Potassium (Blood Pressure)

BACKGROUND/OBJECTIVES: Studies have shown that consistent reductions of 2 mm Hg in systolic blood pressure (SBP) for the general normotensive population can result in significant decreases in mortality from heart disease and stroke. The purpose of this meta-analysis was to determine the optimal dose and duration of treatment for magnesium and potassium supplementation, having previously discovered that both reduce SBP by -2.79 and -2.10 mm Hg, respectively. METHODS: Placebo-controlled, randomized clinical trials examining the effects of magnesium and potassium supplementation on SBP were identified. Pairwise meta-analyses with subgroups for dosage and treatment duration were run. RESULTS: Magnesium at dosages of ≤360 mg/day and durations greater than 3 months reduced SBP by -3.03 and -4.31 mm Hg, respectively. Potassium at dosages of ≤60 mmol/day and durations greater than 1 month reduced SBP by -2.34 and -2.80 mm Hg, respectively. CONCLUSIONS: Both supplements demonstrated greater reductions in SBP for the general population at lower dosages and longer treatment durations. Future studies are needed to validate these findings and provide tailored recommendations. These studies could investigate varying dosages over long-term follow-up to provide robust data on optimal dosages and treatment durations, as our findings were limited due to reliance on previously published trials.

OBJECTIVES: Effects of potassium supplementation on blood pressure (BP) may be offset by an increase in plasma aldosterone. The magnitude of potassium-dependent regulation of aldosterone secretion in humans is not fully characterized; it is not clear whether this is mediated by activation of the renin-angiotensin-aldosterone system (RAAS), as a result of a reduction in BP or other mechanisms. We performed a systematic review and meta-analysis of clinical trials assessing effects of potassium on plasma aldosterone and renin in adult individuals. METHODS: This was carried out in accordance with PRISMA guidelines. Three databases were searched: MEDLINE, EMBASE and CENTRAL. Titles were firstly screened by title and abstract for relevance before full-text articles were assessed for eligibility. The keywords used included "aldosterone", "potassium" and "RAAS". RESULTS: 6395 articles were retrieved and after title/abstract screening, 123 full-text articles were assessed for eligibility. Thirty-six met the prespecified inclusion/exclusion criteria (of which 18/36 also reported systolic BP). Potassium supplementation caused a significant decrease in systolic BP (mean difference [95% CI] -3.69 mmHg [-4.91, -2.46], P < 0.001) and increase in serum potassium (+0.37 [0.23, 0.52] mmol/l, P < 0.001). There was an increase in plasma aldosterone (standardized difference 0.426 [0.299, 0.553], P < 0.001) but not in plasma renin activity. Meta-regression showed a significant positive correlation between change in plasma aldosterone and change in serum potassium ( P < 0.001). CONCLUSIONS: Potassium supplementation increases plasma aldosterone concentrations, which correlates with the increase in serum potassium concentration which does not appear to be mediated by an increase in plasma renin activity.

Hypertension is the leading preventable risk factor for cardiovascular disease and all-cause mortality worldwide. However, studies have shown increased risk of mortality from heart disease and stroke even within the normal blood pressure (BP) range, starting at BPs above 110-115/70-75 mm Hg. Nutraceuticals, such as vitamins and minerals, have been studied extensively for their efficacy in lowering BP and may be of benefit to the general, normotensive population in achieving optimal BP. Our study investigated the effects of six nutraceuticals (Vitamins: C, D, E; Minerals: Calcium, Magnesium, Potassium) on both systolic blood pressure (SBP) and diastolic blood pressure (DBP) in this population. We performed a systematic review and pairwise meta-analysis for all six supplements versus placebo. Calcium and magnesium achieved significant reductions in both SBP and DBP of -1.37/-1.63 mm Hg and -2.79/-1.56 mm Hg, respectively. Vitamin E and potassium only yielded significant reductions in SBP with values of -1.76 mm Hg and -2.10 mm Hg, respectively. Vitamins C and D were not found to significantly lower either SBP or DBP. Future studies should determine optimal dosage and treatment length for these supplements in the general, normotensive population.

Sodium and potassium appear to interact with each other in their effects on blood pressure with potassium supplementation having a greater blood pressure lowering-effect when sodium intake is high. Whether the effect of sodium reduction on blood pressure varies according to potassium intake levels is unclear. We carried out a systematic review and meta-analysis to examine the impact of baseline potassium intake on blood pressure response to sodium reduction in randomized trials in adult populations, with sodium and potassium intake estimated from 24-h urine samples. We included 68 studies involving 5708 participants and conducted univariable and multivariable meta-regression. The median intake of baseline potassium was 67.7 mmol (Interquartile range: 54.6-76.4 mmol), and the mean reduction in sodium intake was 128 mmol (95% CI: 107-148). Multivariable meta-regression that included baseline 24-h urinary potassium excretion, age, ethnicity, baseline blood pressure, change in 24-h urinary sodium excretion, as well as the interaction between baseline 24-h urinary potassium excretion and change in 24-h urinary sodium excretion did not identify a significant association of baseline potassium intake levels with the blood pressure reduction achieved with a 50 mmol lowering of sodium intake (p > 0.05 for both systolic and diastolic blood pressure). A higher starting level of blood pressure was consistently associated with a greater blood pressure reduction from reduced sodium consumption. However, the nonsignificant findings may subject to the limitations of the data available. Additional studies with more varied potassium intake levels would allow a more confident exclusion of an interaction. © 2021. Crown.

Background Epidemiologic studies, including trials, suggest an association between potassium intake and blood pressure (BP). However, the strength and shape of this relationship is uncertain. Methods and Results We performed a meta-analysis to explore the dose-response relationship between potassium supplementation and BP in randomized-controlled trials with a duration ≥4 weeks using the recently developed 1-stage cubic spline regression model. This model allows use of trials with at least 2 exposure categories. We identified 32 eligible trials. Most were conducted in adults with hypertension using a crossover design and potassium supplementation doses that ranged from 30 to 140 mmol/d. We observed a U-shaped relationship between 24-hour active and control arm differences in potassium excretion and BP levels, with weakening of the BP reduction effect above differences of 30 mmol/d and a BP increase above differences ≈80 mmol/d. Achieved potassium excretion analysis also identified a U-shaped relationship. The BP-lowering effects of potassium supplementation were stronger in participants with hypertension and at higher levels of sodium intake. The BP increase with high potassium excretion was noted in participants with antihypertensive drug-treated hypertension but not in their untreated counterparts. Conclusions We identified a nonlinear relationship between potassium intake and both systolic and diastolic BP, although estimates for BP effects of high potassium intakes should be interpreted with caution because of limited availability of trials. Our findings indicate an adequate intake of potassium is desirable to achieve a lower BP level but suggest excessive potassium supplementation should be avoided, particularly in specific subgroups.

BACKGROUND: High sodium intake is a cause of elevated blood pressure in adults. In children and adolescents, less evidence is available and findings are equivocal. We systematically reviewed the evidence from experimental and observational studies on the association between sodium intake and blood pressure in children and adolescents. METHODS: A systematic search of the Medline, Embase, CINAHL and CENTRAL databases up to March 2017 was conducted and supplemented by a manual search of bibliographies and unpublished studies. Experimental and observational studies involving children or adolescents between 0 and 18 years of age were included. Random-effects meta-analyses were performed by pooling data across all studies, separately for experimental and observational studies, and restricting to studies with sodium intake and blood pressure measurement methods of high quality. Subgroup meta-analyses, sensitivity analyses and meta-regressions were conducted to investigate sources of heterogeneity and confounding. The dose-response relationship was also investigated. RESULTS: Of the 6572 publications identified, 85 studies (14 experimental; 71 observational, including 60 cross-sectional, 6 cohort and 5 case-control studies) with 58 531 participants were included. In experimental studies, sodium reduction interventions decreased systolic blood pressure by 0.6 mm Hg [95% confidence interval (CI): 0.5, 0.8] and diastolic blood pressure by 1.2 mm Hg (95% CI: 0.4, 1.9). The meta-analysis of 18 experimental and observational studies (including 3406 participants) with sodium intake and blood pressure measurement methods of high quality showed that, for every additional gram of sodium intake per day, systolic blood pressure increased by 0.8 mm Hg (95% CI: 0.4, 1.3) and diastolic blood pressure by 0.7 mm Hg (95% CI: 0.0, 1.4). The association was stronger among children with overweight and with low potassium intake. A quasi-linear relationship was found between sodium intake and blood pressure. CONCLUSIONS: Sodium intake is positively associated with blood pressure in children and adolescents, with consistent findings in experimental and observational studies. Since blood pressu

IMPORTANCE: Increased dietary potassium intake is thought to be associated with low blood pressure (BP). Whether potassium supplementation may be used as an antihypertensive agent is a question that should be answered. OBJECTIVE: To assess the effect of oral potassium supplementation on blood pressure in patients with primary hypertension. SEARCH METHODS: We searched Medline, Web of Science, Scopus, Cochrane Central Register of Controlled Trials until October 2016. We also screened reference lists of articles and previous reviews. We applied no language restrictions. SELECTION CRITERIA: We included randomized placebo-controlled clinical trials addressing the effect of potassium supplementation on primary hypertension for a minimum of 4 weeks. DATA COLLECTION AND ANALYSIS: We extracted data on systolic and diastolic BP (SBP and DBP) at the final follow-up. We explored the heterogeneity across studies using Cochran's test and I2 statistic and assessed the probability of publication bias using Begg's and Egger's tests. We reported the mean difference (MD) of SBP and DBP in a random-effects model. RESULTS: We found a total of 9059 articles and included 23 trials with 1213 participants. Compared to placebo, potassium supplementation resulted in modest but significant reductions in both SBP (MD -4.25 mmHg; 95% CI: -5.96 to -2.53; I2 = 41%) and DBP (MD -2.53 mmHg; 95% CI: -4.05 to -1.02; I2 = 65%). According to the change-score analysis, based on 8 out of 23 trials, compared to baseline, the mean changes in SBP (MD -8.89 mmHg; 95% CI: -13.67 to -4.11) and DBP (MD -6.42 mmHg; 95% CI: -10.99 to -1.84) was significantly higher in the intervention group than the control group. CONCLUSIONS: Our findings indicated that potassium supplementation is a safe medication with no important adverse effects that has a modest but significant impact BP and may be recommended as an adjuvant antihypertensive agent for patients with essential hypertension.

BACKGROUND: Several intervention studies have investigated the relation between potassium intake and blood-pressure, particularly in hypertensive subjects. However, uncertainties still exist about the existence and the amount of such an effect, and about the role of some potential effect-modifiers, including the baseline potassium intake and geographical area. METHODS: We carried out a systematic review of the evidence concerning such relation in hypertensive subjects, performing a meta-analysis and a meta-regression of RCT with selective and validated long-term (≥4weeks) potassium supplementation. We also implemented 'unconventional' search strategies in order to identify all potentially interesting studies. RESULTS: Overall, potassium supplementation decreased systolic blood pressure of 4.48mmHg (95% CI 3.07-5.90) and diastolic blood pressure of 2.96mmHg (1.10-4.82). There was little evidence of dose-response relation between blood-pressure decrease and potassium supplementation, as assessed through total achieved potassium intake in the intervention groups, difference in achieved potassium intake, and study duration. However, lower (<90mmol/day) potassium intake at baseline was associated with a higher blood-pressure lowering effect, as were higher sodium intake (particularly ≥4g/day), higher sodium-to-potassium ratio and the absence of any anti-hypertensive drug treatment. Trials conducted in Southern Europe showed the highest blood-pressure lowering effect compared with the remaining regions. CONCLUSIONS: Potassium supplementation in hypertensives was generally associated with decreased blood pressure, particularly in high sodium consumers, subjects not on hypertensive drug treatment, and those in the lowest category of potassium intake. An adequate dietary intake of potassium, in the order of 90mmol/day, should be achieved for blood pressure control.

BACKGROUND: Effects of potassium supplementation on vascular function remain conflicting. This meta-analysis aimed to summarized current literature to fill the gaps in knowledge. METHODS: A literature search was performed on PubMed database through April, 2016. The measurements of vascular function included pulse wave velocity (PWV), augmentation index (AI), pulse pressure (PP), flow mediated dilatation (FMD), glycerol trinitrate responses (GTN), and intercellular cell adhesion molecule-1 (ICAM-1). Data were pooled as standardized mean difference (SMD) with 95% confidence intervals. RESULTS: Seven randomized controlled trials examining 409 participants were included, with dosage of potassium ranging from 40 to 150mmol/day, and duration of intervention from 6days to 12months. Pooling results revealed a significant improvement in PP (SMD -0.280, 95% CI -0.493 to -0.067, p=0.010), but no improvement in PWV (SMD -0.342, 95% CI -1.123 to 0·440, p=0.391), AI (SMD -0.114, 95% CI -0.282 to 0.054, p=0.184), FMD (SMD 0·278, 95% CI -0.321 to 0.877, p=0.363), GTN (SMD -0.009, 95% CI -0.949 to 0.930, p=0.984), and ICAM-1 (SMD -0.238, 95% CI -0.720 to 0.244, p=0.333). CONCLUSIONS: Potassium supplementation was associated with significant improvement of PP, rather than other measurements of vascular function. However, the small number of researches and wide variation of evidences make it difficult to make a definitive conclusion.

BACKGROUND AND AIMS: Increasing the intake of potassium has been shown to lower blood pressure, but whether it also affects heart rate (HR) is largely unknown. We therefore assessed the effect of potassium supplementation on HR in a meta-analysis of randomized controlled trials. METHODS AND RESULTS: We searched PubMed (1966-October 2014) for randomized, placebo-controlled trials in healthy adults with a minimum duration of two weeks in which the effect of increased potassium intake on HR was assessed. In addition, reference lists from meta-analysis papers on potassium and blood pressure were hand-searched for publications. Two investigators independently extracted the data. We performed random effects meta-analyses, subgroup and meta-regression analyses for characteristics of the study (e.g. design, intervention duration, potassium dose and salt type, change in potassium excretion, sodium excretion during intervention) and study population (e.g. gender, age, hypertensive status, pre-study HR, pre-study potassium excretion). A total of 22 trials (1086 subjects), with a median potassium dose of 2.5 g/day (range: 0.9-4.7 g/day), and median intervention duration of 4 weeks (range: 2-24 weeks) were included. The meta-analysis showed no overall effect of increased potassium intake on HR (0.19 bpm, 95% CI: -0.44, 0.82). Stratified analyses yielded no significant effects of potassium intake on HR in subgroups, and there was no evidence for a dose-response relationship in meta-regression analyses. CONCLUSION: A chronic increase in potassium intake with supplemental doses of 2-3 g/day is unlikely to affect HR in apparently healthy adults.

OBJECTIVE: The choice of crystalloid solution considerably affects perioperative outcomes in neurosurgery. This study aimed to evaluate the effects of Plasma-Lyte 148 and 0.9% saline on acid-base and hydroelectrolyte balance in adults undergoing elective neurosurgical procedures. METHODS: A double-blind randomized controlled trial was conducted at Botucatu Medical School from November 2019 to May 2020. Patients received either Plasma-Lyte 148 or 0.9% saline at a maintenance rate of 2mL/kg/h, with additional bolus guided by mean arterial pressure and pulse pressure variation. The primary endpoint was arterial pH at the end of surgery. RESULTS: Sixty-eight patients (33 in the Plasma-Lyte 148 group and 35 in the saline group) completed the study. The total median volumes administered (1st-3rd quartiles) were 2,227 (1,416-3,000) and 3,000 (2,000-4,000) mL in the Plasma-Lyte 148 and saline groups, respectively (p=0.107). At procedure completion, Plasma-Lyte 148 demonstrated superior acid-base homeostasis with significantly higher pH (7.39±0.04 versus 7.35±0.05, p<0.001), bicarbonate (22.5±1.8 versus 20.6±2.2mmol/L, p<0.001), and base excess (-1.6±2.3 versus -3.9±2.6, p<0.001), while preventing hyperchloremia (109.1±6.6 versus 113.9±4.5 mmol/L, p=0.001). CONCLUSION: Plasma-Lyte 148 provides superior acid-base homeostasis compared to 0.9% saline in patients undergoing neurosurgery, with significantly better pH, bicarbonate, and base excess profiles while avoiding hyperchloremia. These findings support the preferential use of balanced crystalloids in neurosurgical practice, aligning with current evidence favoring Plasma-Lyte 148 for optimal perioperative fluid management. ReBEC platform registration number: RBR-2592-hd.

BACKGROUND: Hypertension is a key modifiable driver of cardiovascular risk and often clusters with dyslipidemia and insulin resistance within the metabolic syndrome. Olive leaf extract (OLE) and potassium have traditionally been used to support blood pressure (BP) management and cardiometabolic health. PURPOSE: To investigate the effect of this OLE - potassium combination on BP and key cardiometabolic markers. STUDY DESIGN: In this randomized, double-blind, placebo-controlled study, 70 adults with untreated mildly to moderately elevated BP received an OLE - potassium supplement (1000 mg OLE, ≥160 mg oleuropein, 300 mg potassium/day) or placebo for 12 weeks. RESULTS: While office BP fell significantly over time in both groups, 7-day home-based BP monitoring showed a significant greater response, with morning systolic BP decreasing by 5.4 mmHg, in the verum group. Supplementation also reduced total cholesterol by 11.1 mg/dL, LDL-cholesterol by 6.9 mg/dL, and triglycerides by approximately 22 mg/dL at Week 6, while HDL-cholesterol remained stable. Fasting glucose and HbA1c were unchanged, but fasting insulin and HOMA-Index declined in the verum group, indicating a modest improvement in insulin sensitivity. Additionally, oxidized LDL decreased by ∼23 %, without changes in hs-CRP. Quality-of-life scores remained stable, although global self-ratings favoured the combination. The intervention was well tolerated, with no product-related serious adverse events. CONCLUSION: The combination of OLE and potassium is a safe adjunctive strategy for individuals with mildly to moderately elevated BP, with favourable effects on lipid profile, oxidative status, and insulin sensitivity that may help reduce cardiometabolic risk in the context of metabolic syndrome.

Aim To evaluate the impact of digital remote monitoring on the effectiveness of intensive dose titration for guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF) for the achievement of target doses and the reduction of decompensated heart failure rate and all-cause mortality.Materials and methods The study utilized vital sign monitoring via a personal messenger-based questionnaire (chatbot) and weekly therapy optimization recommendations for 6 weeks following hospital discharge. The control group received standard outpatient care. The study is registered at ClinicalTrials.gov (NCT06304753). Between October 27, 2023, and December 27, 2024, 66 HFrEF patients were enrolled and randomized into a remote monitoring (RM) group (n=33) and a standard care (SC) group (n=33). The 6-week observation period was completed by 26 patients in the RM group and all 33 patients in the SC group.Results The RM group showed a statistically significant increase in the dosages of GDMT and a higher number of patients reaching target doses. In contrast, the SC group showed either no changes in therapy or a decrease in dosages of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (87.5 [50; 100]% vs. 25 [12.5; 25]%, p&lt;0.001); beta-blockers (100 [50; 100]% vs. 50 [25; 50]%, p&lt;0.001); and mineralocorticoid receptor antagonists (100 [100; 100]% vs. 50 [50; 100]%, p=0.005). Diuretic doses were reduced in the RM group (2 adjusted doses (AD) [1; 2] at baseline vs. 1 AD [0.5; 2] at 6 weeks; p=0.010) but remained unchanged in the SC group (2 [2; 2] AD at baseline vs. 2 [2; 2] AD at 6 weeks; p=0.9). The incidence of decompensated CHF and death was significantly higher in the SC group compared to the RM group, 16 cases (2 deaths, 14 decompensations) vs. 2 cases (0 deaths, 2 decompensations; p&lt;0.001). Intensive titration proved safe, with no statistically significant differences observed between groups at 6 weeks regarding systolic blood pressure (119 [110-130] mm Hg vs. 120 [110-130] mm Hg; p=0.9), heart rate (70.5 [62-80] bpm vs. 78 [73-91.5] bpm; p=0.062), glomerular fi

BACKGROUND: This study aimed to evaluate the differential effects of normal saline (N/S) (0.9% sodium chloride) and half saline (H/S) (0.45% sodium chloride) preservation solutions on sodium levels, blood pressure, and acid-base balance in critically ill pediatric patients. METHODS: A double-blind interventional clinical trial involving 88 pediatric patients was conducted in the pediatric intensive care unit. Patients were randomly assigned to receive either N/S (Group A) or H/S (Group B). Sodium, potassium, chloride, bicarbonate, pH, and blood pressure were measured at baseline and 6, 24, 48, and 72 hours. The primary outcome was the change in serum sodium concentration, and secondary outcomes included blood pressure and acid-base status. RESULTS: At 72 hours, sodium levels were significantly higher in the N/S group (137.63 ± 2.99 mEq/L) compared to the H/S group (135.33 ± 2.46 mEq/L; P = .007). Blood pressure was significantly higher in the N/S group at 24 hours (98.78 ± 8.08 mm Hg vs 92.70 ± 9.24 mm Hg; P = .002). No significant differences were observed in potassium levels, pH, or bicarbonate concentrations. The incidence of hyponatremia at 72 hours was similar in both the groups (15.9% for N/S vs 13.6% for H/S). CONCLUSION: Normal saline administration resulted in higher sodium levels and increased systolic blood pressure than H/S administration. These findings underscore the importance of tailored fluid therapy in critically ill pediatric patients, highlighting the potential effects of fluid choice on sodium balance and hemodynamics.

PURPOSE: This study aimed to evaluate the effects of remimazolam in conjunction with esketamine on anesthesia and the incidence of early perioperative neurocognitive disorders (PNDs) in patients undergoing thoracoscopic partial lung resection. METHODS: Eighty patients scheduled for thoracoscopic lobectomy were randomly assigned 1:1 to either the remimazolam group (group R) or the propofol group (group P). Group R received remimazolam for induction and maintenance of anesthesia, whereas group P received propofol. Both groups received intravenous esketamine before skin incision. The following parameters were compared: mean arterial pressure, heart rate, and perfusion index; extubation time, postanesthesia care unit stay duration, length of stay; arterial blood gas potassium, sodium, and glucose levels; hepatic and renal function markers; incidence of early PNDs and postoperative delirium (POD); safety indicators including visual analog scale scores, injection pain, Richmond Agitation-Sedation Scale sedation scores, and postoperative nausea and vomiting. FINDINGS: The incidence of POD and early PNDs did not differ significantly between the 2 groups (P > 0.05). Mean arterial pressure in group R was significantly higher than in group P (P < 0.05). Heart rate in group R was higher than in group P at 1 minute after tracheal intubation (P < 0.05). Perfusion index values did not differ significantly between groups (P > 0.05). Extubation time, postanesthesia care unit stay time, and length of stay were shorter in group R than in group P (P < 0.05), whereas sedation depth was greater in group R (P < 0.05). Within group R, blood glucose decreased at 1 minute after intubation and increased at 10 minutes after extubation (P < 0.05). Although total bilirubin showed significant postoperative elevation in both groups (P < 0.05), all other hepatic/renal function parameters remained comparable (P > 0.05). Visual analog scale scores showed no significant intergroup differences (P > 0.05). The incidence of injection pain and postoperative nausea and vomiting was lower in group R than in group P (P < 0.05). IMPLICATIONS: Compared with propofol combined with esketamine, general anesth

Obesity and insulin resistance promote arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, but the vascular effects of ENAC inhibition in adults with obesity and insulin resistance are not well defined. In this phase II, 24-wk, randomized, double-blind, single-center, placebo-controlled trial, 137 adults aged 30-70 yr with overweight or obesity and at least one metabolic syndrome feature were randomized (2:1) to the ENAC inhibitor amiloride (5 mg daily) or placebo. Carotid-femoral pulse wave velocity (cfPWV), blood pressure, and vascular function were assessed at baseline, 12 wk, and 24 wk. Amiloride significantly reduced arterial stiffness, with decreases in cfPWV at 12 and 24 wk, whereas no changes were observed with placebo. Systolic blood pressure was also reduced, with a mean reduction of 5.6 mmHg at 24 wk. Older age was associated with greater reductions in cfPWV and systolic blood pressure. Amiloride increased serum potassium and lowered fasting glucose, but did not significantly affect brachial artery flow-mediated dilation. No severe adverse events were observed. In conclusion, low-dose amiloride improves blood pressure and arterial stiffness in adults with overweight or obesity and features of metabolic syndrome, without major safety concerns. These findings suggest that blood pressure lowering with amiloride is associated with favorable changes in vascular stiffness in this population.NEW & NOTEWORTHY Obesity and insulin resistance accelerate arterial stiffening and hypertension, increasing cardiovascular risk. Activation of the epithelial sodium channel (ENAC) contributes to vascular stiffening in preclinical models, yet the vascular effects of ENAC inhibition in adults with obesity and insulin resistance remain poorly characterized. Here, we demonstrate that low-dose amiloride reduces blood pressure and improves arterial stiffness in adults with overweight or obesity and features of metabolic syndrome, without major safety concerns.

BACKGROUND: Aldosterone dysregulation is an important contributor in the pathogenesis of hard-to-control hypertension. We aimed to assess the effect of baxdrostat, a selective aldosterone synthase inhibitor, on ambulatory blood pressure in patients with resistant hypertension. METHODS: The Bax24 international, phase 3, randomised, double-blind, placebo-controlled trial recruited adults (aged ≥18 years) with seated systolic blood pressure (SBP) ≥140 mm Hg and <170 mm Hg, despite receiving three or more antihypertensive medications, including a diuretic, from 79 clinical sites (primary, secondary, and tertiary centres, in addition to research centres) in 22 countries. Following a 2-week placebo run-in period, patients with 24 h ambulatory SBP ≥130 mm Hg were randomly assigned (1:1) to receive 2 mg baxdrostat or placebo orally once daily for 12 weeks, in addition to background therapy (stratified by baseline ambulatory SBP <140 mm Hg or ≥140 mm Hg). Investigators, patients, and trial staff were masked to treatment assignment. The primary endpoint was change in 24 h ambulatory SBP from baseline to week 12, assessed by analysis of covariance in patients administered at least one dose of study medication with valid ambulatory SBP measurement at baseline and week 12. Missing or invalid ambulatory SBP measurements were not imputed. The safety analysis included all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT06168409, and is complete. FINDINGS: Between March 1, 2024, and April 16, 2025, 854 patients were screened, 636 were excluded (437 before the placebo run-in and 199 during the placebo run-in) and 217 were randomly assigned to and received baxdrostat (n=108) or placebo (n=109). 140 patients (65%) were male, 77 (35%) patients were female, and 170 patients (78%) were White. The median age was 60·0 years (IQR 51·0-68·0). At 12 weeks, the change from baseline in the least-squares mean 24 h ambulatory SBP was -16·6 mm Hg (95% CI -18·8 to -14·3) in the baxdrostat group (n=89) and -2·6 mm Hg (-4·7 to -0·4) in the placebo group (n=95); the estimated placebo-corrected difference was -14·0 mm Hg (-17·2 to -10

BACKGROUND: Hypertension and obesity disproportionately affect veterans and contribute to cardiovascular disease. The sodium-restricted Dietary Approaches to Stop Hypertension eating pattern (DASH-SRD) reduces blood pressure (BP) and is guideline-recommended, but adherence is low in this population. We conducted a randomized trial of a remotely delivered dietary intervention to promote and sustain adoption of DASH-SRD in veterans with hypertension and obesity. METHODS: Veterans with hypertension and obesity received 2 weeks of home-delivered DASH-SRD meals after 2 weeks of ad-lib diet (Phase 1), then 5 telephone-delivered, dietitian-led motivational interviewing counseling sessions over 4 months, with or without a newly developed mobile application (Phase 2). DASH adherence (score 0-9 per 3-day food diary), clinic blood pressure (BP), and urinary sodium:potassium ratio was collected at baseline and at months 1 and 6 of Phase 2. Generalized estimating equations were used to evaluate changes in these parameters during the intervention. RESULTS: Sixty-one veterans (age 67 ± 8 years, 15% female, 16% non-White) with obesity (BMI 34.4 ± 5.2) and hypertension completed the trial. Dietary counseling session attendance was 96%. Between baseline and 6 months, DASH adherence score improved (1.8 ± 1.6-2.3 ± 1.4 points, P = .02), BP decreased (systolic 133 ± 17-128 ± 15 mmHg, P = .048; diastolic 73 ± 11-69 ± 12 mmHg, P = .03), and urinary sodium:potassium ratio declined (2.6 ± 1.1-1.5 ± 0.8, P < .001). There were no significant differences between the mobile application plus counseling and counseling-alone groups. CONCLUSION: In Veterans with hypertension and obesity, a brief interval of home-delivered meals followed by telephone dietitian counseling sustainably improved DASH-SRD adherence and reduced BP. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT03170375. Published by Elsevier Inc.

KEY POINTS: Renin-angiotensin system inhibitors have less effect on decline in eGFR and no greater effect on delaying ESKD/KRT in patients receiving loop diuretics compared with those who do. Although loop diuretic use was not associated with higher rates of ESKD/KRT, it might be associated with a higher mortality. The decline in eGFR was slower in those taking loop diuretics. BACKGROUND: In the STOP-Angiotensin-Converting Enzyme Inhibitor trial, patients with advanced CKD were randomized to continue or stop renin-angiotensin system inhibitors (RASi) and showed no difference in kidney outcomes. This post hoc analysis investigates interactions with loop diuretic use. METHODS: Patients with eGFR <30 ml/min per 1.73 m 2 and progressive CKD were randomized to stop or continue RASi. Primary outcome was eGFR over 3 years using repeated-measures, mixed-effects linear regression, random-slope models. Cox models were used to calculate hazard ratios for time-to-event outcomes, including ESKD and KRT. RESULTS: At baseline, eGFR, arterial pressure, and proteinuria were similar for 133 patients taking loop diuretics and 278 who were not. Those receiving loop diuretics at randomization, least-squares mean (±SE) eGFR at 3 years was 12.3 (±1.1) for those stopping compared with 10.1 (±1.2) for those continuing RASi, trend favoring stopping RASi (+2.2; 95% confidence interval [CI], -0.9 to 5.4), but eGFR slope over 3 years was similar (-7.2 versus -7.7 ml/min per 1.73 m 2 ). Those not receiving loop diuretics, eGFR at 3-years was 8.8 (±0.8) and 11.6 (±0.8; discontinue and continue RASi groups), a difference favoring continuing RASi (-2.8; 95% CI, -4.9 to -0.8), and a steeper eGFR slope for those discontinuing RASi (-9.9 versus -7.6 ml/min per 1.73 m 2 ). The interaction between loop diuretic use and the effect of RASi on eGFR at 3 years and the three-way interaction between diuretic subgroup, effect of RASi, and time were both statistically significant ( P = 0.01 and P = 0.04, respectively). Of patients taking loop diuretics, 73 (55%) developed ESKD/KRT and 23 (17%) died. Of patients not taking loop diuretics, 170 (61%) developed ESKD/KRT and 19 (7%) died. CONCLUSIONS: Withdrawal

BACKGROUND: Dietary sodium reduction and potassium enrichment are recommended non-pharmacological strategies for blood pressure (BP) control; however, randomized evidence evaluating potassium-enriched salt substitutes specifically in patients with resistant arterial hypertension (RAH) remains limited. METHODS: We conducted a randomized, double-blind, controlled pilot trial including adults with RAH. Participants were assigned to receive either a potassium-enriched salt substitute (approximately 50% sodium chloride and 50% potassium chloride) or regular salt for 24 weeks. The primary outcome was the between-group difference in change in 24-h systolic BP assessed by ambulatory blood pressure monitoring (ABPM). The primary analyses used an available-case approach (completers) to prioritize analytical rigor, with intention-to-treat and sensitivity analyses assessing robustness. Between-group comparisons were utilized to control for regression to the mean and white-coat variability. RESULTS: Among 60 randomized participants, 49 completed valid baseline and follow-up ABPM assessments (23 intervention, 26 control). At 24 weeks, patients assigned to potassium-enriched salt exhibited a directionally greater reduction in 24-h systolic blood pressure compared with the control group, resulting in a between-group difference of -2.47 mmHg (95% CI -4.93 to 0.00; P = 0.05). A similar directional pattern was observed for diastolic blood pressure. Office blood pressure measurements showed greater variability and less consistent between-group differences over time. Urinary potassium excretion increased in the intervention group, whereas changes in urinary sodium excretion were modest. No cases of clinically relevant hyperkalemia or serious adverse events were observed. CONCLUSIONS: In this randomized pilot trial, the use of a potassium-enriched salt substitute was safe and associated with modest, directionally greater reductions in ambulatory BP compared with regular salt in patients with RAH. These findings support the feasibility and safety of potassium-enriched salt substitution as a pragmatic adjunctive strategy for blood pressure management in patients with resistant hyperten

Orthosiphon stamineus Benth, commonly used in Southeast Asia for its medicinal properties, is traditionally employed to treat diabetes and hypertension. Scientific research has validated that O. stamineus extract exhibits significant vasodilatory action on rat aorta. This effect is primarily due to the synergistic interaction among key compounds: eupatorin, sinensetin and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Our previous publication identified the optimum formulation, G28, which contains eupatorin, sinensetin and TMF in the ratio of EC20:EC15:EC5. Therefore, the aim of this study was to investigate the antihypertensive effect and mechanism of action of formulation G28. In this study, aortic rings from spontaneously hypertensive rats (SHRs) and Sprague-Dawley (SD) rats were used to examine the vasodilation mechanisms. The antihypertensive effect of G28 was also assessed through repeated-dose administration in SHRs. G28 exhibited stronger vasorelaxant effects in SHR versus SD rat aortic rings, indicating higher potency under hypertensive conditions. The effect was partially endothelium-dependent, as endothelium removal reduced responses in both aortic rings. G28 retained efficacy with Nω-Nitro-1-arginine methyl ester, methylene blue and 1H-[1,2,4]Ox-adiazolol[4,3-α]quinoxaline-1-one, suggesting involvement of the NO/sGC/cGMP pathway. Additionally, G28's effect diminished with glibenclamide, barium chloride, 4-aminopyrine and tetraethylammonium, indicating potassium channel involvements. The vasorelaxant effect was not significantly altered by indomethacin, atropine, or propranolol (in SD rats only), suggesting independence from the cyclooxygenase, beta-adrenergic (in SD rats only) and muscarinic pathways. G28 also reduced intracellular Ca²⁺ in vascular smooth muscle by antagonising voltage-gated calcium channel and Inositol triphosphate receptor. In vivo, G28 significantly reduced blood pressure in SHRs over 21 days of oral administration, underscoring its potential for hypertension control. G28 shows strong antihypertensive effects via NO/sGC/cGMP, potassium and calcium channels. Its sustained blood pressure reduction in SHRs highlights potential as a p

Gout is one of the most prevalent forms of arthritis that is usually accompanied by other comorbidities. For this reason, multiple drugs are routinely prescribed for gout patients, which may affect the clinical course outcomes, and increase the risk of drug-drug interactions. This work presents a novel, simple, and sensitive high performance liquid chromatography (HPLC) method for the simultaneous determination of lesinurad (LES) and other co-administered drugs that are subject to potential pharmacokinetic interactions such as etoricoxib (ETC), eplerenone (EPL), and amiodarone (AMD) in rat plasma. Moreover, a pharmacokinetic study was conducted by co-administration of LES and ETC to rats to assess any possible alteration in their pharmacokinetic profiles and the obtained samples were analyzed using the developed method. Chromatographic separation was achieved using a gradient elution of a mobile phase consisting of acetonitrile and potassium dihydrogen orthophosphate buffer, pH 4.2 on a Zorbax Eclipse Plus C18 (4.6 × 250 mm, 5 μm particle size) column. The developed method exhibits adequate sensitivity with a LLOQ of 100 ng/mL and was successfully validated as per the FDA bioanalytical guidelines and was found to be linear over the range from 100 to 50,000 ng/mL for all the selected drugs. The results of the pharmacokinetic study showed an increase in the area under the curve (AUC) of each of the two drugs (LES and ETC) following the repeated administration of the other. This raises concerns of the possible renal injurious effect of ETC when co-prescribed with LES. Moreover, this work uncovers the necessity for therapeutic dose adjustment or increased clinical vigilance for side effects and/or lack of efficacy upon concomitant administration of the selected drugs to gout patients. © 2025. The Author(s).

Despite that the Japanese package insert for vonoprazan (VPZ) includes a precaution that the potassium ion-competitive acid blocker may potentiate the effects of midazolam (MDZ), reports on the actual effects in clinical practice are lacking. Therefore, in this study, we evaluated whether VPZ-taking patients experience clinical effects under MDZ sedation during endoscopy. The participants were outpatients who underwent upper gastrointestinal endoscopy under MDZ anesthesia between April 2021 and April 2022. Comparisons were made between the VPZ(+) and VPZ(-) groups, and the patient background was adjusted using propensity score matching. The post-examination observation time was prolonged in 16.4% of patients in the VPZ(+) group and 13.7% in the VPZ(-) group, but the difference was not statistically significant (p=0.818). The two patients groups also showed no statistically significant differences in the percentage of individuals who received oxygen administration during the examination or in post-examination oxygen saturation and blood pressure values. These results suggest that the use of MDZ for sedation during upper gastrointestinal endoscopy may have minimal clinical effects arising from drug interaction with VPZ.

BACKGROUND: Children treated in a pediatric intensive care unit (PICU) often receive several drugs together, among them drugs defined as high-alert medications (HAMs). Those drugs carry a high risk of causing patient harm, for example, due to a higher potential for interactions. HAMs should therefore be administered with caution, especially in a PICU. OBJECTIVES: The objective of the current study was to identify drug-drug interactions involving HAMs that increase the risk of interaction-associated symptoms in pediatric intensive care. METHODS: In a retrospective study, we analyzed the electronic documentation of patients hospitalized for at least 48 h in a general PICU who received at least two different drugs within a 24-h interval. We assessed potential drug-drug interactions involving HAM on the basis of the two drug information databases UpToDate and drugs.com. Furthermore, we analyzed whether symptoms were observed after the administration of drug pairs that could lead to interaction-associated symptoms. For drug pairs involving HAM administered on at least 2% of patient days, and symptoms observed at least ten times after a respective drug pair, we calculated odds ratios, 95% confidence intervals, and p-values by using a univariate binary logistic regression. RESULTS: Among 315 analyzed patients, 81.3% (256/315) received drugs defined as high-alert medication for pediatric patients. Those high-alert medications were involved in 20,150 potential drug-drug interactions. In 14.0% (2830/20,150) of these, one or more symptoms were observed that could be a possible consequence of the interaction, resulting in 3203 observed symptoms affecting 56.3% (144/256) of patients receiving high-alert medication. The odds ratios for symptoms observed after a drug-drug interaction were increased for eight specific symptoms (each p ≤ 0.05), especially hemodynamic alterations and disturbances of electrolyte and fluid balance. The odds ratio was highest for decreased blood pressure observed after the administration of the drug pair fentanyl and furosemide (OR 5.06; 95% confidence interval 3.5-7.4; p < 0.001). Increased odds ratios for specific symptoms observed after drug-drug

BACKGROUND & AIMS: The objective is to ascertain the pattern of potential drug-drug interactions (pDDIs) and record any observed DDIs and adverse events (AEs) in hospitalized Beninese cardiology patients from Sub-Saharan Africa and analyze all risk factors associated with DDIs and AEs. METHODS: It was a prospective study in which data including AEs were assessed from medical files and interview of patients and their relatives. Patients who were treated with more than two drugs and who remained in the hospital for at least 48 hours were included. A computerized database system Pharma IAM- VIDAL version 2011 was used to identify the pattern for potential DDIs. RESULTS: 156 patients were included in this study. The prevalence of potential DDIs was estimated at 93 % (145/156). Forty (5.1%) among 804 potential DDIs identified were observed clinically. The observed DDIs were attributable to low blood pressure (27.5%), hyponatremia (22.5%), hemorrhage (20.0%), hyperkalemia (17.5%) and nephrotoxicity (7.5%). The combination of spironolactone and furosemide resulted in hyponatremia while the combination of enoxaparin and potassium resulted in hyperkalemia. ACE inhibitor (or ARAII) in combination with furosemide resulted in the nephrotoxicity cases observed. Enoxaparin, Acetyl salicylic acid, Acenocoumarol and Clopidogrel were decreasingly involved in the pairs of drugs responsible for observed hemorrhages. 29 patients out of 156 (18.6%) had at least one AE. AEs were mainly (34.2%) of metabolic type. Severe AEs, which represented 18.4% was mostly from nephrotoxicity and metabolic disorders. More than 14 active substances multiplied the risk factor for AEs occurrence by 42, while more than 14 days hospitalization increased this risk by 42. CONCLUSION: This study highlights the need to optimize treatments by strictly regulating blood pressure, serum sodium and potassium levels, coagulation parameters and looking for clinical signs of hemorrhage. Physician should be aware of certain drug associations that may carry a risk of severe adverse events.

There is an urgent need for new pharmacological treatments for substance use disorders, including opioid use disorder, particularly for use in relapse prevention. A combination of buprenorphine with naltrexone has shown particular promise, with clinical studies indicating a substantial improvement over treatment with naltrexone alone. OREX-1019 (formerly BU10119) is a compound that mimics the pharmacology of the buprenorphine/naltrexone combination. This study evaluated, in rhesus monkeys, the therapeutic potential of OREX-1019 for treating opioid use disorder. Pretreatment with OREX-1019 (0.01-0.3 mg/kg s.c.) dose-dependently decreased responding for the μ opioid receptor agonist remifentanil in rhesus monkeys but did not maintain levels of responding above vehicle when it was available for self-administration. OREX-1019 (0.01-1.0 mg/kg s.c.) also decreased cue- plus heroin-primed reinstatement of extinguished responding in monkeys that self-administered remifentanil but did not alter cue- plus cocaine-primed reinstatement of responding in monkeys that self-administered cocaine. OREX-1019 (0.3 mg/kg s.c.), like naltrexone (0.1 mg/kg s.c.), increased heart rate and blood pressure, produced overt observable signs, and eliminated food-maintained responding in monkeys treated chronically with morphine. These results confirm that OREX-1019 has little or no efficacy at μ opioid receptorsand has low abuse potential, and, combined with promising safety (clean profile vs. other off-target proteins including the hERG (human ether-a-go-go-related gene) K+ channel) and pharmacokinetic data (supporting administration by subcutaneous or sublingual routes, but with low oral bioavailability), suggest it could be a safe and effective alternative to current treatments for opioid use disorders particularly as applied to relapse prevention. SIGNIFICANCE STATEMENT: The novel opioid OREX-1019 potentially provides an improved relapse prevention agent for use in opioid use disorder. The current study demonstrates that in monkeys OREX-1019 is able to inhibit the self-administration of, and cue- plus heroin-primed reinstatement of, responding previously maintained by remifentanil.

Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs.

This study investigated gastrointestinal drug concentrations of the weakly acidic drug diclofenac when dosed to healthy volunteers after intake of the FDA standard meal. In gastrointestinal aspiration studies, postprandial conditions are usually achieved using liquid or homogenized meals. However, these liquid meals may have a substantially different impact on the gastrointestinal physiology compared to a solid meal. To evaluate the effect of a solid meal on the gastrointestinal behavior of diclofenac, five healthy volunteers were recruited into a clinical study. Twenty minutes prior to diclofenac ingestion (Cataflam, 50 mg of potassium diclofenac), the volunteers were asked to eat a solid meal with the following composition corresponding to the FDA standard meal: 2 eggs, 2 bacon strips, 2 toasts, 4 ounces of hash brown potatoes, and 8 ounces of milk. Gastric and duodenal fluids were collected as a function of time, and blood samples were collected to link the gastrointestinal behavior to systemic exposure. In vivo observations were complemented with in vitro research to obtain a mechanistic understanding of diclofenac's intraluminal behavior. Ingestion of the solid meal resulted in intraluminal pH-profiles similar to earlier studies with a liquid meal. However, intraluminal drug disposition differed. In the stomach, a substantial fraction of diclofenac appeared dissolved, despite an unfavorable acidic pH. Successive in vitro tests suggested that the dissolution of diclofenac is higher in the complex gastric medium resulting from FDA standard meal ingestion compared to liquid meal ingestion. Despite the favorable pH and in contrast to a previous study with a liquid meal, significant amounts of non-dissolved diclofenac were observed in the intestine. Further in vitro tests revealed adsorption of dissolved diclofenac molecules to bacon fragments present in the FDA standard meal. This adsorption negatively affected the permeation of diclofenac across a physical barrier, suggesting that in vivo absorption is affected as well. Being the first time a gastrointestinal aspiration study is combined with the administration of a solid meal, the present study demonstrates t

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

Salt, promoting oxidative stress, contributes to insulin resistance, whereas K, inhibiting oxidative stress, improves insulin sensitivity. Oxidative stress activation of NLRP3 inflammasome is a central player in the induction of insulin resistance. Therefore, we hypothesised that NLRP3 inflammasome may mediate the effects of salt and K on insulin resistance. In all, fifty normotensive subjects were recruited from a rural community of Northern China. The protocol included a low-salt diet for 7 d, then a high-salt diet for 7 d and a high-salt diet with K supplementation for another 7 d. In addition, THP-1 cells were cultured in different levels of Na with and without K. The results showed that salt loading elevated fasting blood glucose, insulin and C-peptide levels, as well as insulin resistance, whereas K supplementation reversed them. Meanwhile, additional K reversed the active effects of high salt on NLRP3 inflammasome in both the subjects and THP-1 cells, and the change of insulin resistance index notably related with the alteration of plasma IL-1β, the index of NLRP3 inflammasome activation, during intervention in the subjects. Additional K ameliorated oxidative stress induced by high salt in both the subjects and cultured THP-1 cells, and the change of oxidative stress related with the alteration of plasma IL-1β during intervention in the subjects. In vitro, antioxidant N-acetyl-l-cysteine significantly prevented the active effects of high Na or oxidant Rosup on NLRP3 inflammasome, so did K. Our study indicates that oxidative stress modulation of NLRP3 inflammasome may be involved in the impacts of Na and K on insulin resistance.