Rabbit polyclonal Anti-Calciumchannel L type DHPR alpha 2 subunit antibody (ab80990) and sheep polyclonal caveolin-1 antibody (ab81397) were purchased from Abcam (Cambridge, MA). Focal Adhesion Staining Kit was purchased from Millipore (Billerica, MA). Secondary antibodies (Alexa Fluor 488 chicken anti-rabbit and Alexa Fluor 488 donkey anti-sheep) were purchased from Invitrogen (Carlsbad, CA). Normal chicken serum was purchased from Zymed Laboratories, CA. For immuno- fluorescence staining, cells were rinsed once with phosphate- buffered saline (PBS), fixed with 4% paraformaldehye in PBS (30 min), washed with PBS, treated with 0.5% Triton X-100 (5 min) for membrane permeablization. To double stain L-type VGCC and caveolin-1, cells were washed with PBS, blocked with normal chicken serum (2% diluted with PBS/0.3% Tween-20) for 30 min at room temperature, washed with PBS (3 times, 5 min per wash), incubated overnight with primary antibodies (1:100), washed with PBS (3 times, 5 min per wash) followed by incubation for 1 h with the secondary antibodies (1:500), washed with PBS (3 times, 5 min per wash), and then loaded with DAPI (1:5000) for 5 min at room temperature. Confocal imaging was performed with a Leica TCS SP2 microscope. Routine negative controls for staining were performed.
With the aim of exploring the structure–activity relationship of 4 and obtaining more efficient calciumchannel blockers, we had cultured single crystals to determine the structure of 4. Furthermore we designed the series of compounds shown in Table S1. In addition, we revealed some haloperidol derivatives (compounds 6a–6c, 9a–9c in Table S1) had vasodilator activity in previous study . The piperidine scaffold, which we consider a supporting structure for novel calciumchannel antagonists, was decorated at the nitrogen atom of piperidine with different substituent groups. We screened these compounds for vasodilatory activity in isolated rat thoracic aorta rings held in a Ca 2+ - containing high-K +
Seizure disorders, such as epilepsy, are a serious health concern because of the large num- ber of patients affected and a limited availability of treatment options. About 10% of the population will have at least one seizure during their lifetime, and 1% will experience per- sistent, recurrent epileptic seizures. Moreover, for about one-third of patients, epilepsy is intractable with seizures that are not controlled with any available drugs. Genetic seizure suppressors are modifier mutations that are capable of reverting seizure susceptibility to wild type levels when combined with seizure-prone mutants in double mutant individuals. Suppressors are valuable in providing an experimental approach that can provide insight into mechanisms underlying seizure susceptibility. Also, they identify novel gene products that may be targets for therapeutic drug development. In the present study we show that a severe seizure phenotype of the Drosophila paralytic bss1 (para bss1 ) mutant is 90% sup- pressed by the N-type calciumchannel mutation cacophony TS2 (cac TS2 ). The effect of
The need for drug combinations to treat visceral leishmaniasis (VL) arose because of resistance to antimoni- als, the toxicity of current treatments and the length of the course of therapy. Calciumchannel blockers (CCBs) have shown anti-leishmanial activity; therefore their use in combination with standard drugs could provide new alternatives for the treatment of VL. In this work, in vitro isobolograms of Leishmania (Leishmania) chagasi us- ing promastigotes or intracellular amastigotes were utilised to identify the interactions between five CCBs and the standard drugs pentamidine, amphotericin B and glucantime. The drug interactions were assessed with a fixed ratio isobologram method and the fractional inhibitory concentrations (FICs), sum of FICs (ΣFICs) and the overall mean ΣFIC were calculated for each combination. Graphical isobologram analysis showed that the combination of nimo- dipine and glucantime was the most promising in amastigotes with an overall mean ΣFIC value of 0.79. Interactions between CCBs and the anti-leishmanial drugs were classified as indifferent according to the overall mean ΣFIC and the isobologram graphic analysis.
Fig 2. Calciumchannel blockers, isradipine and nimodipine, prevent abnormalities in spontaneous IPSCs of DG granule cells caused by amyloid pathology in the EC. A, amplitude of spontaneous IPSCs increased in the EC-Aβ (lower trace) in contrast with the control (upper trace) neurons and there is a significant decrease in monoexponential decay time constant (fast inactivated) compared to the control cells (right plot, p < 0.05). B, cumulative probability plots showed that spontaneous events in the granule cells from Aβ treated rats shifted to larger amplitude (**p = 0.004 by Kolmogorov–Smirnoff test) and the change was blocked by isradipine and nimodipine. C, the amplitude of sIPSC significantly increased in granule cells from Aβ treated rats compared to the control, and isradinpine and nimodipine blocked the change. Cumulative probability plot (D) and mean frequency of spontaneous IPSCs (E) were unaltered between groups. Values are mean ± SEM. ***p < 0.001 contrasted to the control cells, ## p < 0.01 and # p < 0.05 compared to EC-Aβ group. Control group,
adopt the normal horseshoe-shape it had in WT retinae . In most synapses Cplx4 and CtBP2 were co-expressed (white arrows). However, we also found examples of Cplx4-positive/CtBP2- negative synapses (gray arrows). These few terminals could either be remnants of degenerating synapses or a few newly established synapses, as ribbons have been shown to appear late in new ectopic synapses [47,48] and rod photoreceptors are known to be very plastic in synaptopathic models [48,49]. Moreover, in agreement with published evidence of floating ribbons in similar models [16,17], we observed numerous CtBP2 puncta that were not co-localized with Cplx4. Given that the calciumchannel Ca V 1.4(a 1F ) is part of the active zone compartment, we set out to
2. Kors EE, Terwindt GM, Vermeulen FLMG, et al. Delayed ce- rebral edema and fatal coma after minor head trauma: role of the CACNA1A calciumchannel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 2001;49:753-760. 3. McCrory PR, Berkovi SF. Second impact syndrome. Neurolo-
RESULTS: Sixteen randomized clinical trials including 769 participants were selected. They showed that angiotensin-converting enzyme inhibitors had a superior effect in treating hypertensive urgencies, evaluated among 223 participants. The commonest adverse event for calciumchannel blockers were headache (35/206), lushing (17/172) and palpitations (14/189). For angiotensin-converting enzyme inhibitors, the principal side effect was bad taste (25/38).
RESULTS: Approximately 24% of the participants had high blood pressure or were taking antihypertensive drugs, and among these, 33% had had a physician consultation during the month preceding the interview. The monthly mean costs of care for hypertension (R$ 89.90), diabetes (R$ 80.64) and bronchitis (R$ 92.63) were similar. Treatment of hypertension consumed 22.9% of the per-capita income, corresponding to R$ 392.76 spent per year exclusively on antihypertensive drugs. Most of the direct costs associated with hypertension and diabetes were spent on drugs, while patients with bronchitis had greater expenditure on appointments. The cost-effectiveness relationship was more favorable for diuretics (116.3) and beta blockers (228.5) than for ACE inhibitors (608.5) or calciumchannel blockers (762.0).
It has been reported that dihydropirydine- class (nifedipine and amlodipine) caused predominant vasodilation of the afferent arteriole in isolated perfused hydronephrotic kidney (22). Since the traditional calcium antagonists (e.g. nifedipine) act on L-type voltage dependent calciumchannel and these channels prevail predominantly at the afferent arteriole (23, 24). The effects on the efferent arteriole by these calcium antagonists are most likely attributed to additional actions of these antagonists, but not due to the class affects of these agents (4).
Cross-sectional study, with a quantitative approach, con- ducted in a health unit located in a countryside city in the State of Sao Paulo, in the period from February to Novem- ber 2013. We included patients with medical diagnosis of hypertension, antihypertensive monotherapy for more than ive years, being the medication belonging to the classes of drugs: calciumchannel antagonists or inhibitors of angio- tensin-converting enzyme. he name of these patients were identiied by a report in a software from the Pharmacy in the health unit, which generates patients’ reports according to drug class in use.
21- Sánchez-Pastor E, Andrade F, Sánchez-Pastor JM, Elizalde A, Huerta M, Virgen-Ortiz A, et al. Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calciumchannel, voltage-dependent, L type, alpha 1C subunit. Eur J Pharmacol. 2014;15(729):100-6.
The calcium paradox was first mentioned in 1966 by Zimmerman et al. Thereafter gained great interest from the scientiic community due to the fact of the absence of calcium ions in heart muscle cells produce damage similar to ischemia- reperfusion. Although not all known mechanisms involved in cellular injury in the calcium paradox intercellular connection maintained only by nexus seems to have a key role in cellular fragmentation. The addition of small concentrations of calcium, calciumchannel blockers, and hyponatraemia hypothermia are important to prevent any cellular damage during reperfusion solutions with physiological concentration of calcium.
In the present case, to use higher doses of second- generation calciumchannel blockers can be interesting to control angina, in case of ischemic cardiopathy, as well as the use of angiotensin-converting enzyme inhibitors for the secondary prevention of nephropathy. However, these are situations in which the association of other drugs can be troublesome.
MAIN RESULTS: Of 57 trials identiied, 24 trials with 28 arms, including 58,040 patients met the inclusion criteria. Thiazides (19 RCTs) reduced mortality (RR 0.89, 95% CI 0.83, 0.96), stroke (RR 0.63, 95% CI 0.57, 0.71), CHD (RR 0.84, 95% CI 0.75, 0.95) and CVS (RR 0.70, 95% CI 0.66, 0.76). Low-dose thiazides (8 RCTs) reduced CHD (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11 RCTs) did not (RR 1.01, 95% CI 0.85, 1.20). Beta-blockers (5 RCTs) reduced stroke (RR 0.83, 95% CI 0.72, 0.97) and CVS (RR 0.89, 95% CI 0.81, 0.98) but not CHD (RR 0.90, 95% CI 0.78, 1.03) or mortality (RR 0.96, 95% CI 0.86, 1.07). ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85). Calcium-channel blocker (1 RCT) reduced stroke (RR 0.58, 95% CI 0.41, 0.84) and CVS (RR 0.71, 95% CI 0.57, 0.87) but not CHD (RR 0.77 95% CI 0.55, 1.09) or mortality (RR 0.86 95% CI 0.68, 1.09). No RCTs were found for ARBs or alpha-blockers.
The involvement of calcium channels in cellular excit- ability and the differences in the pharmacological and thera- peutic actions of the calciumchannel blockers prompted us to evaluate the effects of nifedipine on seizures and cardiac rhythm during the reperfusion of ischemic myocardium in WAR. We found that nifedipine has antiepileptic and anti- arrhythmic effects in these animals. Indeed, some forms of epilepsy may be due to mutations in cell membrane Ca 2+ channels (10) and changes in Ca 2+ influx. These
35. Kwak SM, Kim JS, Choi Y, Chang Y, Kwon MJ, Jung JG, et al. Dietary intake of calcium and phosphorus and serum concentration in relation to the risk of coronary artery calci- fication in asymptomatic adults. Arterioscler Thromb Vasc Biol. 2014;34:1763---9.