Evidence That Binding of Cyclic GMP to the Extracellular Domain of NKA (Sodium-Potassium ATPase) Mediates Natriuresis.

BACKGROUND: Extracellular renal interstitial guanosine cyclic 3',5'-monophosphate (cGMP) inhibits renal proximal tubule (RPT) sodium (Na+) reabsorption via Src (Src family kinase) activation. Through which target extracellular cGMP acts to induce natriuresis is unknown. We hypothesized that cGMP binds to the extracellular α1-subunit of NKA (sodium-potassium ATPase) on RPT basolateral membranes to inhibit Na+ transport similar to ouabain-a cardiotonic steroid. METHODS: Urine Na+ excretion was measured in uninephrectomized 12-week-old female Sprague-Dawley rats that received renal interstitial infusions of vehicle (5% dextrose in water), cGMP (18, 36, and 72 µg/kg per minute; 30 minutes each), or cGMP+rostafuroxin (12 ng/kg per minute) or were subjected to pressure-natriuresis±rostafuroxin infusion. Rostafuroxin is a digitoxigenin derivative that displaces ouabain from NKA. RESULTS: Renal interstitial cGMP and raised renal perfusion pressure induced natriuresis and increased phosphorylated SrcTyr416 and Erk 1/2 (extracellular signal-regulated protein kinase 1/2)Thr202/Tyr204; these responses were abolished with rostafuroxin coinfusion. To assess cGMP binding to NKA, we performed competitive binding studies with isolated rat RPTs using bodipy-ouabain (2 µM)+cGMP (10 µM) or rostafuroxin (10 µM) and 8-biotin-11-cGMP (2 µM)+ouabain (10 µM) or rostafuroxin (10 µM). cGMP or rostafuroxin reduced bodipy-ouabain fluorescence intensity, and ouabain or rostafuroxin reduced 8-biotin-11-cGMP staining. We cross-linked isolated rat RPTs with 4-N3-PET-8-biotin-11-cGMP (2 µM); 8-N3-6-biotin-10-cAMP served as negative control. Precipitation with streptavidin beads followed by immunoblot analysis showed that RPTs after cross-linking with 4-N3-PET-8-biotin-11-cGMP exhibited a significantly stronger signal for NKA than non-cross-linked samples and cross-linked or non-cross-linked 8-N3-6-biotin-10-cAMP RPTs. Ouabain (10 µM) reduced NKA in cross-linked 4-N3-PET-8-biotin-11-cGMP RPTs confirming fluorescence staining. 4-N3-PET-8-biotin-11-cGMP cross-linked samples were separated by SDS gel electrophoresis and slices corresponding to NKA molecular weight excised and processed for mass spectrometry. NKA was the second most abundant protein with 50 unique NKA peptides covering 47% of amino acids in NKA. Molecular modeling demonstrated a potential cGMP docking site in the ouabain-binding pocket of NKA. CONCLUSIONS: cGMP can bind to NKA and thereby mediate natriuresis.

The Angiotensin AT2 Receptor: From a Binding Site to a Novel Therapeutic Target.

Discovered more than 30 years ago, the angiotensin AT2 receptor (AT2R) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The AT2R represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the AT2R, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the AT2R, including its structure, intracellular signaling, homo- and heterodimerization, and expression. AT2R-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the AT2R and its abundant protective effects in multiple experimental disease models and expound on AT2R ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for AT2R research. SIGNIFICANCE STATEMENT: The angiotensin AT2 receptor (AT2R) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the AT2R, which has progressed from being an enigma to becoming a therapeutic target.

Renal AT2 Receptors Mediate Natriuresis via Protein Phosphatase PP2A.

BACKGROUND: How signals from activated angiotensin type-2 receptors (AT2R) mediate inhibition of sodium ion (Na+) reabsorption in renal proximal tubule cells is currently unknown. Protein phosphatases including PP2A (protein phosphatase 2A) have been implicated in AT2R signaling in tissues other than kidney. We investigated whether inhibition of protein phosphatase PP2A reduced AT2R-mediated natriuresis and evaluated changes in PP2A activity and localization after renal AT2R activation in normal 4- and 10-week-old control Wistar-Kyoto rats and 4-week-old prehypertensive and 10-week-old hypertensive spontaneously hypertensive rats. METHODS AND RESULTS: In Wistar-Kyoto rats, direct renal interstitial administration of selective AT2R nonpeptide agonist Compound-21 (C-21) increased renal interstitial cyclic GMP (cGMP) levels, urine Na+ excretion, and simultaneously increased PP2A activity ≈2-fold in homogenates of renal cortical tubules. The cyclic GMP and natriuretic responses were abolished by concurrent renal interstitial administration of protein phosphatase inhibitor calyculin A. In renal proximal tubule cells in response to C-21, PP2A subunits A, B55α and C, but not B56γ, were recruited to apical plasma membranes together with AT2Rs. Calyculin A treatment abolished C-21-induced translocation of both AT2R and PP2A regulatory subunit B55α to apical plasma membranes. Immunoprecipitation of AT2R solubilized from renal cortical homogenates demonstrated physical association of AT2R with PP2A A, B55α, and C but not B56γ subunits. In contrast, in spontaneously hypertensive rats, administration of C-21 did not alter urine Na+ excretion or PP2A activity and failed to translocate AT2Rs and PP2A subunits to apical plasma membranes. CONCLUSIONS: In renal proximal tubule cells of Wistar-Kyoto rats, PP2A is activated and PP2A subunits AB55αC are recruited to C-21-activated AT2Rs during induction of natriuresis. This response is defective in prehypertensive and hypertensive spontaneously hypertensive rats, presenting a potential novel therapeutic target for treating renal Na+ retention and hypertension.

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines: Comparisons, Reflections, and Recommendations.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Guideline-Driven Management of Hypertension: An Evidence-Based Update.

Several important findings bearing on the prevention, detection, and management of hypertension have been reported since publication of the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline. This review summarizes and places in context the results of relevant observational studies, randomized clinical trials, and meta-analyses published between January 2018 and March 2021. Topics covered include blood pressure measurement, patient evaluation for secondary hypertension, cardiovascular disease risk assessment and blood pressure threshold for drug therapy, lifestyle and pharmacological management, treatment target blood pressure goal, management of hypertension in older adults, diabetes, chronic kidney disease, resistant hypertension, and optimization of care using patient, provider, and health system approaches. Presenting new information in each of these areas has the potential to increase hypertension awareness, treatment, and control which remain essential for the prevention of cardiovascular disease and mortality in the future.

Harmonization of the American College of Cardiology/American Heart Association and European Society of Cardiology/European Society of Hypertension Blood Pressure/Hypertension Guidelines.

The 2017 American College of Cardiology/American Heart Association and 2018 European Society of Cardiology/European Society of Hypertension clinical practice guidelines for management of high blood pressure/hypertension are influential documents. Both guidelines are comprehensive, were developed using rigorous processes, and underwent extensive peer review. The most notable difference between the 2 guidelines is the blood pressure cut points recommended for the diagnosis of hypertension. There are also differences in the timing and intensity of treatment, with the American College of Cardiology/American Heart Association guideline recommending a somewhat more intensive approach. Overall, there is substantial concordance in the recommendations provided by the 2 guideline-writing committees, with greater congruity between them than their predecessors. Additional harmonization of future guidelines would help to underscore the commonality of their core recommendations and could serve to catalyze changes in practice that would lead to improved prevention, awareness, treatment, and control of hypertension, worldwide.

Association of Blood Pressure Classification Using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guideline With Risk of Heart Failure and Atrial Fibrillation.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are growing in prevalence worldwide. Few studies have assessed to what extent stage 1 hypertension in the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines is associated with incident HF and AF. METHODS: Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2018 (n=2 196 437; mean age, 44.0±10.9 years; 58.4% men). No participants were taking antihypertensive medication or had a known history of cardiovascular disease. Each participant was categorized as having normal BP (systolic BP <120 mm Hg and diastolic BP <80 mm Hg; n=1 155 885), elevated BP (systolic BP 120-129 mm Hg and diastolic BP <80 mm Hg; n=337 390), stage 1 hypertension (systolic BP 130-139 mm Hg or diastolic BP 80-89 mm Hg; n=459 820), or stage 2 hypertension (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg; n=243 342). Using Cox proportional hazards models, we identified associations between BP groups and HF/AF events. We also calculated the population attributable fractions to estimate the proportion of HF and AF events that would be preventable if participants with stage 1 and stage 2 hypertension were to have normal BP. RESULTS: Over a mean follow-up of 1112±854 days, 28 056 incident HF and 7774 incident AF events occurred. After multivariable adjustment, hazard ratios for HF and AF events were 1.10 (95% CI, 1.05-1.15) and 1.07 (95% CI, 0.99-1.17), respectively, for elevated BP; 1.30 (95% CI, 1.26-1.35) and 1.21 (95% CI, 1.13-1.29), respectively, for stage 1 hypertension; and 2.05 (95% CI, 1.97-2.13) and 1.52 (95% CI, 1.41-1.64), respectively, for stage 2 hypertension versus normal BP. Population attributable fractions for HF associated with stage 1 and stage 2 hypertension were 23.2% (95% CI, 20.3%-26.0%) and 51.2% (95% CI, 49.2%-53.1%), respectively. The population attributable fractions for AF associated with stage 1 and stage 2 hypertension were 17.4% (95% CI, 11.5%-22.9%) and 34.3% (95% CI, 29.1%-39.2%), respectively. CONCLUSIONS: Both stage 1 hypertension and stage 2 hypertension were associated with a greater incidence of HF and AF in the general population. The American College of Cardiology/American Heart Association BP classification system may help identify adults at higher risk for HF and AF events.

New wrinkles in hypertension management 2022.

PURPOSE OF REVIEW: High blood pressure (BP) is the world's leading risk factor for cardiovascular disease (CVD) and death. This review highlights findings during the past 18 months that apply to the management of high BP in adults in the context of the 2017 American College of Cardiology/American Heart Association (AHA) BP guideline. RECENT FINDINGS: A comprehensive meta-analysis of clinical trials that employed a novel statistical method identified a substantially linear relationship between dietary sodium intake and BP, strongly supporting the AHA daily dietary sodium intake recommendation of less than 1500 mg/day but suggesting that any reduction in sodium intake is likely to be beneficial. Among adults with hypertension, use of a salt substitute (containing reduced sodium and enhanced potassium) led to striking reductions in CVD outcomes. Young adults with stage 1 hypertension and a low 10-year atherosclerotic CVD risk score should be started on a 6-month course of vigorous lifestyle modification; if their BP treatment goal is not achieved, a first-line antihypertensive agent should be added to the lifestyle modification intervention. In patients with stage 4 renal disease, the thiazide-like diuretic chlorthalidone (as add-on therapy) lowered BP markedly compared with placebo. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) represent a new class of MRA that has been shown to lower BP and provide significant CVD protection. In Chinese adults aged 60-80 years at baseline, intensive BP control with a SBP target of 110-129 compared with 130-149 mmHg reduced CVD events with minimal side effects. SUMMARY: Recent findings have advanced our knowledge of hypertension management, clarifying, amplifying and supporting the 2017 ACC/AHA BP guideline recommendations.

Identification of a Primary Renal AT2 Receptor Defect in Spontaneously Hypertensive Rats.

RATIONALE: Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl1-angiotensin II])-elicited AT2R (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR). OBJECTIVE: This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired AT2R signaling and renal sodium (Na+) retention by utilizing the selective AT2R agonist compound-21 (C-21). METHODS AND RESULTS: Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic AT1R (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng/[kg·min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na+ excretion from 0.023±0.01 to 0.064±0.02, 0.087±0.01, and 0.089±0.01 µmol/min (P=0.008, P<0.0001, and P<0.0001, respectively) and renal interstitial fluid levels of AT2R downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91±0.3 to 3.1±1.0, 5.9±1.2 and 5.3±0.5 fmol/mL (P=nonsignificant, P<0.0001, and P<0.0001, respectively). In contrast, C-21 did not increase urine Na+ excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced AT2R translocation to apical plasma membranes of renal proximal tubule cells, internalization/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na+/K+ATPase (sodium-potassium-atpase) and phosphorylation of AT2R-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na+ transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane AT2R recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or AT2R recruitment in SHR. CONCLUSIONS: The results demonstrate a primary renal proximal tubule cell AT2R natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension. Visual Overview: An online visual overview is available for this article.

Inverse Salt Sensitivity of Blood Pressure: Mechanisms and Potential Relevance for Prevention of Cardiovascular Disease.

PURPOSE OF REVIEW: To review the etiology of inverse salt sensitivity of blood pressure (BP). RECENT FINDINGS: Both high and low sodium (Na+) intake can be associated with increased BP and cardiovascular morbidity and mortality. However, little is known regarding the mechanisms involved in the increase in BP in response to low Na+ intake, a condition termed inverse salt sensitivity of BP, which affects approximately 15% of the adult population. The renal proximal tubule is important in regulating up to 70% of renal Na+ transport. The renin-angiotensin and renal dopaminergic systems play both synergistic and opposing roles in the regulation of Na+ transport in this nephron segment. Clinical studies have demonstrated that individuals express a "personal salt index" (PSI) that marks whether they are salt-resistant, salt-sensitive, or inverse salt-sensitive. Inverse salt sensitivity results in part from genetic polymorphisms in various Na+ regulatory genes leading to a decrease in natriuretic activity and an increase in renal tubular Na+ reabsorption leading to an increase in BP. This article reviews the potential mechanisms of a new pathophysiologic entity, inverse salt sensitivity of BP, which affects approximately 15% of the general adult population.

Treatment of Hypertension: A Review.

Importance: Hypertension, defined as persistent systolic blood pressure (SBP) at least 130 mm Hg or diastolic BP (DBP) at least 80 mm Hg, affects approximately 116 million adults in the US and more than 1 billion adults worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death. Observations: First-line therapy for hypertension is lifestyle modification, including weight loss, healthy dietary pattern that includes low sodium and high potassium intake, physical activity, and moderation or elimination of alcohol consumption. The BP-lowering effects of individual lifestyle components are partially additive and enhance the efficacy of pharmacologic therapy. The decision to initiate antihypertensive medication should be based on the level of BP and the presence of high atherosclerotic CVD risk. First-line drug therapy for hypertension consists of a thiazide or thiazidelike diuretic such as hydrochlorothiazide or chlorthalidone, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker such as enalapril or candesartan, and a calcium channel blocker such as amlodipine and should be titrated according to office and home SBP/DBP levels to achieve in most people an SBP/DBP target (<130/80 mm Hg for adults <65 years and SBP <130 mm Hg in adults ≥65 years). Randomized clinical trials have established the efficacy of BP lowering to reduce the risk of CVD morbidity and mortality. An SBP reduction of 10 mm Hg decreases risk of CVD events by approximately 20% to 30%. Despite the benefits of BP control, only 44% of US adults with hypertension have their SBP/DBP controlled to less than 140/90 mm Hg. Conclusions and Relevance: Hypertension affects approximately 116 million adults in the US and more than 1 billion adults worldwide and is a leading cause of CVD morbidity and mortality. First-line therapy for hypertension is lifestyle modification, consisting of weight loss, dietary sodium reduction and potassium supplementation, healthy dietary pattern, physical activity, and limited alcohol consumption. When drug therapy is required, first-line therapies are thiazide or thiazidelike diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blockers, and calcium channel blockers.

Angiotensin Type-2 Receptors: Transducers of Natriuresis in the Renal Proximal Tubule.

Angiotensin II (Ang II) type-2 receptors (AT2R) are expressed in the adult kidney, prominently in renal proximal tubule cells (RPTCs), and play an important role in opposing renal sodium (Na+) retention induced by Ang II stimulation of Ang II type-1 receptor (AT1R). Natriuresis induced by AT1R blockade is due at least in part to AT2R activation and whole body deletion of AT2Rs reduces the natriuretic response to increased blood pressure (BP). The major endogenous AT2R agonist mediating the natriuretic response is Ang III, the Ang II heptapeptide metabolite generated by aminopeptidase A, and the principal nephron site mediating inhibition of Na+ reabsorption by the AT2R is the renal proximal tubule (RPT). AT2Rs induce natriuresis via a bradykinin, nitric oxide and cyclic GMP (cGMP) signaling cascade. Recent studies demonstrated a key role for protein phosphatase 2A (PP2A) in the AT2R-mediated natriuretic response upstream of cGMP. By inducing natriuresis, AT2Rs lower BP in the Ang II-infusion model of hypertension. PP2A activation and the natriuretic response to AT2R stimulation are defective in spontaneously hypertensive rats, a model of primary hypertension in humans. AT2R agonists are candidates for proximal tubule natriuretic agents in Na+ and fluid retention disorders.

New findings bearing on the prevention, detection and management of high blood pressure.

PURPOSE OF REVIEW: Hypertension is the foremost risk factor for cardiovascular disease (CVD) and death. This review highlights recent findings that apply to the prevention, detection, and management of high blood pressure (BP), in the context of the 2017 American College of Cardiology/American Heart Association BP guideline. RECENT FINDINGS: Several new findings on the association of BP measurement with CVD outcomes are now available. (1) Beginning with a systolic BP (SBP) as low as 90 mm Hg, coronary artery calcium deposition and the risk of incident atherosclerotic CVD (ASCVD) increased in stepwise fashion with increasing SBP levels within the normal range in adults at low risk for ASCVD. (2) Isolated diastolic hypertension was not associated with ASCVD, heart failure, or chronic kidney disease. (3) Nocturnal BP appeared to be better associated with CVD outcomes than office or daytime BP. (4) In a head-to-head comparison, home BP monitoring had higher reliability and predictive value than office or ambulatory BP to detect left ventricular hypertrophy, an intermediate form of hypertension-related target organ damage. In addition, new information indicates that autonomous aldosterone production is present in a substantially larger percentage of adults with hypertension than previously recognized. Finally, intensive BP lowering is associated with a significant reduction in the incidence of mild cognitive impairment, a precursor of dementia. SUMMARY: Ongoing research has made significant progress in the prevention, detection, and management of high BP, clarifying, amplifying, and/or supporting the 2017 ACC/AHA BP guideline recommendations.

The Unrecognized Prevalence of Primary Aldosteronism: A Cross-sectional Study.

BACKGROUND: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease. OBJECTIVE: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure. DESIGN: Cross-sectional study. SETTING: 4 U.S. academic medical centers. PARTICIPANTS: Participants with normotension (n = 289), stage 1 hypertension (n = 115), stage 2 hypertension (n = 203), and resistant hypertension (n = 408). MEASUREMENTS: Participants completed an oral sodium suppression test, regardless of aldosterone or renin levels, as a confirmatory diagnostic for primary aldosteronism and to quantify the magnitude of renin-independent aldosterone production. Urinary aldosterone was measured in participants in high sodium balance with suppressed renin activity. Biochemically overt primary aldosteronism was diagnosed when urinary aldosterone levels were higher than 12 µg/24 h. RESULTS: Every blood pressure category had a continuum of renin-independent aldosterone production, where greater severity of production was associated with higher blood pressure, kaliuresis, and lower serum potassium levels. Mean adjusted levels of urinary aldosterone were 6.5 µg/24 h (95% CI, 5.2 to 7.7 µg/24 h) in normotension, 7.3 µg/24 h (CI, 5.6 to 8.9 µg/24 h) in stage 1 hypertension, 9.5 µg/24 h (CI, 8.2 to 10.8 µg/24 h) in stage 2 hypertension, and 14.6 µg/24 h (CI, 12.9 to 16.2 µg/24 h) in resistant hypertension; corresponding adjusted prevalence estimates for biochemically overt primary aldosteronism were 11.3% (CI, 5.9% to 16.8%), 15.7% (CI, 8.6% to 22.9%), 21.6% (CI, 16.1% to 27.0%), and 22.0% (CI, 17.2% to 26.8%). The aldosterone-renin ratio had poor sensitivity and negative predictive value for detecting biochemically overt primary aldosteronism. LIMITATION: Prevalence estimates rely on arbitrary and conventional thresholds, and the study population may not represent nationwide demographics. CONCLUSION: The prevalence of primary aldosteronism is high and largely unrecognized. Beyond this categorical definition of primary aldosteronism, there is a prevalent continuum of renin-independent aldosterone production that parallels the severity of hypertension. These findings redefine the primary aldosteronism syndrome and implicate it in the pathogenesis of "essential" hypertension. PRIMARY FUNDING SOURCE: National Institutes of Health.

Renal functional effects of the highly selective AT2R agonist, ß-Pro7 Ang III, in normotensive rats.

Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding ß-amino acid. ß-Amino acid substitution at the proline residue of Ang III (ß-Pro7-Ang III) resulted in a highly selective AT2R ligand, demonstrating remarkable selectivity for the AT2R in both binding and functional studies. To provide additional functional evidence for the suitability of ß-Pro7 Ang III as a novel AT2R agonist, we tested effects of acute systemic administration of ß-Pro7-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and ß-Pro7-Ang III in the presence of systemic AT1R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of ß-Pro7-Ang III. In both male and female rats, acute systemic administration of ß-Pro7-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of ß-Pro7-Ang III administered. Moreover, intra-renal administration of ß-Pro7-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT2R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of ß-Pro7-Ang III as a novel AT2R agonist and experimental tool for exploring AT2R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT2R stimulation on renal function.

Potential US Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline.

BACKGROUND: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults provides recommendations for the definition of hypertension, systolic and diastolic blood pressure (BP) thresholds for initiation of antihypertensive medication, and BP target goals. OBJECTIVES: This study sought to determine the prevalence of hypertension, implications of recommendations for antihypertensive medication, and prevalence of BP above the treatment goal among US adults using criteria from the 2017 ACC/AHA guideline and the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7). METHODS: The authors analyzed data from the 2011 to 2014 National Health and Nutrition Examination Survey (N = 9 623). BP was measured 3 times following a standardized protocol and averaged. Results were weighted to produce US population estimates. RESULTS: According to the 2017 ACC/AHA and JNC7 guidelines, the crude prevalence of hypertension among US adults was 45.6% (95% confidence interval [CI]: 43.6% to 47.6%) and 31.9% (95% CI: 30.1% to 33.7%), respectively, and antihypertensive medication was recommended for 36.2% (95% CI: 34.2% to 38.2%) and 34.3% (95% CI: 32.5% to 36.2%) of US adults, respectively. Nonpharmacological intervention is advised for the 9.4% of US adults with hypertension who are not recommended for antihypertensive medication according to the 2017 ACC/AHA guideline. Among US adults taking antihypertensive medication, 53.4% (95% CI: 49.9% to 56.8%) and 39.0% (95% CI: 36.4% to 41.6%) had BP above the treatment goal according to the 2017 ACC/AHA and JNC7 guidelines, respectively. CONCLUSIONS: Compared with the JNC7 guideline, the 2017 ACC/AHA guideline results in a substantial increase in the prevalence of hypertension, a small increase in the percentage of US adults recommended for antihypertensive medication, and more intensive BP lowering for many adults taking antihypertensive medication.

Resistant Hypertension Management: Comparison of the 2017 American and 2018 European High Blood Pressure Guidelines.

PURPOSE OF REVIEW: To compare European and American guidelines for the diagnosis, evaluation, and management of resistant hypertension. RECENT FINDINGS: Resistant hypertension is defined as high blood pressure that remains above goal with the use of 3 or more antihypertensive agents, commonly a renin-angiotensin blocker (either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker), a long-acting calcium channel blocker, and thiazide or thiazide-like diuretic. Resistant hypertension is common, with a recent analysis indicating that it affects approximately 17-19% of adult Americans with hypertension. Pseudocauses of apparent resistant hypertension, including inaccurate blood pressure measurement, white coat effect, undertreatment, and poor medication adherence, must be excluded in order to confirm true resistant hypertension. Evaluation of resistant hypertension requires identifying and treating secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, and renal artery stenosis. Treatment of resistant hypertension includes a combined use of lifestyle modification and prescription of effective multiple-drug combinations. Preferential use of a long-acting thiazide-like diuretic, either chlorthalidone or indapamide, and a mineralocorticoid receptor blocker, most commonly spironolactone, is recommended if needed to achieve blood pressure control. Aside for small exceptions, European and American guidelines agree in terms of recommendations for diagnosing, evaluating, and treating resistant hypertension.

Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline.

Description: In November 2017, the American College of Cardiology (ACC) and the American Heart Association (AHA) released a clinical practice guideline for the prevention, detection, evaluation, and treatment of high blood pressure (BP) in adults. This article summarizes the major recommendations. Methods: In 2014, the ACC and the AHA appointed a multidisciplinary committee to update previous reports of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The committee reviewed literature and commissioned systematic reviews and meta-analyses on out-of-office BP monitoring, the optimal target for BP lowering, the comparative benefits and harms of different classes of antihypertensive agents, and the comparative benefits and harms of initiating therapy with a single antihypertensive agent or a combination of 2 agents. Recommendations: This article summarizes key recommendations in the following areas: BP classification, BP measurement, screening for secondary hypertension, nonpharmacologic therapy, BP thresholds and cardiac risk estimation to guide drug treatment, treatment goals (general and for patients with diabetes mellitus, chronic kidney disease, and advanced age), choice of initial drug therapy, resistant hypertension, and strategies to improve hypertension control.

AT2 Receptor Activation Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-Dependent Hypertension.

RATIONALE: Compound 21 (C-21) is a highly selective nonpeptide angiotensin AT2 receptor (AT2R) agonist. OBJECTIVE: To test the hypothesis that chronic AT2R activation with C-21 induces natriuresis via an action at the renal proximal tubule (RPT) and lowers blood pressure (BP) in experimental angiotensin II (Ang II)-dependent hypertension. METHODS AND RESULTS: In rats, Ang II infusion increased both sodium (Na(+)) retention and BP on day 1, and BP remained elevated throughout the 7-day infusion period. Either intrarenal or systemic administration of C-21 prevented Ang II-mediated Na(+) retention on day 1, induced continuously negative cumulative Na(+) balance compared with Ang II alone, and reduced BP chronically. The effects of C-21 are likely to be mediated by action on the RPT as acute systemic C-21-induced natriuresis was additive to that induced by chlorothiazide and amiloride. At 24 hours of Ang II infusion, AT2R activation with C-21, both intrarenally and systemically, translocated AT2Rs from intracellular sites to the apical plasma membranes of RPT cells without altering the total cellular pool of AT2Rs and internalized/inactivated major RPT Na(+) transporters Na(+)-H(+)-exchanger-3 and Na(+)/K(+)ATPase. C-21 lowered BP to a similar degree whether administered before or subsequent to the establishment of Ang II-dependent hypertension. CONCLUSIONS: Chronic AT2R activation initiates and sustains receptor translocation to RPT apical plasma membranes, internalizes/inactivates Na(+)-H(+)-exchanger-3 and Na(+)/K(+)ATPase, prevents Na(+) retention resulting in negative cumulative Na(+) balance, and lowers BP in experimental Ang II-induced hypertension. Acting uniquely at the RPT, C-21 is a promising candidate for the treatment of hypertension and Na(+)-retaining states in humans.

Renal Collectrin Protects against Salt-Sensitive Hypertension and Is Downregulated by Angiotensin II.

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.