Calcium Channel Blockers

BackgroundThis study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.Methods and findingsNILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and ConclusionsThe results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.Trial registrationClinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Transient receptor potential canonical (TRPC) proteins form nonselective cation channels that play physiological roles in a wide variety of cells. Despite growing evidence supporting the therapeutic potential of TRPC6 inhibition in treating pathological cardiac and renal conditions, mechanistic understanding of TRPC6 function and modulation remains obscure. Here we report cryo-EM structures of TRPC6 in both antagonist-bound and agonist-bound states. The structures reveal two novel recognition sites for the small-molecule modulators corroborated by mutagenesis data. The antagonist binds to a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Conformational changes upon ligand binding illuminate a mechanistic rationale for understanding TRPC6 modulation. Furthermore, structural and mutagenesis analyses suggest several disease-related mutations enhance channel activity by disrupting interfacial interactions. Our results provide principles of drug action that may facilitate future design of small molecules to ameliorate TRPC6-mediated diseases.

Early in Alzheimer's disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca2+ entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes. In AD model mice, we identifed pericytes throughout the capillary bed as key drivers of an immune reactive oxygen species (ROS)-evoked and pericyte intracellular calcium concentration ([Ca2+]i)-mediated decrease in microvascular flow. Blocking CaVs with nimodipine early in disease progression improved CBF, reduced leukocyte stalling at pericyte somata and attenuated brain hypoxia. Amyloid β (Aβ)-evoked pericyte contraction in human cortical tissue was also greatly reduced by CaV block. Lowering pericyte [Ca2+]i early in AD may, thus, offer a therapeutic strategy to enhance brain energy supply and possibly cognitive function in AD.

ImportanceThiazide diuretics are a cornerstone for the treatment of hypertension, but their use is associated with development of hyponatremia. Women and older adults are particularly vulnerable, but population-based estimates of absolute risk are largely absent. Such data are a prerequisite for a robust risk-benefit assessment in the clinical setting.ObjectiveTo compare new use of thiazide diuretics with calcium channel blockers (CCBs) and subsequent risk of hyponatremia among different age groups and between the sexes.Design, setting, and participantsThis propensity score-matched cohort study included 159 080 individuals 18 years or older in the Stockholm Sodium Cohort, a research database established to investigate the association between thiazide and hyponatremia among individuals in Stockholm, Sweden, between July 1, 2006, and December 31, 2018. Statistical analysis was performed between January 2025 and January 2026.ExposureNewly initiated treatment with thiazide diuretics and CCBs.Main outcomes and measuresThe primary outcome was profound hyponatremia (ie, a sodium concentration ResultsA total of 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 275 women [51.9%]) initiating thiazide treatment were propensity score matched with 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 168 women [51.8%]) receiving CCBs. The cumulative incidence of profound hyponatremia was 0.80% (95% CI, 0.74%-0.87%) for thiazide users and 0.46% (95% CI, 0.41%-0.51%) for CCB users during the first 2 years of treatment. The occurrence of profound hyponatremia with thiazide treatment was higher among women (cumulative incidence, 1.04% [95% CI, 0.94%-1.15%) and individuals 80 years or older (cumulative incidence, 2.40% [95% CI, 2.07%-2.73%]). Thus, among women 80 years or older, the number needed to harm (NNH) was 53 (95% CI, 41-73) for developing sodium concentrations less than 125 mEq/L, 28 (95% CI, 22-38) for concentrations less than 130 mEq/L, and 16 (95% CI, 13-20) for concentrations less than 135 mEq/L. This was in marked contrast with women younger than 65 years, for whom the corresponding NNH was 790 (95% CI, 408-11 966) for developing sodium concentrations less than 125 mEq/L, 818 (95% CI, 303-∞) for concentrations less than 130 mEq/L, and 120 (95% CI, 78-261) for concentrations less than 135 mEq/L.Conclusions and relevanceIn this cohort study comprising 159 080 individuals, the association between newly initiated thiazide diuretics and hyponatremia was negligible among individuals younger than 65 years of age. In contrast, among older adults, especially among women, the association was substantial. The results may incentivize the prescriber toward choosing an alternative antihypertensive treatment. If thiazides are initiated, subsequent monitoring of serum sodium concentrations should be considered.