Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension.

PURPOSE OF REVIEW: Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10-15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. RECENT FINDINGS: Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH.

The effect of diesel exhaust exposure on blood-brain barrier integrity and function in a murine model.

Epidemiological studies indicate that exposure to diesel exhaust (DE) is associated with vascular-based disorders. To investigate the effect of DE on blood-brain barrier (BBB) function and integrity, 8-week-old BALB/c mice were randomized to DE in a cyclical treatment regimen over a 2-week period. Functional integrity of BBB was determined by considering brain parenchymal abundance of IgG within the hippocampal formation and cortex at 6 h and 24 h intervals following final exposure treatment. Neurovascular inflammation was expressed as the abundance of glial fibrillar acidic protein. Two doses of DE were studied and compared to air-only treated mice. Mice exposed to DE had substantially greater abundance of parenchymal IgG compared to control mice not exposed to DE. Increased parenchymal glial fibrillar acidic protein at 24 h post-DE exposure suggested heightened neurovascular inflammation. Our findings are proof-of-concept that inhalation of DE can compromise BBB function and support the broader contention that DE exposure may contribute to neurovascular disease risk.

Neuropsychological performance is positively associated with plasma albumin in healthy adults.

BACKGROUND: Albumin serves a range of physiological functions that are vital to overall brain and cognitive health. Indeed, associations between cognitive performance and albumin have been demonstrated in individuals with chronic liver or kidney disease and in patients with a high urinary excretion of albumin. However, an association of plasma albumin with cognitive performance has not been reported in otherwise healthy participants with clinically acceptable plasma albumin concentrations. METHOD: This study utilized a wide-ranging neuropsychological test battery to investigate the relationship between cognitive performance and plasma albumin homeostasis in 222 healthy participants (143 females) between the ages of 43 and 84 years (mean 65 years). RESULTS: Albumin both with and without the covariates of age, sex and acute-phase proteins was positively associated with enhanced performance on a range of neuropsychological domains including perceptual speed, Stroop and verbal ability. Albumin manifested generally positive but less robust associations with secondary and primary memory. CONCLUSION: The results indicate that there is a positive association between albumin and cognitive performance in physiologically healthy participants free of chronic renal or liver disease.

Effect of terazosin on lower urinary tract symptoms and pain due to double-J stent: a double-blind placebo-controlled randomized clinical trial.

OBJECTIVE: We evaluated the effect of terazosin in the improvement of lower urinary tract symptoms and flank pain in patients with internal ureteral stents. METHODS: In this double-blind randomized clinical trial, 73 patients with unilateral ureteral stone and hydroureteronephrosis who underwent insertion of an internal ureteral stent after transureteral lithotripsy (TUL) were randomized into two groups. 37 patients received terazosin 2 mg (once nightly) for 4 weeks and 36 patients received placebo for the same time duration. After 4 weeks, all patients were asked about the incidence of frequency, nocturia and urgency by an International Prostate Symptom Score (IPSS) questionnaire, flank pain and pain during urination by a visual analog scale (VAS) score, and hematuria. RESULTS: The mean VAS score was 2.21 in the terazosin group compared with 4.93 in the control group (p < 0.001). Nearly all the patients in the placebo group reported flank pain during urination but this was only reported in 54.5% of the patients in the terazosin group (p < 0.001). All criteria measured by the IPSS in the terazosin group were significantly lower than those in the placebo group (p = 0.0001). CONCLUSIONS: Administration of terazosin for patients with an internal ureteral stent relieved some stent-related symptoms such as flank pain, pain during voiding, frequency, nocturia and urgency, but had no effect on hematuria.