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Key Points: Question: Does targeting hepatic angiotensinogen synthesis with the RNA interference therapeutic zilebesiran reduce blood pressure in adults with mild to moderate hypertension? Findings: In a phase 2 trial, subcutaneous zilebesiran doses of 150, 300, or 600 mg every 6 months or 300 mg every 3 months significantly decreased systolic blood pressure at 3 and 6 months vs placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients, principally injection site reactions and mild hyperkalemia. Meaning: Single subcutaneous doses of zilebesiran significantly lower blood pressure for up to 6 months, suggesting potential for use as an effective antihypertensive with quarterly or biannual dosing. Importance: Angiotensinogen is the most upstream precursor of the renin–angiotensin–aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were −7.3 mm Hg (95% CI, −10.3 to −4.4) with zilebesiran, 150 mg, once every 6 months; −10.0 mm Hg (95% CI, −12.0 to −7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; −8.9 mm Hg (95% CI, −11.9 to −6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were −14.1 mm Hg (95% CI, −19.2 to −9.0; P <.001) with zilebesiran, 150 mg, once every 6 months; −16.7 mm Hg (95% CI, −21.2 to −12.3; P <.001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and −15.7 mm Hg (95% CI, −20.8 to −10.6; P <.001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035 This phase 2 randomized trial examines the antihypertensive efficacy and safety of different zilebesiran dosing regimens. [ABSTRACT FROM AUTHOR]

Although previous studies have revealed a role for the voltage-gated [K.sup.+] channel [alpha]-sub-unit Kv1.5 (KCNA5) in the generation of the 4-aminopyridine (4-AP)-sensitive component of delayed rectification in mouse ventricles ([I.sub.K,slow1]), the phenotypic consequences of manipulating [I.sub.K,slow1] expression in vivo in different (mouse) models are distinct. In these experiments, point mutations were introduced in the pore region of Kv1.5 to change the tryptophan (W) at position 461 to phenylalanine (F) to produce a nonconducting subunit, Kv1.5W461F, that is shown to function as a Kv1 subfamily-specific dominant negative (Kv1.5DN). With the use of the [alpha]-myosin heavy chain promoter to direct cardiac-specific expression, three lines of Kv1.5DN-expressing (C57BL6) transgenic mice were generated and characterized. Electrophysiological recordings from Kv1.5-DN-expressing left ventricular myocytes revealed that the micromolar 4-AP sensitive [I.sub.K,slow1] is selectively eliminated. The attenuation of [I.sub.k,slow1] is accompanied by increased ventricular action potential durations and marked QT prolongation. In contrast to previous findings in mice expressing a truncated (DN) Kv1.1 transgene; however, no electrical remodeling is evident in Kv1.5DN-expressing ventricular myocytes, and the (Kv1.5DN-induced) elimination of [I.sub.K,slow1] does not result in spontaneous ventricular arrhythmias. repolarization; [K.sup.+] currents: long QT

The effects of insulin-like growth factor-I (IGF-I) on the expression of K+-channels was analyzed via whole cell patch-clamp techniques in cultured neonatal rodent ventricular myocytes. Immunofluorescent staining of cultured neonatal rat myocytes that were treated with IGF-I indicated the presence of increased levels of ultrarapid delayed rectifier K+ channels and 4-aminopyridine-sensitive transient outward currents. Furthermore, IGF-I regulated K+-channel expression in developing rodent cardiac myocytes.

An investigation of the electrophysiological properties of cultured neonatal rat ventricular cells showed diverse results in terms of action potential durations and the densities of ion currents. Cells at days 5 and 15 in culture did not display shortening of action potential durations. By contrast, age-matched freshly isolated cells showed changes in action potential durations. Both quiescent and culture cells increased densities of transient outward currents during primary culture two-fold and three-fold, respectively. These results suggest that different types of cultured cells have different electrophysiological properties.

This study assessed the efficacy and safety of angiotensin receptor neprilysin inhibitor sacubitril/valsartan vs olmesartan in Asian patients with mild-to-moderate hypertension. Patients (N = 1438; mean age, 57.7 years) with mild-to-moderate hypertension were randomized to receive once daily administration of sacubitril/valsartan 200 mg (n = 479), sacubitril/valsartan 400 mg (n = 473), or olmesartan 20 mg (n = 486) for 8 weeks. The primary endpoint was reduction in mean sitting systolic blood pressure (msSBP) from baseline with sacubitril/valsartan 200 mg vs olmesartan 20 mg at Week 8. Secondary endpoints included msSBP reduction with sacubitril/valsartan 400 mg, and reductions in clinic and ambulatory BP and pulse pressure (PP) vs olmesartan. In addition, changes in msBP from baseline in the Chinese subpopulation, elderly (≥65 years), and in patients with isolated systolic hypertension (ISH) were assessed. Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP than olmesartan 20 mg at Week 8 (between-treatment difference: -2.33 mm Hg [95% confidence interval (CI) -4.00 to -0.66 mm Hg], P < 0.05 for non-inferiority and superiority). Greater reductions in msSBP were also observed with sacubitril/valsartan 400 mg vs olmesartan 20 mg (-3.52 [-5.19 to -1.84 mm Hg], P < 0.001 for superiority). Similarly, greater reductions in msBP were observed in the Chinese subpopulation, in elderly patients, and those with ISH. In addition, both doses of sacubitril/valsartan provided significantly greater reductions from baseline in nighttime mean ambulatory BP vs olmesartan. Treatment with sacubitril/valsartan 200 or 400 mg once daily is effective and provided superior BP reduction than olmesartan 20 mg in Asian patients with mild-to-moderate hypertension and is generally safe and well tolerated. [ABSTRACT FROM AUTHOR]

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward [K.sup.+] current ([I.sub.K,slow]), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current ([I.sub.to]) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Ky1/ Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of [I.sub.to] and the 4-aminopyridine-sensitive component of [I.sub.K,slow] are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/ Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast [I.sub.to] in addition to [I.sub.K,slow] in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias. electrophysiology; arrhythmia-basic studies; genetically altered mice; cardiac voltage-gated potassium channels

Functional expression of a GFP-tagged Kvl.5 [beta]-subunit in mouse ventricle. Am J Physiol Heart Circ Physiol 281: H1955-H1967, 2001.--The experiments here were undertaken to determine the feasibility of increasing the cell surface expression of voltage-gated ion channels in cardiac cells in vivo and to explore the functional consequences of ectopic channel expression. Transgenic mice expressing a green fluorescent protein (GFP)-tagged, voltage-gated [K.sup.+] (Kv) channel [alpha]-subunit, Kv1.5-GFP, driven by the cardiac-specific [alpha]-MHC promoter, were generated. In recent studies, Kv1.5 has been shown to encode the micromolar 4-aminopyridine (4-AP)-sensitive delayed rectifier [K.sup.+] current ([I.sub.K,slow]) in mouse myocardium. Unexpectedly, Kv1.5-GFP expression is heterogeneous in the ventricles of these animals. Although no electrocardiographic abnormalities were evident, expression of Kv1.5-GFP results in marked decreases in action potential durations in GFP-positive ventricular myocytes. In voltage-clamp recordings from GFP-positive ventricular myocytes, peak outward [K.sup.+] currents are significantly higher, and their waveforms are distinct from those recorded from wild-type cells. Pharmacological experiments revealed a selective increase in a micromolar 4-AP-sensitive current, similar to the 4-AP-sensitive component of [I.sub.K,slow] in wild-type cells. The inactivation rate of the 'overexpressed' current, however, is significantly slower than the Kv1.5-encoded component of [I.sub.K,slow] in wild-type cells, suggesting differences in association with accessory subunits and/or posttranslational processing. transgenic mice; ventricular myocytes

Previous studies have documented the expression of four kinetically distinct voltage-gated K+ (Kv) currents, Ito,f, Ito,s, IK,slow and Iss, in mouse ventricular myocytes and demonstrated that Ito,f and Ito,s are differentially expressed in the left ventricular apex and the interventricular septum. The experiments here were undertaken to test the hypothesis that there are further regional differences in the expression of Kv currents or the Kv subunits (Kv4.2, Kv4.3, KChIP2, Kv1.5, Kv2.1) encoding these currents in adult male and female (C57BL6) mouse ventricles. Whole-cell voltage-clamp recordings revealed that mean (± S.E.M.) peak outward K+ current and Ito,f densities are significantly (P < 0.001) higher in cells isolated from the right (RV) than the left (LV) ventricles. Within the LV, peak outward K+ current and Ito,f densities are significantly (P < 0.05) higher in cells from the apex than the base. In addition, Ito,f and IK,slow densities are lower in cells isolated from the endocardial (Endo) than the epicardial (Epi)surface of the LV wall. Importantly, similar to LV apex cells, Ito,s is not detected in RV, LV base, LV Epi or LV Endo myocytes. No measurable differences in K+ current densities or properties are evident in RV or LV cells from adult male and female mice, although Ito,f, Ito,s, IK,slow and Iss densities are significantly (P < 0.01) higher, and action potential durations at 50% (APD50) are significantly (P < 0.05) shorter in male septum cells. Western blot analysis revealed that the expression levels of Kv4.2, Kv4.3, KChIP2, Kv1.5 and Kv2.1 are similar in male and female ventricles. In addition, consistent with the similarities in repolarizing Kv current densities, no measurable... [ABSTRACT FROM AUTHOR]

Presents a study which investigated the hypothesis that prolongation of action potential duration and Q-T intervals is not per se arrhythmogenic. Materials and methods; Results; Discussion.

Characterizes the time- and voltage-dependent properties of the calcium-dependent, depolarization-activated potassium currents in adult mouse ventricular myocytes. Multiple potassium current components in adult mouse ventricular myocytes; Description of the transient potassium current in adult mouse ventricular myocytes; Pharmacological separation of the potassium currents in adult mouse ventricular myocytes.

Objectives: Cardiac hypertrophy is characterized by a prolongation of action potential duration (APD) and a reduction of outward K+ currents, primarily the transient outward current (Ito). Since the interaction between cardiac non-myocyte cells (NMCs) and cardiomyocytes (MCs) plays a critical role during the process of myocardial hypertrophy, in the present study, we investigated the effects of NMCs on cell growth and K+ channel expression in cultured newborn rat ventricular cells. Methods: Single MCs were isolated from day-old Wistar rat ventricles and cultured for a period of five days. The effects of NMCs were examined by MC–NMC co-culture or incubating pure MCs in NMC-conditioned growth medium (NCGM). Whole-cell voltage–clamp recording and Western blot analysis using a polyclonal antibody against rat Kv4.2 channel protein were performed. Results: A marked increase in surface area and total cell protein concentration of MCs was observed in the MC–NMC co-culture. In the pure MC culture, this hypertrophic effect could be mimicked by a 72-h addition of NCGM, with a significant prolongation of APD25 (APD at 25% repolarization) and a 42% decrease in Ito density (at +30 mV). The rates of inactivation and recovery from inactivation of Ito were unchanged. In the NCGM-treated MC culture, Western blots of MC proteins also showed a 36% reduction of the Kv4.2 K+ channel protein level. In addition, the NCGM-induced MC hypertrophy was partially inhibited by anti-insulin-like growth factor-1 (IGF-1) antibody, while it revealed no effects on Ito density and Kv4.2 channel expression. Conclusions: These findings first demonstrate that some paracrine hypertrophic factors released from cardiac NMCs, although unidentified, downregulate cardiac K+ channel expression. [ABSTRACT FROM PUBLISHER]