Ca Channel Blocker Research Articles

Coronary artery spasm - Clinical features, pathogenesis and treatment.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of ischemic heart disease, including angina pectoris, myocardial infarction, and sudden death, occurring most often from midnight to early morning. CAS is prevalent among East Asians and is associated with an aldehyde dehydrogenase 2 (ALDH2)-deficient genotype (ALDH2*2) and alcohol flushing, which is prevalent among East Asians but is virtually non-existent in other populations. ALDH2 eliminates not only acetaldehyde but also other toxic aldehydes from lipid peroxidation and tobacco smoking, thereby protecting tissues and cells from oxidative damage. Risk factors for CAS include smoking and genetic polymorphisms including those of ALDH2*2, endothelial NO synthase, paraoxonase I, and interleukin-6. Accordingly, oxidative stress, endothelial dysfunction, and low-grade chronic inflammation play an important role in the pathogenesis of CAS, leading to increased coronary smooth muscle Ca2+ sensitivity through RhoA/ROCK activation and resultant hypercontraction. Ca-channel blockers blocking the intracellular entry of Ca2+ are specifically effective for treatment for CAS.

Hypertension, Diabetes and Neurodegenerative Diseases: Is there a Clinical Link through the Ca2+/cAMP Signalling Interaction?

Hypertension, diabetes and neurodegenerative diseases are among the most prevalent medical problems around the world, costing millions of dollars to the medical health systems. Indeed, hypertension has been associated with higher risk for decline of cognition, as evidenced in patients with Alzheimer´s disease (AD). Furthermore, there is a clear relationship between hypertension and diabetes, reflecting substantial overlap in their etiology. Calcium (Ca2+) channel blockers (CCBs) have been classically prescribed for treating hypertension because of their mechanism of action due to reducing the influx of Ca2+ into the smooth muscles cells. In addition, many clinical and experimental studies have been demonstrating pleiotropic effects for CCBs. For instance, in hypertensive patients treated with CCBs, it can be observed lower incidence of neurodegenerative diseases such as AD. The virtual mechanism of action could be attributed to a restoration and maintenance of Ca2+ homeostasis, which is dysregulated in the neurodegenerative diseases, including also a reduction of neuronal apoptosis as part of these CCBs pleiotropic effects. Similarly, in hypertensive patients treated with CCBs, it can be observed an improvement of diabetes status such as glycemic control. A possible mechanism of action under debate could be attributed to a restoration of insulin secretion, then achieving glycemic control, and reduction of pancreatic β-cell apoptosis. Considering the discovery of our group entitled "calcium paradox" due to Ca2+/cAMP signalling interaction, in this review I discussed the virtual involvement of this interaction in the pleiotropic effects of CCBs, including the possible role of the Ca2+/cAMP signalling interaction in the association between hypertension and higher risk for the decline of cognition, and diabetes.

Adenosine A3 receptor activation inhibits pronociceptive N-type Ca2+ currents and cell excitability in dorsal root ganglion neurons.

Recently, studies have focused on the antihyperalgesic activity of the A3 adenosine receptor (A3AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A3AR on the excitability of small- to medium-sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3- to 4-week-old rats. Real-time quantitative polymerase chain reaction experiments and immunofluorescence analysis revealed A3AR expression in DRG neurons. Patch-clamp experiments demonstrated that 2 distinct A3AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca-activated K (KCa) currents evoked by a voltage-ramp protocol. This effect was dependent on a reduction in Ca influx via N-type voltage-dependent Ca channels, as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca currents, and its effect was inhibited by 56% in the presence of A3AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A3AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca measurements confirmed the inhibitory role of A3AR on DRG neuronal firing. We conclude that pain-relieving effects observed on A3AR activation could be mediated through N-type Ca channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A3AR-based therapy as a viable approach to alleviate pain in different pathologies.

The use of nootropics in Alzheimer’s disease: is there light at the end of the tunnel?

Background: The nootropic or simply known as smart drug is a common term given to any compound that is responsible for enhancing mental capability or performance. Alzheimer's disease is characterized clinically by lose of cognitive abilities and pathologically by two hallmark lesions, neurofibrillary tangles and senile plaques. It is unfortunate that AD has no cure yet. In this review attempt has been made to elucidate the general views on AD pathogenic hypotheses and common nootropics being used in AD research.
 Methods: Articles from credible scientific data bases such as Sciencdirect, Scopus Pubmed, and Google scholar were searched and retrieved using keywords nootropics', Alzheimer's disease', amyloid beta hypotheses', tau hypotheses', cholinergic hypotheses', oxidative stress' and cognitive impairments'.
 Results: The nootropics act as Ca-channel blockers, AChE inhibitors, glysine antagonists, antioxidants, serotonergic, dopaminergic and glutamic acid receptors antagonists.
 Conclusion: Based on the available literature searched, there is no doubts the nootropics are attenuating cognitive deficits in both preclinical and clinical studies on AD.

Cytotoxicity of a titanium alloy coated with hydroxyapatite by plasma jet deposition

Background/Aim. The deposition of hydroxyapatite (HAP) on the surface of titanium (Ti) alloys enhances bioactivity and osseointegration of the alloys which are widely used as implant materials in dentistry and orthopaedic surgery. However, the stability of HAP and subsequent biocompatibility of such alloys depends on the coating technique. The aim of this work was to test the cytotoxicity of a Ti alloy (Ti6Al4V), coated with HAP by a new plasma deposition method. Methods. The Ti6Al4V samples prepared as discs, 10 mm in diameter and 2 mm in thickness, were coated with HAP (one or both sides of the alloy) by an innovative atmospheric plasma jet method. The cytotoxicity of uncoated and HAP coated Ti6Al4V samples was evaluated by examining the morphological changes and viability of L929 fibroblasts in direct contact with the test materials. Adequate negative (polystyrene) and positive (nickel) control discs of the same size were used. The indirect cytotoxicity was determined by cultivating L929 cells with conditioning medium (CM), prepared as extract of the test samples incubated in the complete Roswell Park Memorial Institute (RPMI) 1640 medium for cell cultures. The cytotoxic effect was evaluated based on the degree of metabolic activity, necrosis, apoptosis and proliferation of L929 cells, using the appropriate assays. Results. Uncoated and one side HAP coated Ti6Al4V alloys were classified as non-cytotoxic according to the current ISO 10993-5 criteria, whereas two sides HAP coated Ti6Al4V alloy samples were slightlymoderate cytotoxic. The cytotoxicity manifested as the inhibition of metabolic activity and proliferation of L929 cells as well as the induction of their apoptosis and necrosis was significantly reduced by conditioning of HAP/Ti6Al4V alloys for 24 hours. The cytotoxic effect of HAP/Ti6Al4V CM only partly decreased in the presence of nifelate, a calcium (Ca) channel blocker, suggesting that Ca ions were not the only responsible cytotoxic agent. Conclusion. The original HAP coating procedure by atmospheric plasma spraying with high energy input enables the production of the stable adhesive coatings on Ti6Al4V alloys. Their cytotoxicity, which depends on the quantity of HAP coating layer, could be significantly reduced up to the non-cytotoxic level by prior conditioning of the alloys in culture medium. Such a procedure, which removes leachable toxic components, could be useful before implantation of HAP coated alloys in vivo.

Management of preterm labour In Sohag University hospital: A clinical audit

Objective : Auditing the current management of preterm labor in department of Obstetrics and Gynaecology, Sohag University hospital against RCOG recommendations ,Identifying the gap between the current practice and ideal practice and Setting recommendations for filling the gap(if present) to improve neonatal and maternal out comes. Methods : This is an observational study which was conducted at Sohag University hospital durin the period from 1 march 2017 to 31 December 2017. All patients with preterm birth who admitted to Sohag university hospital during the study period were included into the study and their data were recorded in a special check list sheet. IBM-SPSS ( version 24) was used for statistical data analysis. Results : The mean age of our studied group was 26.01±5.15 and 81.1 % of them were rural,48 cases had scarred uterus due to mostly previous caesarean section, while the other 79 cases had non scarred uterus. Also, a little more than half of our cases (66 cases, 52%) .UTI were the only indication for the use of antibiotics .Antibiotics not used for prophylactic in management of preterm birth in our study which is recommended by RCOG .Vaginal swab for oncofetal fibronictine or GBS/vaginal infection were not done as it is not accepted in our department which is against RCOG recommendation .Tocolysis failed in 12 cases out of the 15 multiple pregnancy cases, with a significant difference from the failure rate among singleton pregnancy women .As regard RCOG recomendatins : There is insufficient evidence for any firm conclusions about whether or not tocolysis leads to any benefit in preterm labour in multiple pregnancy. Conclusion : The use of Mgso4 as IV tocolytic drug in our hospital play effective role in prevention of preterm labour and giving the chance for receving the dexamethasone but we need to modyfiy our strategy and using other tocolytic drugs as Ca channel blocker as recommended

Nickel uptake mechanisms in two Iranian nickel hyperaccumulators, Odontarrhena bracteata and Odontarrhena inflata

Mechanisms and transporters responsible for Ni uptake in plants are largely unknown. To characterize Ni uptake mechanisms in Ni hyperaccumulators, we compared the effects of channel blockers, high Ca, high Fe, Zn, Mn, Cu, or Co, and low temperature on Ni uptake in two Iranian serpentine endemics, Odontarrhena bracteata and (two populations of) O. inflata. Ni uptake was measured in the presence and absence of the K and Ca channel blockers, tetraethylammonium (TEA) and verapamil, respectively, at high and low Ca, and with and without (additional) Fe, Zn, Cu, Mn or Co (100 μM) in the nutrient solution. To estimate the potential contribution of passive uptake, Ni uptake was also measured at low and high temperature (4 and 25 °C). Verapamil inhibited Ni uptake by 65, 72, and 91% in O. bracteata, O. inflata from Baneh, and O. inflata from Marivan, respectively, but TEA was without effect. High Ca inhibited Ni uptake by 30 to 40%. Mn inhibited Ni uptake by about 40% in all species/populations. Fe inhibited Ni uptake, by about 30%, in O. bracteata, but not at all in O. inflata. Other metals had no effect. Low temperature decreased Ni uptake by ±70% in both species/populations. In Odontarrhena Ni hyperaccumulators Ni is predominantly taken up via Ca channels. A Fe-deficiency inducible transporter contributes to Ni uptake in O. bracteata, but not in O. inflata. A relative small part of the Ni uptake in O. inflata (10–30%) remains unexplained. In any case, it is most probably neither mediated by apoplastic transport, nor by more or less specific transporters of Zn, Fe, Mn, or Co.

Preliminary analysis of the effect of Stevia (Stevia rebaudiana) in patients with chronic kidney disease (stage I to stage III).

BackgroundStevia, Stevia rebaudiana (Bertoni), has become an important economic plant for its commercial use as a sweetener. Stevia plays a significant role in the healthcare practice of different cultures and in population. Previous animal and clinical studies demonstrated the efficacy of Stevia against chronic diseases like diabetes and hypertension. This study aimed to investigate the beneficial effect of Stevia in chronic kidney disease (CKD) patients after three (3) months of treatment along with the conventional antihypertensive and anti diabetic medications.MethodsA prospective, interventional, randomized, single-blind, placebo-controlled trial has been done with 97 participants. Stevia capsule (250 mg) or matching placebo was given to the participants twice daily along with Angiotensin-II Receptor Blocker (ARB) and/or Ca2+ Channel Blocker (CCB). First follow up visits were done after 3 months of the interval. Blood and urine samples were collected for the biochemical tests. A structured questionnaire was used for the baseline assessment. Informed consent was taken from each participant.ResultsBoth hypertension and diabetes were found to be associated with CKD. Most of the participants (52.3%) of Stevia group were in CKD Stage II. Significant changes were found in Serum creatinine (p < 0.027), Serum Uric acid (p < 0.009), Fasting blood sugar (p < 0.041) and Postprandial blood sugar (p < 0.013) and Microalbumin (p < 0.041) level in the treatment group.ConclusionThe initial result demonstrated that Stevia has the potential for a significant improvement of some biochemical parameters in CKD patients. After completion of the nine (9) months clinical trial, the constructive effect of Stevia can be confirmed in this group of patients.

Treatment of cyclosporine induced hypertension: Results from a long-term observational study using different antihypertensive medications

Post-transplant hypertension (PTH) is a common complication in cyclosporine immunosuppressed patients; however choosing the right antihypertensive medication is challenging. In a long-term observational study (≤13y) we examined different antihypertensive medications on graft/patient survival of kidney recipients with pre-existing and PTH. Altogether thirty-three co-variables were analyzed including dose and type of immunosuppressive and antihypertensive medication, co-medications, serum biochemistries and the glomerular filtration rate (GFR). A Cox proportional-hazard multivariable survival model was developed to detect a Hazard Ratio (HR) of 3.0 at the Bonferroni corrected level α = 0.0015. Importantly, a significant relationship between immunosuppressive cyclosporine dose/serum concentration, systolic blood pressure (SBP) and GFR (p < 0.001) was observed with post-transplant hypertension being a major risk factor (HR6.1) for graft/patient survival. Although all medications lowered effectively elevated SBP the risk of graft failure/death was significantly increased when hypertension was treated with ACE inhibitors or β-blockers (HR3.3 and 3.1) but not with angiotensin receptor- and/or Ca-channel blockers. Antihypertensive medication was associated with a decline in GFR but β-blockers alone or in combination with ARB and/or CCB improved GFR. Neither BMI nor any of the drug combinations used in immunosuppression, i.e. prednisolone, mycophenolic acid, azathioprine and/or sirolimus influenced patient and/or graft survival while decision tree analyses informed on complex dependencies between immunosuppressive medications, dose of anti-hypertensive drug and diuretics in the management of hypertension. In conclusion, our study is suggestive for graft/patient survival to be influenced by the class of antihypertensive medication. A prospective randomized clinical trial is needed to confirm the results.

A Sialylated Voltage-Dependent Ca2+ Channel Binds Hemagglutinin and Mediates Influenza A Virus Entry into Mammalian Cells

Influenza A virus (IAV) infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV infection has remained unidentified. Here, we show that HA binds to the voltage-dependent Ca2+ channel Cav1.2 to trigger intracellular Ca2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca2+ channel blockers (CCBs) or by knockdown of Cav1.2. The CCB diltiazem also inhibited virus replication invivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Cav1.2 restored Ca2+ oscillations and virus infection in Cav1.2-depleted cells, demonstrating the significance of Cav1.2 sialylation. Taken together, we identify Cav1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.

Contribution of BKCa channel to tone regulation by PDE3 and PDE4 depends on the mode of cAMP stimulation and is lost in heart failure

Regulation of vascular tone by 3’,5’-cyclic adenosine monophosphate (cAMP) involves many effectors, including large conductance, Ca 2+ -activated, K + (BK Ca ) channels. In arteries, cAMP is mainly hydrolyzed by type 3 and 4 phosphodiesterases (PDE3 and PDE4). Here, we examined the specific contribution of BK Ca channels to tone regulation by these PDEs in rat coronary arteries (CA), and how it may be altered in heart failure (HF). CA were isolated from young adult rats or rats with HF sacrificed 22 weeks after surgical stenosis of the ascending aorta. Age-matched sham animals were used as controls. Tension measurements were conducted on CA contracted using the thromboxan analogue U46619. Myocytes were isolated from CA and used for patch clamp recordings or for proximity ligation assay (PLA). Selective PDE3 (cilostamide, Cil) or PDE4 (Ro-20-1724, Ro) inhibition evoked vasorelaxation that was greatly reduced by iberiotoxin (IBTX), a BK Ca channel blocker. Ro and Cil potentiated the relaxation induced by the β-adrenergic agonist isorenaline or the adenylyl cyclase activator L-858051. IBTX abolished the effect of PDE inhibitors on isoprenaline but did not on L-858051. Ro and Cil together increased single BK Ca channel activity in myocytes. CA isolated from rats displaying robust signs of HF showed poor contractile capacity and relaxation to acetylcholine compared to sham rats. In contrast to sham, relaxations induced by PDE inhibitors in HF-CA were not sensitive to IBTX. Expression of the BK Ca channel was 2-fold lower in HF-CA compared to sham-CA. Amount of a 70kDa-PDE4B was increased in HF. PLA demonstrated that PDE3 and PDE4 were localized in the vicinity of the channel. BK Ca -PDE4B duplex was less abundant in HF. BK Ca channels mediate the relaxation of rat CA induced by PDE3 and PDE4 inhibition. Their relative contribution, however, vary with the grade of cAMP stimulation and the physiopathological context of HF.

Abstract TP299: Early Mortality Prediction in Ischemic Stroke

Introduction: Ischemic stroke (IS) is a medical emergency with a high risk of morbidity, leading to disability, and mortality. IS’s impact on our patients’ lives and healthcare system make it essential to optimize its immediate management, triage requirements, and plans for transfer to comprehensive stroke centers. In this study, we hypothesized that it is possible to predict the mortality of IS patients within the first hour of hospital admission. Methods: With the approval of the Human Studies Committee (IRB #: 13.0396), we performed a retrospective analysis from the Stroke Quality Database. Patients who were admitted between 2007-2012 were included. In-hospital mortality was the main outcome of the study. Patients’ demographics, baseline illnesses, home medications, baseline neurological assessment scores, and basic laboratory values on admission were included in the analysis as potential factors. Multivariate analysis was performed to assess the independent contributing factors. Data is presented as odds ratio and 95% confidence intervals. Results: IS in-hospital mortality was about 10% in our study population. Multivariate analysis was performed in 2,131 patients. NIH Stroke Scale on admission, recurrent stroke, high WBC levels (&gt;11K), elderly age, AHA Stage II hypertension, baseline use of Ca-channel blockers, and beta-blockers, admission glucose levels and albumin levels independently contributed to in-hospital mortality (Table). Conclusions: IS patients’ baseline characteristics, hospital admission assessment scales, and laboratory values on admission contributed to prediction of in-hospital mortality. Therefore, it is essential to rapidly initiate acute care for high-risk and complex stroke patients. Additionally, focusing on the modifiable factors such as blood pressure management, treating acute infections, and managing glucose levels may help to decrease acute IS mortality.

Ca2+ and Camp: Do these Intracellular Messengers Work’Independently? Of Course Not, and the History Goes Ahead…

Our group has been pioneering in exploring that the pharmacological handling of Ca2+/cAMP signalling interaction could be a better therapeutic method for increasing neurotransmission in psychiatric disorders, and stimulating neuroprotection for combating neurodegenerative diseases, such as Alzheimer´s disease. Indeed, Ca2+ is a classic intracellular second messenger, now well recognized as a ubiquitous molecule that controls several processes, including gene transcription, cell cycle regulation, mobility, apoptosis, neurotransmitter release and muscle contraction. In addition, cAMP, another vital intracellular messenger, modulates since cardiac contraction to neurotransmitter release. Do these intracellular messengers ´work´ independently? Of course not, and we demonstrated it! Through groundbreaking experiments (including one by accident!), our group discovered that the paradoxical effects (e.g. reduction of intracellular Ca2+ concentration, and enhancing of neurotransmitter release?!) produced by L-type Ca2+ channel blockers (CCBs) resulted from interferences on the Ca2+/ cAMP signalling interaction. Considering the widely use of CCBs as antihypertensive drugs, and for combating arrhythmia, the elucidation of these paradoxical effects proved to be very important (specially for clinical reasons). How does this history correlate to cancer field? Considering the notion that Ca2+/cAMP signalling interaction is a fundamental cellular process, which exists in many cell types, whether this interaction may be a novel therapeutic target to alter cancer tumor growth, angiogenesis and metastasis, without affecting normal cell physiology deserves special consideration. Thus, this editorial article highlights the latest advances made by our group in the field of Ca2+/cAMP signalling interaction.

Functional Comparison of Cultures of IPSC-Derived Human Neurons and Rodent Neurons

Functional Comparison of Cultures of IPSC-Derived Human Neurons and Rodent Neurons

O11-2 - Is ARB/CCB Combination Superior to ARB/HCTZ Combination in Day-by-day Blood Pressure Variability Reduction? A Prospective Randomized Trial

Background: Day-by-day blood pressure variability (DDV) is an independent risk for cardiovascular events. An angiotensin II receptor blocker (ARB) combined with a Ca channel blocker (CCB) or hydrochlorothiazide (HCTZ) is an established option for combination therapy to achieve target blood pressure (BP). However, little is known about the effects of these combinations on DDV of home BP. Thus, we investigated whether ARB/CCB combination would be superior to ARB/HCTZ combination in DDV reduction. Methods: This prospective, randomized, open-labeled, multicenter trial enrolled 926 outpatients who had not achieved home BP target (<135/85 mmHg) despite antihypertensive medications. Patients were randomly assigned to receive a 8-mg candesartan/5-mg amlodipine tablet (ARB/CCB group) or a 8-mg candesartan/6.25-mg HCTZ tablet (ARB/HCTZ group) once every morning. Intra-individual DDV was assessed by standard deviation and coefficient of variance of systolic BP of home BP home BP of the consecutive 7 mornings. Results: After 6-month treatment, ARB/CCB and ARB/HCTZ reduced morning home BP and DDV to the similar levels. On subgroup analysis, ARB/CCB group showed greater reductions in morning home BP and DDV than ARB/HCTZ group in February, May, April, and October. Conclusions: Strict BP lowering is important for DDV reduction in home BP, irrespectively of antihypertensive regimen. ARB/CCB combination may have advantage to reduce DDV when the seasons change.

Community Noise Exposure and its Effect on Blood Pressure and Renal Function in Patients with Hypertension and Cardiovascular Disease

Road traffic noise (RTN) is a risk factor for cardiovascular disease (CVD) and hypertension; however, few studies have looked into its association with blood pressure (BP) and renal function in patients with prior CVD. This study aimed to explore the effect of residential RTN exposure on BP and renal function in patients with CVD from Plovdiv Province. We included 217 patients with ischemic heart disease and/or hypertension from three tertiary hospitals in the city of Plovdiv (March - May 2016). Patients' medical history, medical documentation, and medication regimen were reviewed, and blood pressure and anthropometric measurements were taken. Blood samples were analyzed for creatinine, total cholesterol, and blood glucose. Participants also filled a questionnaire. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. All participants were asked about their annoyance by different noise sources at home, and those living in the city of Plovdiv (n = 132) were assigned noise map Lden and Lnight exposure. The effects of noise exposure on systolic blood pressure (SBP), diastolic blood pressure (DBP), and estimated glomerular filtration rate (eGFR) were explored using mixed linear models. Traffic noise annoyance was associated with higher SBP in the total sample. The other noise indicators were associated with non-significant elevation in SBP and reduction in eGFR. The effect of Lden was more pronounced in patients with prior ischemic heart disease/stroke, diabetes, obesity, not taking Ca-channel blockers, and using solid fuel/gas at home. Lnight had stronger effect among those not taking statins, sleeping in a bedroom with noisy façade, having a living room with quiet façade, and spending more time at home. The increase in Lden was associated with a significant decrease in eGFR among men, patients with ischemic heart disease/stroke, and those exposed to lower air pollution. Regarding Lnight, there was significant effect modification by gender, diabetes, obesity, and time spent at home. In some subgroups, the effect of RTN was statistically significant. Given that generic risk factors for poor progression of cardiovascular diseases cannot be controlled sufficiently at individual level, environmental interventions to reduce residential noise exposure might result in some improvement in the management of blood pressure and kidney function in patients with CVD.

Carvedilol in the everyday interventional cardiology practice

The treatment of severe coronary stenoses with stent implantation is very effective nevertheless, the underlying problem of atherosclerosis remains unsolved with the implantation of a stent. Therefore, besides lifestyle changes, the adequate medication therapy is of pivotal importance. In the majority of patients scheduled for or acutely undergoing catheterisation, beta-blockers form the basis of medication therapy. Members of the group, however, show significant differences in terms of pharmacodynamics. The third-generation beta-blocker and vasodilator carvedilol possesses complex adrenerg-blocking and Ca-channel blocking effects as well. In the background of the favourable effects, a further positive property is its anti-free-radical effect which most beta-blockers do not have. Therefore, as has been proven by several studies, it provides considerable benefits in hypertension, after myocardial infarction, in diabetes and also in the treatment of patients with cardiac failure. These positive effects have been markedly observed in interventional cardiology practice, as the majority of patients undergoing cardiac catheterisation have hypertension, diabetes or hyperlipidaemia. Its anti-free-radical effect is especially beneficial together with its smooth muscle proliferation-inhibitor effect which may favourably affect in-stent restenosis (ISR) as well. To summarise, due to its vasculoprotective effect, carvedilol is an ideal drug of choice following stent implantation in routine everyday practice. Orv Hetil. 2017; 158(37): 1453-1457.

Pharmaceutical intervention on Ca2+/cAMP signaling interaction: benefits for combating neurodegeneration and diseases related to aging

The pharmaceutical intervention on the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) could bring important benefits for combating neurodegeneration and diseases related to aging. This discovery emerged from classical neurotransmission studies using rodent vas deferens as a model. From classical reports using this model, the concept of Ca2+-dependent processes involved in the neurotransmission (Ca2+ influx triggers muscle contraction and neurotransmitter release) is amply accepted. Thus, Ca2+ channel blockers (CCB) due to reduction of Ca2+ influx through L-type voltage-activated Ca2+ channels (VACC) should reduce neurotransmission. Nonetheless, using this model, some studies performed since 1975 reported that reduction of Ca2+ influx by low concentrations of CCB (verapamil, diltiazem or nifedipine) produced a paradoxical increase of the contractions mediated by sympathetic nerves, a phenomenon known as “calcium paradox”. Recent studies using adrenal chromaffin cells have also demonstrated that CCB caused a paradoxical increase of the catecholamine release. Because these compounds are blocking the L-type VACC, an augmented nerve-mediated response due to increased neurotransmitter release was an unexpected outcome. In 2013, we revealed that the Ca2+/cAMP signaling interaction could properly explain the so-called “calcium paradox”. The original paper published by us in Cell Calcium (2013) has appeared four times in ScienceDirect TOP 25 Hottest Articles lists. In conclusion, these findings may significantly impact on neurodegenerative diseases, thus may stimulate the development of new pharmacological strategies to combat the diseases related to aging.

Effect of Crude Venom of Odonthobuthus doriae Scorpion in Cell Culture using Ion Channel Modulators.

Scorpion venom toxicity is one of the major medical concerns from old years, due to its influence on human activities and health. From many years ago a lot of researches established to examine different aspects of venom toxicity and its effects on different organs. During these years researchers are doing more specific studies on the cytotoxicity of scorpion venom. In Iran, Odonthobuthus doriae, the yellow scorpion is one of the major threats based on its neuro toxicity and severe pathophysiologic effects and researchers tried to find the mechanism of these neuro toxic effects. The previous studies have shown that in isolated organs the yellow scorpion venom is affecting the ion channels. Also some studies showed that this venom has severe cytotoxic effects on the cell lines with many ion channels like nerve cell lines. In this study, the cytotoxic effect of the crude venom of O.doriae on the 1321N1 cell line (cancerous nerve cells) was studied. Primary cell cultured investigated in the presence of different ion channel blockers: Ouabain (1mmol as Na channel blocker), Nifedipin (100 µmol as Ca channel blocker), and TEA (40 mmol as K channel blocker) by MTT method. The result showed that the O.doriae crude venom has cytotoxic effect via Na channels.

From a "Eureka Insight" to a Novel Potential Therapeutic Target to Treat Alzheimer's Disease

It has been almost 4 years since we revealed the solution for the enigma of the so-called 'calcium paradox'. Our discovery of the involvement of Ca2+/cAMP signaling interaction in the regulation of neurotransmitter release, and neuro protection, was clearly a serendipitous discovery. It has produced new avenues in the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease. Interestingly, this discovery initiated decades ago when numerous clinical studies have reported that use of L-type Ca2+ channel blockers (CCBs) by hypertensive patients decreased arterial pressure, but produced typical symptoms of sympathetic hyperactivity, such as tachycardia and increment of catecholamine plasma levels.