Gallaghermerritt5599

Intracerebroventricular Ang (angiotensin) II, but not TRV027, increased water and saline intake in the absence of DOCA. In a separate cohort, blood pressure responses to acute intracerebroventricular injection of vehicle, TRV, or losartan were measured by radiotelemetry in mice with established DOCA-salt hypertension. Central administration of intracerebroventricular TRV027 or losartan each caused a significant and similar reduction of blood pressure and heart rate. We conclude that administration of TRV027 a selective β-arrestin biased agonist directly into the brain increases aversion to saline and lowers blood pressure in a model of salt-sensitive hypertension. These data suggest that selective activation of AT1R β-arrestin pathways may be exploitable therapeutically.Genomic sequence and gene expression association studies in animals and humans have identified genes that may be integral in the pathogenesis of various diseases. PORCN inhibitor CD14 (cluster of differentiation 14)-a cell surface protein involved in innate immune system activation-is one such gene associated with cardiovascular and hypertensive disease. We previously showed that this gene is upregulated in renal macrophages of Dahl salt-sensitive animals fed a high-salt diet; here we test the hypothesis that CD14 contributes to the elevated pressure and renal injury observed in salt-sensitive hypertension. Using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9), we created a targeted mutation in the CD14 gene on the Dahl SS (SS/JrHSDMcwi) background and validated the absence of CD14 peptides via mass spectrometry. Radiotelemetry was used to monitor blood pressure in wild-type and CD14-/- animals challenged with high salt and identified infiltrating renal immune cells via flow cytometry. Germline knockout of CD14 exacerbated salt-sensitive hypertension and renal injury in female animals but not males. CD14-/- females demonstrated increased infiltrating macrophages but no difference in infiltrating lymphocytes. Transplant of CD14+/+ or CD14-/- bone marrow was used to isolate the effects of CD14 knockout to hematopoietic cells and confirmed that the differential phenotype observed was due to knockout of CD14 in hematopoietic cells. Ovariectomy was used to remove the influence of female sex hormones, which completely abrogated the effect of CD14 knockout. These studies provide a novel treatment target and evidence of a new dichotomy in immune activation between sexes within the context of hypertensive disease where CD14 regulates immune cell activation and renal injury.Beat-to-beat variability in blood pressure (BP) is associated with recurrent stroke despite good control of hypertension. However, no study has identified rates of progression of beat-to-beat BP variability (BPV), its determinants, or which patient groups are particularly affected, limiting understanding of its potential as a treatment target. In consecutive patients one month after a transient ischaemic attack or nondisabling stroke (Oxford Vascular Study), continuous noninvasive BP was measured beat-to-beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). Repeat assessments were performed at the 5-year follow-up visit and agreement determined by intraclass correlation coefficient. Rates of progression of systolic BPV (SBPV) and diastolic BPV (DBPV) and their determinants were estimated by mixed-effect linear models, adjusted for age, sex, and cardiovascular risk factors. One hundred eighty-eight of 310 surviving, eligible patients had repeat assessments after a median of 5.8 years. Pulse wave velocity was highly reproducible but SBPV and DBPV were not (intraclass correlation coefficient 0.71, 0.10, and 0.16, respectively), however, all 3 progressed significantly (pulse wave velocity, 2.39%, P less then 0.0001; SBPV, 8.36%, P less then 0.0001; DBPV, 9.7, P less then 0.0001). Rate of progression of pulse wave velocity, SBPV, and DBPV all increased significantly with age (P less then 0.0001), with an increasingly positive skew and were particularly associated with female sex (pulse wave velocity P=0.00035; SBPV P less then 0.0001; DBPV P less then 0.0001) and aortic mean SBP (SBPV P=0.037, DBPV P less then 0.0001). Beat-to-beat BP variability progresses significantly in high-risk patients, particularly in older individuals with elevated aortic systolic pressure. Beat-to-beat BPV and its progression represent potential new therapeutic targets to reduce cardiovascular risk.Primary aldosteronism is the most common secondary endocrine form of hypertension and causes many cardiovascular injuries. KCNJ5 somatic mutations have recently been identified in aldosterone-producing adenoma. However, their impacts on left ventricular remodeling precluding the interference of age, sex, and blood pressure are still uncertain. We enrolled 184 aldosterone-producing adenoma patients who received adrenalectomy. Clinical, biochemical, and echocardiographic data were analyzed preoperatively and 1 year postoperatively. KCNJ5 gene sequencing of aldosterone-producing adenoma was performed. After propensity score matching for age, sex, body mass index, blood pressure, hypertension duration, and number of hypertensive medications, there were 60 patients in each group with and without KCNJ5 mutations. The mutation carriers had higher left ventricular mass index (LVMI) and inappropriately excessive LVMI (ieLVMI) and lower e' than the noncarriers. After adrenalectomy, the mutation carriers had greater decreases in LVMI and ieLVMI than the noncarriers. In addition, only mutation carriers had a significant decrease in E/e' after surgery. In multivariate analysis, baseline LVMI correlated with KCNJ5 mutations, the number of hypertensive medications, and systolic blood pressure. Baseline ieLVMI correlated with KCNJ5 mutations and the number of hypertensive medications. The regression of both LVMI and ieLVMI after surgery was mainly correlated with KCNJ5 mutations and changes in systolic blood pressure. Aldosterone-producing adenoma patients with KCNJ5 mutations had higher LVMI and ieLVMI and a greater regression of LVMI and ieLVMI after adrenalectomy than those without mutations. The patients with KCNJ5 mutations also benefited from adrenalectomy with regard to left ventricular diastolic function, whereas noncarriers did not.