Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels.Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships.Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27–37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2–3 μM), while Q52R inhibition was 15–20% at 10 μM.Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.

Retroviral Glycoprotein-Mediated Immune Suppression via the potassium Channel KCa3.1- A new strategy for treatment of Inflammatory Bowel Diseases.

Background and Purpose: Peptides derived from retroviral envelope proteins have been shown to possess a wide range of immunosuppressive and anti-inflammatory activities. We have previously reported identification of such a peptide derived from the envelope protein coded by a human endogenous retrovirus (HERV). In this study we assessed effects of this peptide treatment on inhibition of immune response in the DSS-induced mice model of colitis. Furthermore, we identified that in vitro the peptide inhibits the KCa3.1 potassium channel, a potential target for therapy of immune diseases. Experimental Approach: We characterized an immunosuppressive peptide ENV59, from a specific HERV envelope protein, in vivo effects on inflammation control in acute colitis mice model and in vitro on the production of pro-inflammatory cytokines. Furthermore, we described in vitro ENV59-GP3 effects with respect to potency of inhibition on KCa3.1 channels and calcium influx. Key Results: ENV59-GP3 peptide treatment showed reduction of the disease score in the DSS-induced acute colitis mice model, which was comparable to effects of the KCa3.1 channel blocker NS6180. Analysis of cytokine production from DSS-mice model treated animals revealed equipotent inhibitory effects of the ENV59-GP3 and NS6180 compounds on the production of IL-6, TNF-α, IL-1β. Patch clamp studies show that the peptide ENV59-GP3 is a blocker of the potassium channel KCa3.1. Conclusion and Implications: Env59-GP3 represents KCa3.1 channel inhibitor underlining the implications of using virus derived channel blockers for treatment of autoimmune diseases. There are no drugs with a similar mechanism of action currently on the market.

Myocardial Infarction

Myocardial infarction (MI), commonly known as a heart attack is the disease of the blood vessels supplying the heart muscle (Myocardium) i.e. coronary heart disease. The area of heart muscle that has either zero flow or so little flow that it cannot sustain cardiac muscle function is said to be infracted and the overall process is called a myocardial infarction. MI are of two types; transmural and subendocardial. Mainly it is caused due to oxidative stress and atherosclerosis.Chest pain is the most common symptom of acute MI and is often described as a sensation of tightness, pressure, or squeezing. Other symptoms include diaphoresis (an excessive form of sweating), Shortness of breath (dyspnea), weakness, light-headedness, nausea, vomiting, and palpitations. The most common symptoms of MI in women include dyspnea, weakness, and fatigue, sleep disturbances. It can be treated by using blockers, diuretics, ACE inhibitors, calcium channel blockers and nitrates.

Oral Antihypertensives for Nonsevere Pregnancy Hypertension: Systematic Review, Network Meta- and Trial Sequential Analyses

Background: We aimed to address which antihypertensives are superior to placebo/no therapy or another antihypertensive for controlling nonsevere pregnancy hypertension and provide future sample size estimates for definitive evidence. Methods: Randomized trials of antihypertensives for nonsevere pregnancy hypertension were identified from online electronic databases, to February 28, 2021 (registration URL: https://www.crd.york.ac.uk/PROSPERO/ ; unique identifier: CRD42020188725). Our outcomes were severe hypertension, proteinuria/preeclampsia, fetal/newborn death, small-for-gestational age infants, preterm birth, and admission to neonatal care. A Bayesian random-effects model generated estimates of direct and indirect treatment comparisons. Trial sequential analysis informed future trials needed. Results: Of 1246 publications identified, 72 trials were included; 61 (6923 women) were informative. All commonly prescribed antihypertensives (labetalol, other β-blockers, methyldopa, calcium channel blockers, and mixed/multi-drug therapy) versus placebo/no therapy reduced the risk of severe hypertension by 30% to 70%. Labetalol decreased proteinuria/preeclampsia (odds ratio, 0.73 [95% credible interval, 0.54–0.99]) and fetal/newborn death (odds ratio, 0.54 [0.30–0.98]) compared with placebo/no therapy, and proteinuria/preeclampsia compared with methyldopa (odds ratio, 0.66 [0.44–0.99]) and calcium channel blockers (odds ratio, 0.63 [0.41–0.96]). No other differences were identified, but credible intervals were wide. Trial sequential analysis indicated that 2500 to 10 000 women/arm (severe hypertension or safety outcomes) to >15 000/arm (fetal/newborn death) would be required to provide definitive evidence. Conclusions: In summary, all commonly prescribed antihypertensives in pregnancy reduce the risk of severe hypertension, but labetalol may also decrease proteinuria/preeclampsia and fetal/newborn death. Evidence is lacking for many other safety outcomes. Prohibitive sample sizes are required for definitive evidence. Real-world data are needed to individualize care.

Korea hypertension fact sheet 2021: analysis of nationwide population-based data with special focus on hypertension in women

Background The Korean Society of Hypertension has published the Korea Hypertension Fact Sheet 2021 to provide an overview of the magnitude and management status of hypertension and their recent trends. Methods The Fact Sheets were based on the analyses of Korean adults aged 20 years or older of the 1998–2019 Korea National Health and Nutrition Examination Survey and the 2002–2019 National Health Insurance Big Data. Results Currently, the population average of systolic/diastolic blood pressure was 119/76 mmHg in Korean adults aged 20 years or older showing little change in the recent decade. It is estimated that 28% of the adult population aged 20 or older (33% of adults aged 30 or older) have hypertension. The estimated number of people with hypertension was 6.30 million for men and 5.77 million for women, and 1.96 million for men and 2.99 million for women among the population aged 65 or older. The number of people diagnosed with hypertension increased from 3.0 million in 2002 to 10.1 million in 2019. During the same period, the number of people using antihypertensive medication increased from 2.5 million to 9.5 million, and the number of people adherent to treatment increased from 0.6 million to 6.9 million. Among antihypertensive prescriptions, 40.6% of the patients received monotherapy, 43.4% received dual therapy, and 16.0% received triple or more therapy. The most commonly prescribed antihypertensive medication was angiotensin receptor blockers (ARB), followed by calcium channel blockers (CCB) and diuretics. In young women, angiotensin-converting enzyme inhibitors (ACEi), ARB and CCB are less frequently prescribed than in men, but 59.5% of hypertensive women aged 20–39 are prescribed ACEi or ARBs. Hypertensive disorders during pregnancy have been increasing over the past 10 years. In 2019, 5.4% of women who gave birth were diagnosed with chronic hypertension and 3.1% with pregnancy-induced hypertension. Conclusions To achieve further improvement in management of hypertension, we need to encourage awareness and treatment in young adults. It is required to develop tailored prevention and management strategies that are appropriate for and inclusive of various demographics.

Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

Hereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

Juxtaglomerular cell tumour of the kidney: a rare cause of resistant hypertension

Summary Juxtaglomerular cell tumour (JGCT) is an unusually encountered clinical entity. A 33-year-old man with severe long-standing hypertension and hypokalaemia is described. The patient also suffered from polyuria, polydipsia, nocturia and severe headaches. On admission, laboratory investigation revealed hypokalaemia, kaliuresis, high aldosterone and renin levels, and the abdomen CT identified a mass of 4 cm at the right kidney. Kidney function was normal. Following nephrectomy, the histological investigation revealed the presence of a JGCT. Immunostaining was positive for CD34 as well as for smooth muscle actin and vimentin. Following surgery, a marked control of his hypertension with calcium channel blockers and normalization of the serum potassium, renin or aldosterone levels were reached. According to our findings, JGCT could be included in the differential diagnosis of secondary hypertension as it consists of a curable cause. The association of JGCT with hypertension and hypokalaemia focusing on the clinical presentation, diagnostic evaluation and management is herein discussed and a brief review of the existing literature is provided. Learning points Juxtaglomerular cell tumours (JGCT), despite their rarity, should be included in the differential diagnosis of secondary hypertension as they consist of a curable cause of hypertension. JGCT could be presented with resistant hypertension along with hypokalaemia, kaliuresis and metabolic alkalosis. Early recognition and management can help to prevent cardiovascular complications. Imaging (enhanced CT scans) may be considered as the primary diagnostic tool for the detection of renal or JGCT. For the confirmation of the diagnosis, a histopathologic examination is needed.