.20-1.72), hypothermia (odds ratio, 1.37; 1.10-1.69), altered gas exchange (odds ratio, 1.33; 1.12-1.57), initial lactate greater than or equal to 4.0 mmol/L (odds ratio, 1.28; 1.08-1.52), immunocompromise (odds ratio, 1.23; 1.03-1.47), and coagulopathy (odds ratio, 1.23; 1.03-1.48). High-risk patients (≥ three risk factors) had 70% higher (CI, 48-96%) refractory risk (19% higher absolute risk; CI, 14-25%) versus low-risk (zero risk factors) patients. Initiating fluids in greater than 2 hours also predicted refractoriness (odds ratio, 1.96; CI, 1.49-2.58). Mortality was 15% higher (CI, 10-18%) for refractory patients., Conclusions: Two in three hypotensive sepsis patients were responsive to initial fluid resuscitation. Heart failure, hypothermia, immunocompromise, hyperlactemia, and coagulopathy were associated with the refractory phenotype. Fluid resuscitation initiated after the initial 2 hours more strongly predicted refractoriness than any patient factor tested.

Immunoglobulin E (IgE) has been suggested as a risk factor for allergy-induced low blood pressure, which has not been well explained in molecular details. Our current study shows a novel mechanism involving IgE, FcɛR1, miRNA-212-5p (miR-212-5p), and sodium/calcium exchanger protein 1(NCX1) for asthma to induce hypotension. In arterial smooth muscle cells, IgE up-regulated miR212-5p via its receptor FcɛR1, which resulted in down-regulation of NCX1 that is a regulating factor for blood pressure. In mice, asthma induced hypotension by interfering vasoconstrictive function; knockout of FcɛR1 kept the asthmatic mice from developing hypotension; knock-down of miR-212-5p in asthmatic mice resulted in a significant restoration of blood pressure. In human, asthma and IgE were positively correlated with hypotension in cohort study on NIH epidemiological data. This study suggests a novel therapeutic target (miR-212-5p) for treatment of asthma-induced hypotension., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a major deubiquitinating enzyme of the nervous system and associated with the development of neurodegenerative diseases. We have previously shown that UCH-L1 is found in tubular and parietal cells of the kidney and is expressed de novo in injured podocytes. Since the role of UCH-L1 in the kidney is unknown we generated mice with a constitutive UCH-L1-deficiency to determine its role in renal health and disease. UCH-L1-deficient mice developed proteinuria, without gross changes in glomerular morphology. Tubular cells, endothelial cells, and podocytes showed signs of stress with an accumulation of oxidative-modified and polyubiquitinated proteins. Mechanistically, abnormal protein accumulation resulted from an altered proteasome abundance leading to decreased proteasomal activity, a finding exaggerated after induction of anti-podocyte nephritis. UCH-L1-deficient mice exhibited an exacerbated course of disease with increased tubulointerstitial and glomerular damage, acute renal failure, and death, the latter most likely a result of general neurologic impairment. Thus, UCH-L1 is required for regulated protein degradation in the kidney by controlling proteasome abundance. Altered proteasome abundance renders renal cells, particularly podocytes and endothelial cells, susceptible to injury., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

We aimed to identify the potential genes related to blood pressure regulation and screen target genes for high blood pressure (BPH) and low blood pressure (BPL) treatment. The GSE19817 microarray dataset, which included the aorta, liver, heart, and kidney samples from BPH, BPL, and normotensive mice, was downloaded from the Gene Expression Omnibus. Principal component analysis (PCA) was performed based on the entire expression profile. Differentially expressed genes (DEGs) were screened, followed by pathway enrichment analysis. Finally, gene regulatory networks were constructed based on BPH-related and BPL-related DEGs in the aorta, liver, heart, and kidney samples. As a result, DEGs were screened within their respective tissues due to high heterogeneity of different tissues. Totally, 2,726 BPH-related DEGs and 2,472 BPL-related DEGs were screened, which were mainly enriched in pathways such as immune response. The topology data of gene regulatory networks constructed by DEGs in the heart, kidney, and liver were similar than that in aorta. Finally, among BPH-related DEGs, Sept6 and Pigx were found in the top 10 differentially regulated DEGs by comparing the BPH-related DEGs of the aorta with the DEGs of the other 3 tissues in the regulatory network. Although among the top 10 differentially regulated BPL-related DEGs, no common differentially regulated DEGs were found, Wif1, Urb2, and Gtf2ird1 were found among the top ten DEGs in the three tissues other than the kidney tissue. Sept6 and Pigx might participate in the pathogenesis of BPH, whereas Gtf2ird1, Urb2, and Wif1 might be critical target genes for BPL treatment.

Introduction: Cardiac abnormalities are observed frequently after aneurysmal subarachnoid hemorrhage (aSAH). A subset of aSAH patients develops neurogenic cardiomyopathy, likely induced by catecholamine excess. Genetic polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been linked to decreased nitric oxide (NO) levels, coronary artery spasm, and myocardial infarction. The role of the eNOS single nucleotide polymorphism (SNP) -786 T/C in cardiac instability following aSAH has not been previously investigated., Methods: From 2012 to 2015, aSAH patients were prospectively enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study at two academic institutions. Blood samples were used to assess the eNOS SNP -786 T/C rs2070744 through 5'exonuclease (Taqman) genotyping assays. Associations between this polymorphism and cardiac instability following aSAH were analyzed., Results: Multivariable analysis demonstrated a dominant effect of the C allele of eNOS SNP -786 T/C on cardiac instability in patients with aSAH. A lower Glasgow Coma Scale score and a history of ischemic vascular disease were also associated with cardiac instability. Furthermore, cardiac instability independently predicted poor functional outcome upon discharge from the hospital., Conclusions: The C allele of the eNOS SNP -786 T/C was independently associated with an increased risk for cardiac instability following aSAH. Cardiac instability itself was a risk factor for an unfavorable functional outcome upon discharge from the hospital., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.

Reduced renal Na + reabsorption along with restricted dietary Na + depletes intravascular plasma volume which can then result in hypotension. Whether hypotension occurs and the magnitude of hypotension depends in part on compensatory angiotensin II-mediated increased vascular resistance. We investigated whether the ability of vascular resistance to mitigate the hypotension was compromised by decreased contractile reactivity. In vitro reactivity was investigated in aorta from mouse models of reduced renal Na + reabsorption and restricted dietary Na + associated with considerable hypotension and renin-angiotensin system activation: (1) the Na + -Cl - -Co-transporter (NCC) knockout (KO) with Na + restricted diet (0.1%, 2 weeks) and (2) the relatively more severe pendrin (apical chloride/bicarbonate exchanger) and NCC double KO. Contractile sensitivity to KCl, phenylephrine, and/or U46619 remained unaltered in aorta from both models. Maximal KCl and phenylephrine contraction expressed as force/aorta length from NCC KO with Na + -restricted diet remained unaltered, while in pendrin/NCC double KO were reduced to 49 and 64%, respectively. Wet weight of aorta from NCC KO with Na + -restricted diet remained unaltered, while pendrin/NCC double KO was reduced to 67%, consistent with decreased medial width determined with Verhoeff-Van Gieson stain. These findings suggest that hypotension associated with severe intravascular volume depletion, as the result of decreased renal Na + reabsorption, may in part be due to decreased contractile reactivity as a consequence of reduced vascular hypertrophy.

Background: Arterial hypotension is frequent in patients undergoing anesthesia and may aggravate the outcome. Common genetic variations may influence the cardiovascular response to anesthesia. In this retrospective cohort study, we tested whether variation in the gene encoding the β2-adrenergic receptor (ADRB2) influences perioperative arterial blood pressure and consequently the use of vasopressors., Methods: Five hundred seventy-one Danish Caucasians undergoing neurosurgery were genotyped for 5 marker single-nucleotide polymorphisms (SNPs) within ADRB2 (Gly16Arg, Gln27Glu, Thr164Ile, Arg175Arg, and Gly351Gly). A pairwise tagging principle was used to identify ADRB2 haplotypes. Mean arterial blood pressure (MAP) was recorded in the supine awake state and, together with administration of vasopressors (ephedrine and/or phenylephrine), for 30 minutes after induction of general anesthesia (sevoflurane/remifentanil or propofol/remifentanil)., Results: Four hundred thirteen (72%) patients received ephedrine and/or phenylephrine. Only baseline MAP (P < 0.001) and the Arg175Arg SNP (P = 0.01) were associated with nadir perioperative MAP. The Gly16Arg SNP but no other SNPs showed a trend toward an association with the amount of vasopressors used during anesthesia with Arg16 homozygotes receiving less ephedrine equivalents. The Arg16-Gln27-Thr164-Arg175-Gly351 haplotype was associated with approximately 13% lower vasopressor requirements than the most common Gly16-Glu27-Thr164-Arg175-Gly351 haplotype (P = 0.01)., Conclusions: Gly16 carriers received larger amounts of vasopressor compared with Arg16 homozygotes. This corresponds to previous studies demonstrating that the Gly16 allele in ADRB2 is associated with vasodilation and high cardiac output.

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.

Objective: Palmitoylation, the reversible addition of the lipid palmitate to a cysteine, can alter protein localization, stability, and function. The ZDHHC family of protein acyl transferases catalyzes palmitoylation of numerous proteins. The role of ZDHHC enzymes in intact tissue and in vivo is largely unknown. Herein, we characterize vascular functions in a mouse that expresses a nonfunctional ZDHHC21 (F233Δ)., Approach and Results: Physiological studies of isolated aortae and mesenteric arteries from F233Δ mice revealed an unexpected defect in responsiveness to phenylephrine, an α1 adrenergic receptor agonist. In vivo, F233Δ mice displayed a blunted response to infusion of phenylephrine, and they were found to have elevated catecholamine levels and elevated vascular α1 adrenergic receptor gene expression. Telemetry studies showed that the F233Δ mice were tachycardic and hypotensive at baseline, consistent with diminished vascular tone. In biochemical studies, ZDHHC21 was shown to palmitoylate the α1D adrenoceptor and to interact with it in a molecular complex, thus suggesting a possible molecular mechanism by which the receptor can be regulated by ZDHHC21., Conclusions: Together, the data support a model in which ZDHHC21 F233Δ diminishes the function of vascular α1 adrenergic receptors, leading to reduced vascular tone, which manifests in vivo as hypotension and tachycardia. This is to our knowledge the first demonstration of a ZDHHC isoform affecting vascular function in vivo and identifies a novel molecular mode of regulation of vascular tone and blood pressure., (© 2015 American Heart Association, Inc.)

Objective: Endothelium-derived nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) play important roles in modulating vascular tone in a distinct vessel size-dependent manner; NO plays a dominant role in conduit arteries and EDH in resistance vessels. We have recently demonstrated that endothelial NO synthase (eNOS) is functionally suppressed in resistance vessels through caveolin-1 (Cav-1)-dependent mechanism, switching its function from NO to EDH/hydrogen peroxide generation in mice. Here, we examined the possible importance of the physiological balance between NO and EDH in cardiovascular homeostasis., Approach and Results: We used 2 genotypes of mice in which eNOS activity is genetically upregulated; Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice. Isometric tension recordings and Langendorff experiments with isolated perfused hearts showed that NO-mediated relaxations were significantly enhanced, whereas EDH-mediated relaxations were markedly reduced in microcirculations. Importantly, impaired EDH-mediated relaxations of small mesenteric arteries from Cav-1-KO mice were completely rescued by crossing the mice with those with endothelium-specific overexpression of Cav-1. Furthermore, both genotypes showed altered cardiovascular phenotypes, including cardiac hypertrophy in Cav-1-KO mice and hypotension in eNOS-Tg mice. Finally, we examined cardiac responses to chronic pressure overload by transverse aortic constriction in vivo. When compared with wild-type mice, both Cav-1-KO and eNOS-Tg mice exhibited reduced survival after transverse aortic constriction associated with accelerated left ventricular systolic dysfunction, reduced coronary flow reserve, and enhanced myocardial hypoxia., Conclusions: These results indicate that excessive endothelium-derived NO with reduced EDH impairs cardiovascular homeostasis in mice in vivo., (© 2015 American Heart Association, Inc.)

Background: Maternal hypotension after spinal anesthesia for cesarean delivery is common. Many studies performed on the b2-adrenoceptor (b2AR) gene variants and their association with vasopressor requirements during and after neuroaxial block have contradictory conclusions., Objectives: The aim of the study was to evaluate the influence of the b2AR in codons 16 and 27 on the incidence of maternal hypotension and ephedrine consumption after spinal anesthesia for cesarean delivery in an Arab ethnic group., Design: A prospective gene association study., Setting: Jordan University Hospital from 1 July 2013 to 31 January 2014., Patients and Methods: We enrolled parturients who underwent cesarean delivery under spinal anesthesia. Spinal anesthesia was performed with 10 mg plain bupivacaine along with 25 micro g fentanyl. Hypotension was treated with ephedrine and the amount consumed in the first 30 minutes after spinal anesthesia was calculated. The b2AR genotype at codons 16 and 27 was determined. We studied the correlation between the b2AR genotype and the amount of ephedrine consumption after spinal anesthesia., Main Outcome Measures: Amount of ephedrine used., Results: Of 250 patients enrolled in the study, genotype and clinical data were available for 234 cases. Ephedrine was used in 94% of patients. There was a significant effect of b2AR genotype on ephedrine dose in the first 30 minutes after spinal anesthesia in codon 16 and 27. Arg16 homozygotes received less ephedrine (14.0 [11.2] mg) than Gly16 homozygotes (38.6 [25.7] mg) and Arg16Gly heterozygotes (33.42 [22.70] mg) (P < .0001). Gln27 homozygotes received less ephedrine (18.2 [12.8] mg) than Glu 27 homozygotes (47.5 [27.0] mg) and Gln27Glu heterozygotes (48.2 [23.7] mg). (P < .0001)., Conclusion: In an Arab ethnic group, the b2AR gene has a role in maternal hypotension after spinal anesthesia. The Gly16 and Glu27 alleles have a higher incidence of arterial hypotension and required a greater amount of vasopressor to treat hypotension compared with homozygous Arg16 and Gln27 carriers., Limitations: Fasting time and hydration protocol, the use of a fixed dose of ephedrine, and relatively small sample size.

The rate of neonatal sepsis is not reduced varying inversely proportional to the gestational age at birth, and may reach 60% in the most immature infants. The high mortality rate of this disease and adverse neurological effects are associated with the development of cardiovascular changes and shock. The main leadership role in the regulation of blood pressure and blood volume in the body plays a renin-angiotensin system. Synthesis of angiotensin-converting enzyme is regulated by the ACE gene. The aim of the study was to identify and analyze the associations between the development of arterial hypotension in premature infants and insertion-deletion (I/D) polymorphism of the ACE gene. We conducted a prospective cohort study, which included 118 prematurely born children with early onset bacterial infections (n=57 with clinical manifestations in the form of hypotension, n=61 without hypotension). Both groups were genotyped to determine the insertion-deletion polymorphism ACE gene. We compared the clinical, laboratory and instrumental parameters in premature infants with hypotension and II, ID, DD genotype of the ACE gene. Also an analysis of the associations between different genotypes of ACE gene and the development of arterial hypotension in prematurely born children was conducted. The distribution of neonates in relation to the three polymorphic variants of ACE gene with respect to I/D polymorphism was identical among the study groups. The study found that children with a variety of I/D polymorphic variants of ACE gene had no significant differences in hemodynamic parameters. The rate of hemodynamic support use did not differ in both groups. The study of the associations between the ACE gene polymorphism and major ultrasound, Doppler indices that characterized both systemic and organ hemodynamics, revealed no significant differences in mean values of all the criteria that have been studied. It can be concluded no effect of I/D polymorphism of ACE gene on the occurrence of hemodynamic disorders in premature born children with early onset bacterial infections.

Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.

Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3'-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (~1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (~2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3'-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3'-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈ 58,000-96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Defects of the gap junction protein connexin 40 (Cx40) in renin-secreting cells (RSCs) of the kidney lead to a shift of the localization of RSCs from the media layer of afferent arterioles to the periglomerular interstitium. The dislocation of RSCs goes in parallel with elevated plasma renin levels, impaired pressure control of renin secretion, and hypertension. The reasons for the extravascular shift of RSCs and the blunted pressure regulation of renin secretion caused by the absence of Cx40 are still unclear. We have therefore addressed the question if Cx40 is essential for the metaplastic transformation of preglomerular vascular smooth muscle cells (SMCs) into RSCs and if Cx40 is essential for the pressure control of renin secretion from RSCs located in the media layer of afferent arterioles. For our study, we used mice lacking the angiotensin II type 1A (AT1A) receptors, which display a prominent and reversible salt-sensitive metaplastic transformation of SMCs into RSCs. This mouse line was crossed with Cx40-deficient mice to obtain AT1A and Cx40 double deleted mice. The kidneys of AT1A (-/-)Cx40(-/-) mice kept on normal salt (0.3 %) displayed RSCs both in the inner media layer of preglomerular vessels and in the periglomerular interstitium. In contrast to hypotensive AT1A (-/-) (mean bp syst 112 mmHg) and hypertensive Cx40(-/-) (mean bp syst 160 mmHg) mice AT1A (-/-)Cx40(-/-) mice were normotensive(mean bp syst 130 mmHg). Pressure regulation of renin secretion from isolated kidneys was normal in AT1A (-/-) mice, but was absent in AT1A (-/-)Cx40(-/-) mice alike in Cx40(-/-) mice. Low-salt diet (0.02 %) increased RSC numbers in the media layer, whilst high-salt diet (4 %) caused disappearance of RSCs in the media layer but not in the periglomerular interstitium. Blood pressure was clearly salt sensitive both in AT1A (-/-) and in AT1A (-/-)Cx40(-/-) mice but was shifted to higher pressure values in the latter genotype. Our data indicate that Cx40 is not a requirement for intramural vascular localization of RSCs nor for reversible metaplastic transformation of SMCs into RSCs. Therefore, the ectopic localization of RSCs in Cx40(-/-) kidneys is more likely due to a disturbed intercellular communication rather than being the result of chronic overactivation of the renin-angiotensin-aldosterone system or hypertension. Moreover, our findings suggest that Cx40 is a requirement for the pressure control of renin secretion irrespective of the localization of RSCs.

The role of serotonin in the hemodynamic response to blood loss remains controversial. Caudal raphe serotonin neurons are activated during hypotensive hemorrhage, and their destruction attenuates sympathetic increases following blood loss in unanesthetized rats. Caudal raphe neurons provide serotonin-positive projections to the nucleus tractus solitarii (NTS), and disruption of serotonin-positive nerve terminals in the NTS attenuates sympathetic recovery following hemorrhage. Administration of 5-HT1A-receptor agonists following hemorrhage augments sympathetic-mediated increases in venous tone and tissue hypoxia. These findings led us to hypothesize that severe blood loss promotes activation of 5-HT1A receptors in the NTS, which facilitates sympathetic recovery and peripheral tissue perfusion. Here, we developed an adeno-associated viral vector encoding an efficacious small hairpin RNA sequence targeting the rat 5-HT1A receptor. Unanesthetized rats subjected to NTS injection of the anti-rat 5-HT1A small hairpin RNA-encoding vector 4 wk prior showed normal blood pressure recovery, but an attenuated recovery of renal sympathetic nerve activity (-6.4 ± 12.9 vs. 42.6 ± 15.6% baseline, P < 0.05) 50 min after 21% estimated blood volume withdrawal. The same rats developed increased tissue hypoxia after hemorrhage, as indicated by prolonged elevations in lactate (2.77 ± 0.5 vs. 1.34 ± 0.2 mmol/l, 60 min after start of hemorrhage, P < 0.05). 5-HT1A mRNA levels in the commissural NTS were directly correlated with renal sympathetic nerve activity (P < 0.01) and inversely correlated with lactate (P < 0.05) 60 min after start of hemorrhage. The data suggest that 5-HT1A receptors in the commissural NTS facilitate tissue perfusion after blood loss likely by increasing sympathetic-mediated venous return., (Copyright © 2015 the American Physiological Society.)

We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820&#95;821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition., (© 2015 Wiley Periodicals, Inc.)

Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension., (© 2015 American Heart Association, Inc.)

Salt retention or salt deficit has a bearing on the body fluid volume. Both states are clinically difficult to recognize and quantitate. Salt deficit is particularly cumbersome in that regard since orthostatic blood pressure, heart rate changes, and simple physical inspection are inaccurate and unreliable. Salt deficit can be acute such as after hemorrhage or massive diarrhea, or more chronic as observed in Addison's disease, failure of renal sodium chloride transporters, drug-related effects, or distal nephron disease. Molecular genetics has given us important new insights into salt deficit syndromes. Recent recognition of a novel sodium storage compartment involving sodium binding to proteoglycans adds to the overall complexity of these syndromes.

Considerably, variability in the clinical response to inotropic agents is observed and could be explained partially by the genetic variants, such as single-nucleotide polymorphism (SNP) in genes encoding for enzymes implicated in catecholamines synthesis, metabolism, storage and release or in the signaling pathway. This review highlights the potential effect of pharmacogenetics studies in hemodynamic response and identified 11 SNPs that could be relevant to explain the high variability drug response for a same dose. Cardiovascular instability, such as hypotension, is one of the premature birth complications. The pharmacogenetics studies evaluating these SNP may be useful to better understand the clinical outcome, particularly in this population.

Vascular smooth muscle cells (vSMCs) are key in the regulation of blood pressure and the engagement of vascular pathologies, such as hypertension, arterial remodeling, and neointima formation. The role of the Rac1 GTPase in these cells remains poorly characterized. To clarify this issue, we have utilized genetically engineered mice to manipulate the signaling output of Rac1 in these cells at will using inducible, Cre-loxP-mediated DNA recombination techniques. Here, we show that the expression of an active version of the Rac1 activator Vav2 exclusively in vSMCs leads to hypotension as well as the elimination of the hypertension induced by the systemic loss of wild-type Vav2. Conversely, the specific depletion of Rac1 in vSMCs causes defective nitric oxide vasodilation responses and hypertension. Rac1, but not Vav2, also is important for neointima formation but not for hypertension-driven vascular remodeling. These animals also have allowed us to dismiss etiological connections between hypertension and metabolic disease and, most importantly, identify pathophysiological programs that cooperate in the development and consolidation of hypertensive states caused by local vascular tone dysfunctions. Finally, our results suggest that the therapeutic inhibition of Rac1 will be associated with extensive cardiovascular system-related side effects and identify pharmacological avenues to circumvent them., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

In our previous study, we demonstrated that Xuebijing (XBJ), a traditional Chinese medicine, attenuates hypotension in rats suffering from heatstroke (HS). However, the underlying mechanisms have not yet been fully elucidated. Thus, the current study was carried out to investigate the mechanisms underlying the effects of XBJ on hypotension n rats suffering from HS. For this purpose, 72 anesthetized rats were randomized into 3 groups and intravenously injected twice daily for 3 days with XBJ (4 ml/kg body weight, XBJ group) or phosphate‑buffered saline (PBS) (HS and sham-operated groups). Models of HS were established in the HS and XBJ groups by placing the rats in a simulated climate chamber with a temperature of 40˚C and a humidity of 60%. Rectal temperature, arterial pressure and heart rate were monitored and recorded. Angiotensin Ⅱ (Ang Ⅱ) levels were increased during HS (shown by ELISA), and XBJ had no apparent effect on Ang Ⅱ levels. The levels of Ang Ⅱ type 1 (AT1) receptor surface expression and AT1 receptor-associated protein 1 (Arap1) were decreased during HS; however, these effects were attenuated by pre-treatment with XBJ (shown by RT-qPCR and western blot analysis). For in vitro experiments, rat macrophages pre-treated with XBJ were stimulated with lipopolysaccharide (LPS). Pre-treatment with XBJ induced a marked inhibitory effect on the release of pro-inflammatory cytokines in the LPS-stimulated macrophages. Furthermore, XBJ inhibited the activation of nuclear factor κB (NF-κB) induced by LPS in the macrophages. Taken together, our data demonstrate that XBJ promotes Arap1 expression by inhibiting the activation of the NF-κB signaling pathway and the release of pro-inflammatory cytokines, which may be the molecular mechanisms through which XBJ alleviates blood pressure reduction in rats suffering from HS.