Calcium Channel Blockade Research Articles

Specific Localization of an Auto-inhibition Mechanism at Presynaptic Terminals of Identified Serotonergic Neurons

Auto-regulation mechanisms in serotonergic neurons regulate their electrical activity and secretion. Since these neurons release serotonin from different structural compartments – including presynaptic terminals, soma, axons and dendrites – through different mechanisms, autoregulation mechanisms are also likely to be different at each compartment. Here we show that a chloride-mediated auto-inhibitory mechanism is exclusively localized at presynaptic terminals, but not at extrasynaptic release sites, in serotonergic Retzius neurons of the leech. An auto-inhibition response was observed immediately after intracellular stimulation with an electrode placed in the soma, in neurons that were isolated and cultured retaining an axonal stump, where presynaptic terminals are formed near the soma, but not in somata isolated without axon, where no synaptic terminals are formed, nor in neurons in the nerve ganglion, where terminals are electrotonically distant from the soma. Furthermore, no auto-inhibition response was detected in either condition during the longer time course of somatic secretion. This shows that the auto-inhibition effects are unique to nerve terminals. We further determined that serotonin released from peri-synaptic dense-core vesicles contributes to auto-inhibition in the terminals, since blockade of L-type calcium channels, which are required to stimulate extrasynaptic but not synaptic release, decreased the amplitude of the auto-inhibition response. Our results show that the auto-regulation mechanism at presynaptic terminals is unique and different from that described in the soma of these neurons, further highlighting the differences in the mechanisms regulating serotonin release from different neuronal compartments, which expand the possibilities of a single neuron to perform multiple functions in the nervous system.

Abstract 12885: Sleepless Nights and Squeamish Days: A Conundrum of Recurrent Myocardial Ischemia

A 63-year old Caucasian female with history of aortic valve replacement and CAD with prior drug-eluting stent placement (DES) to proximal LAD and LCX, presented as a hospital transfer with recurrent episodes of chest pain. Chest discomfort was described as severe chest pressure, radiating to bilateral upper extremities. Episodes were not associated with significant exertion and frequently occurred at night/early morning. Of note, the patient had undergone coronary angiography at the outside hospital, revealing no in-stent restenosis or new coronary lesions. Soon after the patient’s arrival in the CCU, she developed profound chest pressure, accompanied by hypotension, diaphoresis and nausea. Her 12-lead ECG revealed 2-mm ST-elevation in aVR, accompanied by ST-depression in inferior, anterior, and apical leads. Initial high-sensitivity (hs)-troponin T was 26 ng/L. She was given sublingual nitroglycerin and was started on a nitroglycerin and nicardipine infusion, with resolution of symptoms after ~30 minutes, followed by normalization of hs-troponin T. A transthoracic echocardiogram did not reveal focal left ventricular (LV) wall motion abnormalities, mild LV hypertrophy was present. Given the patients’ presentation with no in-stent restenosis or new lesions, frequent episodes of chest pain-not related to exertion with occurrence at nighttime and early morning, her presentation was deemed to be consistent with epicardial coronary vasospasm. Subsequently, the patients’ anti-anginal regimen was uptitrated to include extended-release nitrates, calcium-channel blockade, and I Na blockade. Unfortunately, she continued to have frequent episodes of profound angina, accompanied by hypotension, and significant ischemic ECG changes. This prompted us to pursue bilateral sympathectomy. Subsequently, the patient had resolution of prior symptoms. She was continued on an anti-vasospastic regimen, consisting of extended release nitrates and calcium-channel blockade. This case represents the challenging management of medication-resistant epicardial coronary artery vasospasm. As previously described, sympathectomy remains an effective therapeutic option for management in these difficult and life-threatening situations.

Antispasmodic effects of the essential oil of Croton zehnteneri, anethole, and estragole, on tracheal smooth muscle

Croton zehntneri is a plant well adapted to the semi-arid climate of northeastern region of Brazil. The essential oil of C. zehntneri (EOCz) has been described to have several pharmacologic properties, including effect on airflow resistance of in vivo respiratory system. For this reason, we investigated the hypothesis that EOCz and its major constituents, anethole and estragole, have antispasmodic activity on tracheal muscle. In tracheal rings of Wistar rats, maintained in Krebs-Henseleit's solution, EOCz, anethole and estragole inhibited contractions induced by 60mM [K+], ACh (10μM), Ba2+ and Phorbol dibutirate (1 μM). For EOCz, anethole and estragole, the IC50 for inhibition of KCl-induced contractions were 145.8 ± 14.8, 89.9 ± 7.4 and 181.0 ± 23.3 μg/mL, respectively, and for ACh-induced contraction, they were 606.1 ± 122.0, 160.5 ± 33.0 and 358.6 ± 49.2 μg/mL. Pharmacodynamic efficacy was maximal in all cases. These data in Ba2+-induced contraction and the differential IC50 suggested that blockade of Voltage Dependent Calcium Channels (VDCC) is a component of the mechanism of action of the three agents. Evaluation of the direct effect of anethole, on VDCC, showed inhibition of the Ca2+ current through this type of channel. These results show that EOCz and the constituents have antispasmodic activity and the mechanism includes blockade of VDCC channels.

Binge Alcohol Exposure Triggers Atrial Fibrillation Through T-Type Ca2+ Channel Upregulation via Protein Kinase C (PKC) / Glycogen Synthesis Kinase 3β (GSK3β) / Nuclear Factor of Activated T-Cells (NFAT) Signaling - An Experimental Account of Holiday Heart Syndrome.

The association between binge alcohol ingestion and atrial fibrillation (AF), often termed "holiday heart syndrome", has long been recognized. However, the underlying cellular and molecular mechanisms are unknown. An experimental model of binge alcohol-induced AF was developed to elucidate the mechanisms linking acute ethanol exposure to changes in ion channel transcription and AF susceptibility. AF-susceptibility during transesophageal electrical stimulation was enhanced 8 h after, but not immediately or 24 h after, acute alcohol intake. T-type calcium channel (TCC) blockade and calcineurin inhibition diminished the AF-promoting effect of ethanol. Long-term (8-24 h) exposure to ethanol augmented TCC isoform-expression (Cav3.1 and Cav3.2) and currents in cardiomyocytes, accompanied by upregulation of the transcription factors, Csx/Nkx2.5 and nuclear factor of activated T-cells (NFAT), in the nucleus, and of phospho-glycogen synthesis kinase 3β (GSK3β) in the cytosol. Inhibition of protein kinase C (PKC) during the 7- to 8-h period following ethanol exposure attenuated susceptibility to AF, whereas acute exposure did not. GSK3β inhibition itself upregulated TCC expression and increased AF susceptibility. The present study results suggest a crucial role for TCC upregulation in the AF substrate following binge alcohol-drinking, resulting from ethanol-induced PKC-activation that hyperphosphorylates GSK3β to cause enhanced calcineurin-NFAT-Csx/Nkx2.5 signaling. These observations elucidate for the first time the potential mechanisms underlying the clinically well-recognized, but mechanistically enigmatic, "holiday heart syndrome".

Spasmolytic effect of Acmella oleracea flowers extract on isolated rat ileum

Introduction: Acmella oleracea has been used as a traditional medicine for the treatment of asthma, sore throat, haemorrhoids and toothache. However, whether A. oleracea has gastrointestinal functions, such as regulation of intestinal contractions, has not been fully elucidated. Therefore, the aim of the present study was to investigate the effect of A. oleracea flowers extract (AFE) on rat ileum contractions and the possible mechanism(s) of its action. Methods: The extract was prepared using the Soxhlet apparatus with 95% ethanol. Ileum was removed from male Wistar rats and mounted in an organ bath containing Krebs solution. The tissue contractions were recorded by an isotonic transducer under 1 g tension.Results: The cumulative concentrations of the AFE (0.01–1 mg/mL) reduced the ileum contractions induced by KCl (80 mM) (n = 6, P < 0.05). AFE (1 mg/mL) attenuated the contractions induced by cumulative concentrations of CaCl2 (1–20 mM), while the spasmolytic effects of the extract were not reduced after tissue incubation with N (ω)-nitro-L-arginine methyl ester (L-NAME) (100 μM, 20 minutes).Conclusion: These results suggest that AFE inhibits ileum contractions without involving the nitric oxide pathway, which is possibly mediated via blockade of voltage-dependent calcium channels. A. oleracea may be useful in gastrointestinal disorders such as diarrhoea.

Effects of the ovary and conceptus on uterine blood flow in the pig

Summary. Changes in uterine blood flow throughout pregnancy appear to be due to steroid-induced alterations in uterine arterial tone and contractility. Arterial contractility is a transient reduction in luminal diameter in response to nerve stimulation or to an alpha-1 adrenergic agonist, leading to short-term reduction in uterine blood flow. Tone is the pressure exerted by an arterial segment against an intraluminal flow (distensibility) and is considered to set the baseline rate of flow. These phenomena appear to be regulated individually, with tone changes predominating during pregnancy. In pregnancy, tone is markedly depressed as oestrogen concentrations rise, and the vessel is distended and flaccid. Arterial tone is a function of the amount of calcium available to the contractile proteins of the arterial smooth muscle, which is derived from extracellular sources. Calcium availability is regulated by the opening and closing of calcium channels in the surface membrane in response to changes in the membrane potential. The loss of uterine arterial tone associated with oestrogen results from a markedly depressed uptake of calcium by the vessels. A significant negative correlation (P < 0.001; r = – 0.93) is observed between uterine arterial uptake of calcium and the concentrations of oestrogens in systemic blood of pigs throughout gestation. Several lines of evidence suggest that the blockade of potential-sensitive calcium channels associated with uterine hyperaemia is produced by catechol oestrogens, short-lived metabolites of oestrogens that are found in the circulation when oestrogen levels are high. Synthesis of catechol oestrogens from the parent oestrogens has been shown to occur in the placenta, endometrium and uterine arteries of pigs. In addition, perfusion of uterine arteries from nonpregnant pigs with catechol oestrogens, but not free oestrogens, in vitro significantly reduces both the tone and the uptake of calcium by the vessels. Contractility of the arteries to nerve stimulation or phenylephrine, however, is not affected. These data suggest that the pig conceptus, through production of catechol oestrogens, locally increases arterial distensibility, resulting in increased baseline flow to each fetal—placental unit. The contractility (reactivity) of the uterine arterial vasculature to adrenergic agonists or other vasoactive agents, however, is not affected. In this way, the conceptus can maintain the locally elevated flows necessary for its survival while the maternal system can continue to respond to life-threatening stimuli by transiently rerouting blood flow away from the uterus and towards other vascular beds more necessary for maternal survival.

Antihypertensive and vasorelaxant mode of action of the ethanol-soluble extract from Tagetes lucida Cav. aerial parts and its main bioactive metabolites

Ethnopharmacological relevanceTagetes lucida Cav. commonly known as “yauhtli” or “pericón” is used in Mexican traditional medicine for the treatment of anxiety, depressant diseases, pain, hypertension, among others. AimTo evaluate the antihypertensive and vasorelaxant modes of action of a crude ethanolic extract from T. lucida aerial parts and to isolate the bioactive compounds. Materials and methodsEthanolic extract was tested in an in vivo assay in SHR rats by intragastric administration at 10 and 100 mg/kg dosages, to measure and to compare hemodynamic parameters like diastolic and systolic blood pressure and heart rate. Also, extract (3.03–1000 μg/ml), fractions (3.03–1000 μg/ml) and pure isolated compounds (1.75–550 μM) were evaluated on isolated aortic rings contracted with noradrenaline (0.1 μM) to determine their vasorelaxant effect and extract-mode of action. ResultsEthanolic extract of T. lucida lowered systolic and diastolic blood pressure on SHR rats without heart rate modification (P > 0.05). Moreover, the extract showed concentration-dependent relaxant effect in a partially endothelium-dependent manner (P < 0.05), through NO/cGMP system activation and calcium channel blockade. 6,7,8-trimethoxycoumarin (1), 6,7-dimethoxycoumarin (2), and 7-methoxycoumarin (3) from T. lucida are the main bioactive compounds of the extract and showed significant vasorelaxant activity. ConclusionsResults provide evidence and endorsed the antihypertensive properties attributed to T. lucida in traditional medicine, which is produced by vasorelaxant effect mainly through multitarget NO/cGMP system activation and calcium channel blockade. Coumarin derivatives 1, 2 and 3 are the responsible of the vasorelaxant activity.

T-type calcium channel blockade induces apoptosis in C2C12 myotubes and skeletal muscle via endoplasmic reticulum stress activation.

Loss of T-type calcium channel (TCC) function has been reported to result in decreased cell viability and impaired muscle regeneration, but the underlying mechanisms remain largely unknown. We previously found that expression of TCC is reduced in aged pelvic floor muscle of multiple vaginal delivery mice, and this is related to endoplasmic reticulum stress (ERS) activation and autophagy flux blockade. In the present work, we further investigated the effects of TCC function loss on C2C12 myotubes and skeletal muscle, which is mediated by promotion of ERS and ultimately contributes to mitochondrial-related apoptotic cell death. We found that application of a TCC inhibitor induced mitochondria-related apoptosis in a dose-dependent manner and also reduced mitochondrial transmembrane potential (MMP), induced mito-ROS generation, and enhanced expression of mitochondrial apoptosis proteins. Functional inhibition of TCC induced ERS, resulting in disorder of Ca2+ homeostasis in endoplasmic reticulum, and ultimately leading to cell apoptosis in C2C12 myotubes. Tibialis anterior muscles of T-type α1H channel knockout mice displayed a smaller skeletal muscle fiber size and elevated ERS-mediated apoptosis signaling. Our data point to a novel mechanism whereby TCC blockade leads to ERS activation and terminal mitochondrial-related apoptotic events in C2C12 myotubes and skeletal muscles.

M3, a 1,4-Dihydropyridine Derivative and Mixed L-/T-Type Calcium Channel Blocker, Attenuates Isoproterenol-Induced Toxicity in Male Wistar Rats.

Recent evidence indicates that Ca2+ dysregulation is involved in the pathogenesis of isoproterenol (ISP)-induced biochemical toxicity and associated oxidative stress. In this study, we investigated the chemopreventive benefit of M3, a 1,4-dihydropyridine calcium channel blocker, against ISP-induced toxicity in male Wistar rats. Adult rats were divided into eight groups of six rats/group. Groups 1-5 received normal saline (control, 10mL/kg/day, p.o.), ISP (85mg/kg/day, s.c.), M3 lower dose (M3LD, 5mg/kg, p.o.), M3 upper dose (M3UD, 20mg/kg/day, p.o.), and Nifedipine (NFD, 20mg/kg/day, p.o.), respectively. Others (groups 6-8) were pretreated with either M3LD, M3UD or NFD one hour before ISP administration. All rats were sacrificed 24h after the last administration and changes in biochemical, hematological, and antioxidant parameters were assessed. Histologic examination of the heart, liver and kidney was also conducted. ISP elevated (p < 0.05) Ca2+, alanine aminotransferase, lactate dehydrogenase, triglycerides, and low-density lipoprotein levels when compared with control. Similarly, ISP increased levels of markers of renal function (p < 0.01), C-reactive protein (148.1%) and myocardial malondialdehyde (MDA, 88.7%) and tumor necrosis factor-alpha (109.2%). Platelet level was reduced (p < 0.05) in the ISP-intoxicated control rats. M3 exhibited antioxidant property, reduced levels of triglycerides, MDA and improved biochemical and hematological alterations associated with ISP toxicity. M3, however, was not effective in restoring histological changes that characterized ISP toxicity at the doses used. M3 offers chemopreventive benefits against ISP toxicity possibly through L-/T-type calcium channels blockade and modulatory actions on biochemical and antioxidant homeostasis.

Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking. Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (LZTR1). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level. Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype. Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in LZTR1 and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes.

ObjectiveWe employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.MethodsWe selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).ResultsGenetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.ConclusionsThis study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.

606 Small molecule blockade of T-type calcium channels by DX416 inhibits itch and reduces corresponding inflammation in acute and chronic itch mouse models

The processing of itch signals is regulated by many different ion channels. Among those are T-type calcium channels which are important regulators that contribute to the firing behavior of pruriceptors, or itch sensing neurons. The human genome encodes three different T-type channels: Cav3.1, Cav3.2, Cav3.3. It has been shown recently that pharmacological blockade of T-type calcium channels inhibits acute itch and that immune cells can express Cav 3 channels with roles in effector function. Thus, we hypothesized that local administration of the novel small molecule T-Type calcium channel inhibitor, DX416, would decrease cutaneous itch both through reducing pruriceptors signals triggering itch and decreasing local inflammatory immune responses potentiating itch.

Chemical and Pharmacological Screening of Rhinella icterica (Spix 1824) Toad Parotoid Secretion in Avian Preparations.

The biological activity of Rhinella icterica parotoid secretion (RIPS) and some of its chromatographic fractions (RI18, RI19, RI23, and RI24) was evaluated in the current study. Mass spectrometry of these fractions indicated the presence of sarmentogenin, argentinogenin, (5β,12β)-12,14-dihydroxy-11-oxobufa-3,20,22-trienolide, marinobufagin, bufogenin B, 11α,19-dihydroxy-telocinobufagin, bufotalin, monohydroxylbufotalin, 19-oxo-cinobufagin, 3α,12β,25,26-tetrahydroxy-7-oxo-5β-cholestane-26-O-sulfate, and cinobufagin-3-hemisuberate that were identified as alkaloid and steroid compounds, in addition to marinoic acid and N-methyl-5-hydroxy-tryptamine. In chick brain slices, all fractions caused a slight decrease in cell viability, as also seen with the highest concentration of RIPS tested. In chick biventer cervicis neuromuscular preparations, RIPS and all four fractions significantly inhibited junctional acetylcholinesterase (AChE) activity. In this preparation, only fraction RI23 completely mimicked the pharmacological profile of RIPS, which included a transient facilitation in the amplitude of muscle twitches followed by progressive and complete neuromuscular blockade. Mass spectrometric analysis showed that RI23 consisted predominantly of bufogenins, a class of steroidal compounds known for their cardiotonic activity mediated by a digoxin- or ouabain-like action and the blockade of voltage-dependent L-type calcium channels. These findings indicate that the pharmacological activities of RI23 (and RIPS) are probably mediated by: (1) inhibition of AChE activity that increases the junctional content of Ach; (2) inhibition of neuronal Na+/K+-ATPase, leading to facilitation followed by neuromuscular blockade; and (3) blockade of voltage-dependent Ca2+ channels, leading to stabilization of the motor endplate membrane.

158-OR: Calcium Channel Blockade Protects against Severe Hypoglycemia–Induced Fatal Cardiac Arrhythmias in Rats

It was hypothesized that in response to insulin-induced severe hypoglycemia, excess calcium influx into the heart causes fatal cardiac arrhythmias. To test if blocking the calcium channels would decrease fatal cardiac arrhythmias during severe hypoglycemia, L-type calcium channel blocker (Verapamil; 1 mg/kg, n = 25) or saline (n = 24) were infused into Sprague Dawley rats during a hyperinsulinemic (0.2 mU/kg/min) severe hypoglycemic (10-15 mg/dl) clamp for 3 hours with ECG. During severe hypoglycemia, verapamil completely prevented mortality compared to 21% mortality in controls (p &amp;lt; 0.05; Figure). Decreased mortality was associated with a 99% decrease in 2nd degree heart block (Figure) and prevention of 3rd degree heart block compared to saline (p &amp;lt; 0.05). Glucagon and epinephrine were similar between the groups suggesting verapamil does not affect hypoglycemic counterregulation. Consistent with the notion of calcium-mediated arrhythmias, separate experiments demonstrated that pharmacological blockade of ryanodine receptor-mediated calcium signaling also reduced heart block by 97% and prevented mortality due to hypoglycemia. In summary, blocking calcium channels protects against severe hypoglycemia-induced fatal cardiac arrhythmias. Blockade of cardiac calcium channels could be a potential approach to prevent arrhythmias in people with diabetes at risk for hypoglycemia. Disclosure C.M. Reno: None. Y. Huang: None. C.G. Christensen: None. M.B. Oxspring: None. J. Bayles: None. S.J. Fisher: None. Funding National Institutes of Health (5T32DK091317, R01NS070235); JDRF (3-APF-2017-407-A-N)

Effect of Calcium-Channel Blockade on the Cold-Induced Vasodilation Response

Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud's syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied. A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orallytwice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD). Twelve volunteers (age 29±3 [24-34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo). Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.

A molecular approach to treating cognition in schizophrenia by calcium channel blockade: An open-label pilot study of the calcium-channel antagonist isradipine

Cognitive impairment is a prominent and difficult to treat symptom in schizophrenia (SZ), which is directly related to functional disability. A variant in the gene coding for the alpha 1C subunit of L-type voltage gated calcium channel (CACNA1C) has been shown to negatively affect several neurocognitive domains. We conducted a 4-week, open label, pilot study of isradipine, a calcium channel blocker, to determine its feasibility, safety, and efficacy in improving cognition in SZ patients.Ten adults with stable SZ were started on a flexible dose of isradipine 5 mg/day (up to 10 mg/day) for 4 weeks. Weekly in-person visits tracked side effects and symptoms while neurocognition and functional capacity were assessed at baseline and week 4.There were no serious adverse events reported. Newly emergent side effects were dizziness (1 new incidence at week 4); difficulty sleeping (2 new incidences at week 4); and decreased energy (3 new incidences at week 4). 1 patient discontinued medication and was withdrawn. Treatment did not exacerbate clinical symptoms. Although power is limited, results indicate no clear benefit on neurocognition but a positive effect (baseline mean = 6.8 ± 1.3 to week 4 mean = 7.9 ± 1.1; t = 2.91, p = 0.017) on functional capacity was noted.This open label, pilot study provides preliminary evidence that isradipine is a relatively safe medication when used adjunctively in SZ patients. This study suggests that isradipine offers no clear cognitive and only minimal functional benefit; however, additional studies may be warranted in symptomatic patients, or those with specific CACNA1C genotypes.

The antispasmodic effect of aqueous root bark extract of Carissa edulis (Forssk.) Vahl on isolated rabbit jejunum is mediated through blockade of calcium channels

The antispasmodic effect of aqueous root bark extract of Carissa edulis (Forssk.) Vahl on isolated rabbit jejunum is mediated through blockade of calcium channels

Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid.

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

Composição química, atividade biológica e segurança de uso de plantas do gênero Mikania

Mikania, guaco é utilizado popularmente há muitos anos, devido às propriedades medicinais atribuídas às folhas, incluindo a ação tônica, depurativa, antipirética e broncodilatora, além de estimulante do apetite e antigripal. Também é empregado no tratamento de doenças respiratórias como asma e bronquite, na forma de xaropes para tosse. Várias dessas ações benéficas à saúde foram comprovadas cientificamente. Estudos foram publicados sobre a ação direta do guaco causando broncodilatação e relaxamento da musculatura lisa respiratória, o que pode estar relacionado ao bloqueio dos canais de cálcio, acompanhado de ações anti-inflamatória e antialérgica, sendo estas benéficas ao tratamento da asma, problema caracterizado por obstrução e inflamação das vias aéreas. Conforme indicações da ANVISA recomenda-se o uso do guaco sob as formas de tintura e extrato, sendo a cumarina o marcador de escolha no controle de qualidade da matéria prima e de produtos fitoterápicos contendo essa droga vegetal. Nesse trabalho, apresenta-se uma revisão sobre plantas do gênero Mikania, incluindo a farmacobotânica, a composição química, atividades biológicas e farmacológicas, interações medicamentosas, toxicidade e controle de qualidade.

Severe Calcium Channel Blocker Overdose and Successful Management: a Case Report and Literature Review

Background: Calcium channel blocker (CCB) toxicity is one of the most lethal and common drug overdoses encountered in the emergency department (ED). The toxicity of these drugs results from blockade of L-type calcium channels in smooth cells, myocardial cells, and beta cells of the pancreas. Severe toxicity can result in bradycardia, hypotension, hyperglycemia, metabolic acidosis, shock, cardiac arrest and death. According to the American Association of Poison Control Centers’ National Poison Data System’s annual report in 2015, cardiovascular medications were the fourth most common adult poisoning exposure and second most common cause of adult poisoning fatality in the USA. CCBs are responsible for a substantial portion of the mortality associated with cardiovascular medication overdose cases. Understanding the emergent management of CCB toxicity is essential. Treatment of patients with CCB overdose remains challenging especially in those with refractory hypotension and end organ dysfunction. Case Presentation: A 45-year-old male with massive amlodipine overdose presented to ED with syncope and severe hypotension. Intensive medical therapy (fluid resuscitation, inotropes, calcium gluconate, and hyperinsulinemia euglycemia therapy [HIET]) was initiated in the ED and continued in the Intensive Care Unit (ICU), and resulted in the patient’s total recovery, without any major complications. Fortunately, ECMO implantation (extracorporeal membrane oxygenation) was not required in this patient. Conclusion: Urgent administration of fluids, calcium, vasopressors, and HIET therapy seem to be the most well validated initial approaches to CCBs overdose treatment. Our successful management strategy should serve as a good learning experience as well as a recommendation for managing such patients.