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Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high- and low-frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic-motility stages E18.5-P3 showed that Ca V 1.2-positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2-aminoethoxydiphenyl borate (2-APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2-APB resistant. We extended our results on L-type channel-dependent spontaneous activity and TTX-resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro-mechanical sensitivity in the enteric nervous system. HIGHLIGHTS: What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L-type calcium channels and IP 3 R receptors, and the enteric nervous system exhibits a tetrodotoxin-resistant mechanosensitive response. Abstract figure legend Tetrodotoxin-resistant Ca 2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Calcium channel blockers (CCB) of astrocytes can blockade the calcium ions entry through the voltage gated calcium channels (VGCC), and is widely used in the diseases related with VGCC of astrocytes. But many aspects of the interaction mechanisms between the CCB and VGCC of astrocytes still remain unclear due to the limited resolution of the approaches. Herein the effects of the nicardipine (a type of CCB) on VGCC of astrocytes were investigated at very high spatial, force and electrical resolution by multiple modes of Atomic Force Microscopy (AFM) directly. The results reveal that after the addition of nicardipine, the recognition signals of VGCC disappeared; the specific unbinding forces vanished; the conductivity of the astrocytes decreased (the current decreased about 2.9 pA and the capacitance was doubled); the surface potential of the astrocytes reduced about 14.2 mV. The results of electrical properties investigations are consistent with the simulation experiments. The relations between these biophysical and biochemical properties of VGCC have been discussed. All these demonstrate that the interactions between nicardipine and VGCC have been studied at nanometer spatial resolution, at picoNewton force resolution and very high electrical signal resolution (pA in current, pF in capacitance and 0.1 mV in surface potential) level. The approaches are considered to be high resolution and high sensitivity, and will be helpful and useful in the further investigations of the effects of other types of CCB on ion channels, and will also be helpful in the investigations of mechanisms and therapy of ion channelopathies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Hypertensive crisis is an acute increase in blood pressure >180/120 mm Hg. A titratable antihypertensive agent is preferred to lower blood pressure acutely in a controlled way and prevent an abrupt overcorrection. Nicardipine and clevidipine are both dihydropyridine calcium channel blockers that provide unique benefits for blood pressure control., Objective: The purpose of this study was to compare the efficacy and safety of nicardipine or clevidipine for blood pressure control in the setting of hypertensive crisis., Methods: This was a single-center, retrospective cohort study. Eligible patients received either nicardipine or clevidipine for the treatment of hypertensive crisis. The primary outcome was achievement of 25% reduction in mean arterial pressure at 1 h. The secondary outcome was achievement of a systolic blood pressure (SBP) of <160 mm Hg at 2-6 h from the start of the infusion., Results: This study included a total of 156 patients, 74 in the nicardipine group and 82 in the clevidipine group. The SBP on admission and at the start of the infusion were similar between groups. There was no difference between groups in achieving a 25% reduction in mean arterial pressure at 1 h. Nicardipine achieved an SBP goal of <160 mm Hg at 2-6 h significantly more often than the clevidipine group (89.2% vs. 73.2%; p = 0.011)., Conclusions: There is no difference between agents for initial blood pressure control in the treatment of hypertensive crisis. Nicardipine showed more sustained SBP control, with a lower risk of rebound hypertension and a significant cost savings compared with clevidipine., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Two randomized crossover trials evaluated the effects of nicardipine constant rate infusion (CRI) on 1) the anesthetic potency of sevoflurane and 2) the ability to attenuate dexmedetomidine-induced cardiovascular depression in anesthetized dogs. First, six healthy Beagle dogs weighing 11.7 ± 0.9 kg were allocated to one of three treatments that administered a CRI of carrier (saline) or dexmedetomidine 0.5 or 3.0 μg/kg/h following a loading dose. The minimum alveolar concentration (MAC) of sevoflurane was determined utilizing electric stimuli before and after the loading dose of nicardipine (20 μg/kg intravenously for 10 min), followed by CRI at 40 μg/kg/h with 60 min of equilibration. Subsequently, cardiovascular and blood gas variables were evaluated in another trial under sevoflurane anesthesia at the individual 1.5 MAC. After baseline measurements, the dogs were assigned to two treatments (dexmedetomidine CRI at 0.5 or 3.0 μg/kg/h following a loading dose) with sevoflurane doses adjusted to 1.5 times of MAC equivalent, and the measurements were repeated every 15 min for 120 min. After 60 min, nicardipine CRI at 40 μg/kg/h with a loading dose was added to the dexmedetomidine CRI. Dexmedetomidine infusions significantly decreased the sevoflurane MAC but nicardipine did not significantly alter the MAC either with or without dexmedetomidine CRI in dogs. Dexmedetomidine dose-dependently decreased the cardiac index and increased the systemic vascular resistance index; these effects were fully counteracted by concomitant nicardipine CRI. Nicardipine CRI can be useful for controlling the cardiovascular depression elicited by dexmedetomidine in anesthetized dogs without affecting the anesthetic potency of sevoflurane., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers., Methods: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa., Results: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts., Conclusion: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC 50 ) value of 3.54 ± 0.96 μM in RLM and 1.52 ± 0.038 μM in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague-Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC (0-t) , AUC (0-∞) , T max and C max of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Intra-arterial (IA) infusion of calcium channel blockers (CCBs) has been widely applied in treating medically refractory vasospasm; however, surprisingly little is known regarding their vasodilatory duration. This study was undertaken to compare attributes of nicardipine and dantrolene, focusing on efficacy and capacity for sustained vasodilation., Methods: In New Zealand white rabbits (N = 22), vasospasm was individually provoked through experimentally induced subarachnoid hemorrhage and confirmed via conventional angiography, grouping animals by IA-infused drug (nicardipine vs. dantrolene). Controls received normal saline. After chemoangioplasty, follow-up angiography was performed at intervals of 1-3 h for 6 h to compare vasospastic and dilated (i.e., treated) arterial diameters. Drug efficacy, duration of action, and changes in mean arterial pressure (relative to baseline) were analyzed by group., Results: Compared with controls, effective vasodilation was evident in both nicardipine and dantrolene test groups after IA infusion. Vasodilatory effects of nicardipine peaked at 1 h, returning to former vasospastic states at 3 h. In dantrolene recipients, vasodilation endured longer, lasting >6 h. Only the nicardipine group showed a significant 3‑h period of lowered blood pressure., Conclusion: Unlike the vasodilatory action of a CCB, sustained for < 3 h after IA infusion, the effect of dantrolene endured for > 6 h. This outcome suggests that IA dantrolene infused alone or together with a conventional CCB infusion may be a new means of prolonging vasodilatory effect. Further research is needed to assess durations of IA-infused vasodilatory drug based on perfusion status., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Acute blood pressure (BP) management in neurologic patients is paramount. Different neurologic emergencies dictate various BP goals. There remains a lack of literature determining the optimal BP regimen regarding safety and efficacy. The objective of this study was to identify which intravenous antihypertensive is the most effective and safest for acute BP management in neurologic emergencies., Methods: Ovid EBM (Evidence Based Medicine) Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection were searched from inception to August 2020. Randomized controlled trials or comparative observational studies that evaluated clevidipine, nicardipine, labetalol, esmolol, or nitroprusside for acute neurologic emergencies were included. Outcomes of interest included mortality, functional outcome, BP variability, time to goal BP, time within goal BP, incidence of hypotension, and need for rescue antihypertensives. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the degree of certainty in the evidence available., Results: A total of 3878 titles and abstracts were screened, and 183 articles were selected for full-text review. Ten studies met the inclusion criteria; however, the significant heterogeneity and very low quality of studies precluded a meta-analysis. All studies included nicardipine. Five studies compared nicardipine with labetalol, three studies compared nicardipine with clevidipine, and two studies compared nicardipine with nitroprusside. Compared with labetalol, nicardipine appears to reach goal BP faster, have less BP variability, and need less rescue antihypertensives. Compared with clevidipine, nicardipine appears to reach goal BP goal slower. Lastly, nicardipine appears to be similar for BP-related outcomes when compared with nitroprusside; however, nitroprusside may be associated with increased mortality. The confidence in the evidence available for all the outcomes was deemed very low., Conclusions: Because of the very low quality of evidence, an optimal BP agent for the treatment of patients with neurologic emergencies was unable to be determined. Future randomized controlled trials are needed to compare the most promising agents., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Introduction: Women with severe hypertension during pregnancy require prompt stabilization with a combination of magnesium sulfate and rapidly acting intravenously administered antihypertensives. It remains unknown which antihypertensive is best suited for pregnancy. The present study evaluated the intravenous use of the calcium antagonist, nicardipine., Material and Methods: This multicenter, retrospective case series included all pregnant women beyond 20 weeks of gestation with severe antepartum hypertension that were treated with intravenous nicardipine., Primary Outcome Measures: successful treatment, time to successful treatment, and maternal safety. Severe hypertension was defined as systolic blood pressure (SBP) of 160 mm Hg or more and/or diastolic blood pressure (DBP) of 110 mm Hg or more., Results: This study included 830 women. After 1 h of treatment, two-thirds of the women had SBP below 160 mm Hg and DBP below 100 mm Hg. In three out of four women, the mean arterial pressure was below 120 mm Hg. Within 2 h of treatment, 77.4% of women achieved successful treatment. In all cases, nicardipine was eventually effective. Within the first 2 h, 42.7% of women experienced temporary low DBP (ie below 70 mm Hg) without clinical consequences for the mother or fetus. In all cases, the low DBP resolved after discontinuing or reducing the dosage of nicardipine. One case of fetal distress was attributable to maternal hypotension, and a cesarean section was performed at more than 2 h after initiating therapy. During treatment, headache, nausea, and vomiting decreased significantly., Conclusions: To date, this was the largest case-series study on the use of nicardipine for treating severe antepartum hypertension in pregnancy. We found that nicardipine could effectively and safely treat this condition. Based on its high success rate and acceptable safety profile, nicardipine should be considered a first-line treatment in women with severe hypertension in pregnancy., (© 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Intracranial hemorrhage is associated with high mortality and morbidity. Lowering systolic blood pressure (SBP) with an intravenous antihypertensive, such as nicardipine or clevidipine, may reduce the risk of hematoma expansion and rebleeding. Previous studies comparing nicardipine and clevidipine in patients with stroke found no significant difference in blood pressure management. The inclusion of patients with ischemic stroke limited those studies because of convoluted results related to faster door-to-needle times. The purpose of this study was to compare clevidipine with nicardipine in time to goal SBP in hemorrhagic stroke., Methods: This single-center retrospective observational cohort study evaluated adult hemorrhagic patients with stroke who received clevidipine or nicardipine from January 1, 2015, to December 31, 2020. Patients were excluded if they had trauma-related hemorrhage, received concurrent continuous intravenous antihypertensives, received the study drug for less than 1-h duration, had a less than 24-h washout period between agents, required any dialysis, were pregnant, or were incarcerated. The primary outcome was time to goal SBP. Secondary outcomes included need for additional antihypertensives, percentage of time at goal SBP, all-cause mortality, 30-day readmission, rebleeding, total volume of antihypertensive infusion, hematoma expansion, intensive care unit length of stay (LOS), hospital LOS, and cost of infusion. Safety outcomes included hypotension, severe hypotension, rebound hypertension, bradycardia, tachycardia, onset of atrial fibrillation, and acute kidney injury., Results: Of 89 patients included in this study, 60 received nicardipine and 29 received clevidipine. There was no significant difference between nicardipine and clevidipine in time to goal SBP in the unmatched cohort (30 vs. 45 min; p = 0.73) or the propensity-score-matched cohort (30 vs. 45 min; p = 0.47). Results were not affected by potential confounders in the multiple linear regression. The nicardipine group had a higher total volume from infusion compared with the clevidipine group (1410 vs. 330 mL; p < 0.0001) but significantly lower cost ($99.6 vs. $497.4; p < 0.0001). There were no significant differences in need for additional antihypertensives, percentage of time at goal SBP, all-cause mortality, 30-day readmission, rebleeding, hematoma expansion, intensive care unit LOS, and hospital LOS. Compared with the clevidipine group, the nicardipine group had less rebound hypertension (40% vs. 75.9%; p = 0.0017) and less bradycardia (23.3% vs. 44.8%; p = 0.05). There were no significant differences in hypotension, severe hypotension, tachycardia, and acute kidney injury., Conclusions: In patients with hemorrhagic stroke, nicardipine appeared to have similar efficacy as clevidipine in SBP reduction, with a more likely reduction of rebound hypertension and drug cost. This retrospective study was underpowered, which may limit these implications. Further prospective studies are warranted to confirm these results., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

The higher permeability of the venules in jejunal microcirculation to albumin contributes to the increased mesenteric lymph formation. Recently, we demonstrated that water intake induced serotonin release from enterochromaffin cells in rat jejunum, serotonin of which circulated through the portal vein into blood circulation and then increased the mesenteric lymph formation. The mode of action of serotonin remains unclear. Therefore, we aimed to clarify the mechanisms involved in the regulation of the jejunal lymph formation with permeant albumin in in vivo rat experiments. We investigated the effects of intravenous administration of serotonin or water intake on the jejunal-originated lymph volume and the concentration of albumin in the lymph in the presence or absence of L-NAME. The effects of intravenous administration of L-NAME, nicardipine, A23187, and ML-7 on the lymph formation with permeant albumin were also evaluated. Serotonin or water intake significantly increased the mesenteric lymph volume with permeant albumin in the jejunal microcirculation. The serotonin- and water intake-mediated responses were significantly reduced by the pretreatment with intravenous administration of L-NAME. Intravenous administration of L-NAME itself also decreased significantly the jejunal lymph formation. Administration of A23187 and ML-7 significantly reduced the jejunal lymph formation with permeant albumin. In contrast, administration of nicardipine significantly increased the lymph formation. In conclusion, portal venous blood flow- or serotonin-mediated NO release from venular endothelial cells plays physiologically key roles in the lymph formation in rat jejunum via the extrusion of calcium ions and inactivation of MLCK in endothelial cells., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: The cardio-ankle vascular index (CAVI) consists of intrinsic and functional arterial stiffness mainly regulated by vasoactive compounds. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was determined by applying the CAVI theory to the whole aorta and iliac-femoral arteries. We investigated the changes in aBeta and ifBeta in response to decreased blood pressure (BP) induced by the Ca 2＋ channel blocker nicardipine to elucidate the involvement of Ca 2＋ in aBeta and ifBeta., Methods: Pressure waves at the origin of the aorta (oA), distal end of the abdominal aorta (dA), and left femoral artery (fA) as well as flow waves at the oA were simultaneously recorded before and after the infusion of nicardipine (50 µg/kg/min) for 2 min in 12 male rabbits under pentobarbital anesthesia. Beta was calculated using the following formula: Beta=2ρ / PP×ln (SBP / DBP)×PWV 2 , where ρ, SBP, DBP, and PP denote blood density and systolic, diastolic, and pulse pressures, respectively. aBeta, ifBeta, and aortic-iliac-femoral Beta (aifBeta) were calculated using aPWV, ifPWV, and aifPWV, respectively., Results: SBP, mean arterial pressure (MAP), DBP, and total peripheral vascular resistance significantly decreased during the administration of nicardipine, whereas cardiac output significantly increased. aBeta and ifBeta significantly increased and decreased, respectively, whereas aifBeta did not change despite the decrease in BP. ifBeta and aBeta positively and negatively correlated with BP, respectively, whereas aifBeta did not correlate with SBP., Conclusions: There were contradictory arterial responses to nicardipine between the elastic and muscular arteries. Unknown vasoconstriction mechanisms that are not involved in Ca 2＋ influx may function in the aorta in response to decreased BP.

Gastrointestinal motility was disturbed in W/Wv, which were lacking of interstitial cells of Cajal (ICC). In this study, we have investigated the role of arecoline hydrobromide (AH) on smooth muscle motility in the jejunum of W/Wv and wild-type (WT) mice. The jejunum tension was recorded by an isometric force transducer. Intracellular recording was used to identify whether AH affects slow wave and resting membrane potential (RMP) in vitro. The whole-cell patch clamp technique was used to explore the effects of AH on voltage-dependent potassium channels for jejunum smooth muscle cells. AH enhanced W/Wv and WT jejunum contractility in a dose-dependent manner. Atropine and nicardipine completely blocked the excitatory effect of AH in both W/Wv and WT. TEA did not reduce the effect of AH in WT, but was sufficient to block the excitatory effect of AH in W/Wv. AH significantly depolarized the RMP of jejunum cells in W/Wv and WT. After pretreatment with TEA, the RMP of jejunum cells indicated depolarization in W/Wv and WT, but subsequently perfused AH had no additional effect on RMP. AH inhibited the voltage-dependent K+ currents of acutely isolated mouse jejunum smooth muscle cells. Our study demonstrate that AH enhances the contraction activity of jejunum smooth muscle, an effect which is mediated by voltage-dependent potassium channels that acts to enhance the excitability of jejunum smooth muscle cells in mice.

Glioblastoma multiforme (GBM) is the most invasive malignant central nervous system tumor with poor prognosis. Nicardipine, a dihydropyridine calcium channel antagonist, has been used as an adjuvant to enhance sensitivity to chemotherapeutic drugs. However, whether glioma stem cells (GSCs) can be sensitized to chemotherapy via combined treatment with temozolomide (TMZ) and nicardipine is unclear. In this study, surgical specimen derived GSCs SU4 and SU5 were applied to explore the sensitization effect of nicardipine on temozolomide against GSCs, and further explore the relevant molecular mechanisms. Our results showed that nicardipine can enhance the toxic effect of temozolomide against GSCs, promote apoptosis of GSCs, and inhibit autophagy of GSCs. The relevant mechanisms were related to activation of mTOR, and selective inhibition of mTOR by rapamycin could weaken the sensitization of nicardipine to temozolomide, which suggest that nicardipine can be applied as an adjuvant to inhibit autophagy in GSCs, and enhance apoptosis-promoting effect of temozolomide in GSCs as well. Nicardipine can inhibit autophagy by activating expression of mTOR, thus play tumor inhibition roles both in vitro and in vivo . Repurposing of nicardipine can help to improving therapeutic effect of TMZ against GBM, which deserves further clinical investigations.

The Nod-like receptor protein 3 (NLRP3) inflammasome is a multi-protein complex composed of NLRP3, pro-caspase-1, and apoptosis-associated speck-like protein that contains a caspase recruitment domain (ASC). After NLRP3 priming by lipopolysaccharide (LPS), the ligand of toll-like receptor 4 (TLR4), activation of the NLRP3 inflammasome triggers caspase-1 maturation, leading to pyroptosis and release of interleukin-1beta (IL-1beta). Expression of TLR4 modulates LPS-triggered inflammatory cascades as well as the NLRP3 signaling. L-type calcium channel antagonists are widely used as anti-hypertensive drugs and also exert anti-inflammatory effects through inhibiting release of cytokines including IL-1beta. However, few studies reveal effects of L-type calcium channel antagonists on the NLRP3 inflammasome. In this study, we investigated the effects of nicardipine and verapamil, both L-type calcium channel antagonists, on the NLRP3 inflammasome using differentiated THP-1 cells. Pyroptosis or levels of IL-1beta and caspase-1 were assayed by flow cytometry or enzyme-linked immunosorbent assay, respectively. ASC oligomerization was assayed by immunofluorescence microscopy. Expression of NLRP3 or TLR4 was assayed by polymerase chain reaction and immunoblotting. Nuclear factor-kappaB (NF-kappaB) pathway was also studied. Our results showed that pyroptosis and IL-1beta release were attenuated by nicardipine, but not verapamil. Nicardipine also mitigated caspase-1 activation, inhibited ASC oligomerization, and reduced NLRP3 expression. Furthermore, nicardipine downregulated phosphorylation or nuclear translocation of NF-kappaB p65, consistent with the inhibitory effect of nicardipine on LPS-induced TLR4 expression. In conclusion, nicardipine exerted anti-inflammatory effects through inhibiting NLRP3 inflammasome pathway. Nicardipine may mitigate NLRP3 priming via inhibiting NF-kappaB activation, mediated by suppressing LPS-induced TLR4 expression.

Purpose: Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Na v 1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified through a drug repurposing screen an FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Na v 1.8., Methods: We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3 mg/kg once a day for 3 weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force., Results: Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results., Conclusions: These in vivo results in the well characterized Tcf4(± ) PTHS mice may suggest the potential to test this already approved drug further in a clinical study with PTHS patients or suggest the potential for use off label under compassionate use with their physician.

Modes of interactions of small ligands with CYP3A4 have been defined using the Template established in our previous studies (DMPK. 34: 113-125 2019 and 34 351-364 2019). Interactions of polyaromatic hydrocarbons such as benzo[a]pyrene, pyrene and dibenzo[a,j]acridine were refined with the idea of Right-side movement of ligands at Rings A and B of Template. Expected formation of metabolites from the placements faithfully matched with experimentally observed sites of their metabolisms and also with preferred orders of regio-isomeric metabolite abundances in recombinant CYP3A4 system. In comparison of CYP3A4-ligand data with the placements on simulations, a futile sitting of non-substituted and free rotatable phenyl structures was suggested as a cause of poor oxidations of the phenyl parts of CYP3A4 ligands. These data were in turn indicative of the role of the rotation-ceasing action for the function. Typical inhibitors, ketoconazole, nicardipine, mibefradil and GF-I-1 shared mutuality on their sittings, in which the inhibitor molecules hold a CYP3A4 residue from dual sides on Template. In addition, clotrimazole would be stuck between facial- and rear-side walls of CYP3A4 and interact with ferric iron through nitrogen atom of the imidazole part. These data offered structural bases of CYP3A4-inhibitory actions of ligands., (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Taken into consideration that oxidative stress response after preconditioning with phosphodiesterase inhibitors (PDEIs) and moderate physical activity has still not been clarified, the aim of this study was to assess the effects of PDEIs alone or in combination with physical activity, on systemic redox status. The study was carried out on 96 male Wistar albino rats classified into two groups. The first group included animals exposed only to pharmacological preconditioning (PreC) maneuver (sedentary control (CTRL, 1 ml/day saline, n = 12), nicardipine (6 mg/kg/day of NIC, n = 12), vinpocetine (10 mg/kg/day of VIN, n = 12), and nimodipine (NIM 10 mg/kg/day of, n = 12). The second included animals exposed to preconditioning with moderate-intensity training (MIT) on treadmill for 8 weeks. After 5 weeks from the start of training, the animals were divided into four subgroups depending on the medication to be used for pharmacological PreC: moderate-intensity training (MIT+ 1 ml/day saline, n = 12), nicardipine (MIT+ 6 mg/kg/day of NIC, n = 12), vinpocetine (MIT+ 10 mg/kg/day of VIN, n = 12), and nimodipine (MIT+ 10 mg/kg/day of NIM, n = 12). After three weeks of pharmacological preconditioning, the animals were sacrificed. The following oxidative stress parameters were measured spectrophotometrically: nitrites (NO 2 - ), superoxide anion radical (O 2 - ), hydrogen peroxide (H 2 O 2 ), index of lipid peroxidation (TBARS), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH). Our results showed that PDE1 and MIT preconditioning decreased the release of prooxidants and improved the activity of antioxidant enzymes thus preventing systemic oxidative stress., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Jelena Ristic et al.)

Alterations in the autophagosomal-lysosomal pathway are a major pathophysiological feature of CLN3 disease, which is the most common form of childhood-onset neurodegeneration. Accumulating autofluorescent lysosomal storage material in CLN3 disease, consisting of dolichols, lipids, biometals, and a protein that normally resides in the mitochondria, subunit c of the mitochondrial ATPase, provides evidence that autophagosomal-lysosomal turnover of cellular components is disrupted upon loss of CLN3 protein function. Using a murine neuronal cell model of the disease, which accurately mimics the major gene defect and the hallmark features of CLN3 disease, we conducted an unbiased search for modifiers of autophagy, extending previous work by further optimizing a GFP-LC3 based assay and performing a high-content screen on a library of ~2000 bioactive compounds. Here we corroborate our earlier screening results and identify expanded, independent sets of autophagy modifiers that increase or decrease the accumulation of autophagosomes in the CLN3 disease cells, highlighting several pathways of interest, including the regulation of calcium signaling, microtubule dynamics, and the mevalonate pathway. Follow-up analysis on fluspirilene, nicardipine, and verapamil, in particular, confirmed activity in reducing GFP-LC3 vesicle burden, while also demonstrating activity in normalizing lysosomal positioning and, for verapamil, in promoting storage material clearance in CLN3 disease neuronal cells. This study demonstrates the potential for cell-based screening studies to identify candidate molecules and pathways for further work to understand CLN3 disease pathogenesis and in drug development efforts., Competing Interests: U.C., E.B., S.L.C., M.C.K., W.-N.Z., and S.A.R. declare no conflicts of interest. A.P. is a shareholder in Enspire Bio, Inc, which played no role in the study. M.O.R. is currently an employee of Image Computing & Information Technologies (ICIT). This company played no role in the study. S.J.H. is a member of the SAB and equity holder in Rodin Therapeutics, Frequency Therapeutics, Psy Therapeutics and Souvien Therapeutics, as well as having received consulting or speaking fees from Sunovion, Biogen, AstraZeneca, Amgen, and Merck, none of whom were involved in the study. The funders had no role in the design, data collection, interpretation, writing of the manuscript, or in the decision to the publish the study.

Premature trypsinogen activation is the early event of acute pancreatitis. Therefore, the studies on the processes of trypsinogen activation induced by compounds are important to understand mechanism underly acute pancreatitis under various conditions. Calcium overload in the early stage of acute pancreatitis was previously found to cause intracellular trypsinogen activation; however, treatment of acute pancreatitis using calcium channel blockers did not produced consistent results. Proteasome activity that could be inhibited by some calcium channel blocker has recently been reported to affect the development of acute pancreatitis; however, the associated mechanism were not fully understood. Here, the roles of nicardipine were investigated in trypsinogen activation in pancreatic acinar cells. The results showed that nicardipine could increase cathepsin B activity that caused trypsinogen activation, but higher concentration of nicardipine or prolonged treatment had an opposite effect. The effects of short time treatment of nicardipine at low concentration were studied here. Proteasome inhibition was observed under nicardipine treatment that contributed to the up-regulation in cytosolic calcium. Increased cytosolic calcium from ER induced by nicardipine resulted in the release and activation of cathepsin B. Meanwhile, calcium chelator inhibited cathepsin B as well as trypsinogen activation. Consistently, proteasome activator protected acinar cells from injury induced by nicardipine. Moreover, proteasome inhibition caused by nicardipine depended on CaMKII. In conclusion, CaMKII down-regulation/proteasome inhibition/cytosolic calcium up-regulation/cathepsin B activation/trypsinogen activation axis was present in pancreatic acinar cells injury under nicardipine treatment., (© 2019 The Author(s).)

Intracerebral hemorrhage (ICH) is responsible for approximately 15% of strokes annually in the United States, with nearly 1 in 3 of these patients dying without ever leaving the hospital. Because this disproportionate mortality risk has been stagnant for nearly 3 decades, a main area of research has been focused on the optimal strategies to reduce mortality and improve functional outcomes. The acute hypertensive response following ICH has been shown to facilitate ICH expansion and is a strong predictor of mortality. Rapidly reducing blood pressure was once thought to induce cerebral ischemia, though has been found to be safe in certain patient populations. Clinicians must work quickly to determine whether specific patient populations may benefit from acute lowering of systolic blood pressure (SBP) following ICH. This review provides nurses with a summary of the available literature on blood pressure control following ICH. It focuses on intravenous and oral antihypertensive medications available in the United States that may be utilized to acutely lower SBP, as well as medications outside of the antihypertensive class used during the acute setting that may reduce SBP.

Background: Blood pressure variability (BPV) is an independent predictor for early hematoma expansion, neurologic deterioration, and mortality. There are no studies on the effect of intravenous (IV) antihypertensive drugs on BPV. We sought to determine whether patients have more BPV with certain antihypertensive agents, in particular the effect of IV nicardipine., Methods: We conducted a single-center, retrospective chart review of individuals diagnosed with spontaneous intracerebral hemorrhage (ICH) receiving labetalol, hydralazine, and/or nicardipine within 24 h of hospital admission to assess the primary endpoint of BPV, defined as the standard deviation of systolic BP, with labetalol and/or hydralazine compared to nicardipine ± labetalol and/or hydralazine. Repeated measures linear regression was performed to compare BPV over 24 h between regimens, and Cox proportional hazards regression was used to compare the time to goal SBP between regimens., Results: Of the 1330 patients screened, 272 were included in our analysis; those included had a mean age of 69 years with 87.9% of Caucasian race. A total of 164 patients received IV bolus antihypertensives alone (labetalol, hydralazine or both), and 108 patients received IV nicardipine with or without additional IV boluses (labetalol, hydralazine, or both). Those who had IV nicardipine had significantly less BPV (p = 0.04) and was more likely to attain an SBP goal < 140 mmHg (p < 0.01)., Conclusion: Our study suggests patients with ICH who do not receive a nicardipine-based antihypertensive regimen have more BPV, which has been associated with poor clinical outcomes. Prospective, randomized, controlled trials are needed to determine the impact of specific antihypertensive regimens on clinical outcomes.

A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium.

Objectives: The aim of this study was to evaluate the ability of four calcium channel blockers (CCBs), namely verapamil, diltiazem, nicardipine (NIC) and nifedipine (NIF), to enhance the susceptibility of Candida glabrata strains to fluconazole (FLC)., Methods: Synergistic antifungal effects of the CCBs with FLC were examined by the chequerboard method, and fractional inhibitory concentration indices (FICIs) were determined. The time-kill curve method was used for the most promising combination to further evaluate the synergetic effects., Results: NIC showed an additive effect with FLC against FLC-resistant and FLC-susceptible-dose-dependent strains (DSY 565 and CBS 138) known to express efflux pumps, but not against FLC-susceptible strains. NIF exhibited an additive effect with FLC both by the chequerboard method (0.510 CFU/mL decrease in viable count). In addition, NIF had its own antifungal effect consistently against most of the strains used in this study, with minimum inhibitory concentrations (MICs) of 8μg/mL., Conclusions: NIC showed an additive effect with FLC against FLC-resistant C. glabrata strains, most probably via efflux pump inhibition as demonstrated selectively in FLC-resistant strains with known efflux pumps. NIF displayed a promising antifungal effect alone as well as an additive effect with FLC against most of the strains., (Copyright © 2018 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.)

The objective of the present study was to develop a sustained release gastro-retentive (SRGR) tablet formulation of nicardipine hydrochloride (HCl) for once-a-day dosing using the quality by design (QbD) approach. The quality target product profile of nicardipine HCl SRGR tablet formulation was defined, and critical quality attributes (CQAs) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tool and screened by the Plackett-Burman design, and finally nicardipine HCl SRGR tablet formulation was optimized using the Box-Behnken design. The tablets were prepared by a direct compression technique using polymers such as hydroxypropylmethylcellulose (HPMC K15M), glyceryl behenate, alone or in combinations and other standard excipients. Sodium bicarbonate was incorporated as a gas-generating agent. The effects of polymers and sodium bicarbonate on the drug release profile and floating properties were investigated as these parameters are likely to affect the desired once-a-day dosing regimen and finally the therapeutic efficacy of SRGR drug delivery systems. It was observed that formulation variables X 1 : Glyceryl behenate (mg/tab) and X 2 : HPMC K15M (mg/tab) strikingly influenced the drug release (%) (Y 1 ), whereas floating lag time (min) (Y 2 ) was significantly impacted by the formulation variable X 3 : Sodium bicarbonate (mg/tab). A design space plot within which the CQAs remained unchanged was established at a lab scale. In conclusion, this study demonstrated the suitability of a glyceryl behenate-HPMC K15M polymer combination along with sodium bicarbonate to achieve SRGR tablet formulation for once-a-day dosing of nicardipine HCl using the systematic QbD approach.

The possible role of voltage-sensitive calcium channels (VSCC) activation on the HgCl 2 -induced dopamine release was investigated using selective VSCC blockers and the dopamine levels were measured by HPLC from samples obtained by in vivo brain microdialysis. Infusion of HgCl 2 in nicardipine (10 or 100 μM) or flunaricine (10 μM) pretreated animals had no significant effect on dopamine release induced by HgCl 2 . Pretreatment with 100 μM flunaricine, 20 μM ω-conotoxin MVIIC, or ω-conotoxin GVIA significantly decreased the HgCl 2 -induced dopamine release over 61%, 88%, and 99%, respectively. HgCl 2 -induced dopamine release could be produced, at least in part, by activation of VSCC at dopaminergic terminals, especially N- and P/Q-type., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The polypeptide ghrelin is an endogenous ligand at the growth hormone secretagogue receptor 1a. To ghrelin multiple functions have been ascribed including promotion of gastrointestinal motility. Postprandial ghrelin levels have been reported to be reduced in patients suffering from Parkinson disease (PD). Experimental studies revealed neuroprotective effects of ghrelin in different PD models. The purpose of the present study was (i) to further elucidate the mechanism underlying the neuroprotective action of ghrelin and (ii) to determine whether these effects occur with both the acylated and the unacylated form. The study was conducted in primary mesencephalic cultures treated with mitochondrial complex I and complex II inhibitors. We show that protective effects of ghrelin against complex I inhibition with MPP + were independent of the acylation status of ghrelin, although acylated ghrelin appeared to be more potent. Protection by both forms was also observed when neurons were exposed to the complex II inhibitor 3-NP. Both forms led to higher oxygen consumption rates upon electron transport chain uncoupling, indicating that the two peptides may exert uncoupling effects themselves. We demonstrate that the rescue provided by ghrelin required calcium influx through L-type voltage-gated calcium channels. Whereas the protective effects of acylated ghrelin required receptor binding, effects of the unacylated form remained unaffected by treatment with a ghrelin receptor antagonist. Importantly, inhibition of ghrelin O-acyltransferase failed to reduce the activity of unacylated ghrelin. Overall, our data suggest that both acylated and unacylated ghrelin afford protection to dopamine neurons but through mechanisms that only partially overlap., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

In rat vascular smooth muscle cells (RVSMC), 3-h Na + ,K + -ATPase inhibition by ouabain or in K + -free medium resulted in the inversion of the [Na + ] i /[K + ] i ratio and elevation up to 7-fold the content of Egr1, Atf3, Nr4a1 and Ptgs2 mRNAs. Ouabain increased the rate of 45Ca 2+ influx by 2-fold that was abolished by L-type voltage-gated Ca 2+ channel blocker nicardipine, but it was resistant to Na + /Ca 2+ exchanger inhibitor KB-R7943. To study the role of Ca 2+ -mediated signaling in the expression of Na + i /K + i -sensitive genes we used intracellular Ca 2+ chelator BAPTA and incubated RVSMC in Ca 2+ -free medium. The elevation of Nr4a1 and Ptgs2 expression triggered by ouabain was diminished in Ca 2+ -depeleted cells as well as in the presence of nicardipine and calmodulin antagonists A-7 and W-7. Ptgs2 expression was also suppressed by inhibitor of Ca 2+ /calmodulin-dependent protein kinase (CaMKII) KN-93 whereas increment of Nr4a1 content triggered by ouabain was attenuated by inhibitor of Ca 2+ /calmodulin-dependent protein phosphatase (calcineurin, CaN) cyclosporin A. Neither Ca 2+ depletion nor above listed compounds had any impact on the augmented expression of Egr1 and Atf3 in ouabain-treated RVSMC. Our results strongly suggest that dissipation of transmembrane gradient of monovalent cations increases Ptgs2 and Nr4a1 transcription via augment Ca 2+ influx through L-type Ca 2+ channels that, in turn, leads to CaMKII-mediated phosphorylation of CREB and calcineurin-mediated dephosphorylation of NFAT, respectively. Additional experiments should be performed to identify intermediates of Na + i ,K + i -mediated Ca 2+ -independent excitation-transcription coupling involved the regulation of Egr1 and Atf3 expression., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Study Design: Single-center, prospective, randomized, and single-blinded clinical trial was conducted in patients (n=64) undergoing anterior or posterior spinal interbody fusion., Objective: To investigate the renal protective effect of nicardipine during deliberate hypotension for spine surgery by measuring creatinine clearance (Ccr), serum cystatin C, urine output, and fractional excretion of sodium (FENa)., Summary of Background Data: Deliberate hypotension during spine surgery may result in ischemic tissue damage of the kidney. Nicardipine is reported to dilate the renal artery and increase glomerular filtration rate. Previous studies reported the renal protective effect of nicardipine during cardiac surgery under cardiopulmonary bypass and robot-assisted laparoscopic surgery., Materials and Methods: Patients were randomized to receive nicardipine (nicardipine group, n=32) or normal saline (control group, n=32). Deliberate hypotension of mean arterial pressure at 50-65 mm Hg was maintained during surgery. Ccr, serum cystatin C, urine output, and FENa were measured before surgery, after surgery, and postoperative day 1 (POD1). The RIFLE (risk, injury, failure, loss, and end stage renal disease) criteria of the patients were evaluated., Results: In the nicardipine group, Ccr at POD1 was increased compared with that after surgery. In both groups, serum cystatin C at POD1 was decreased compared with that before surgery and urine output at POD1 was decreased compared with that after surgery. FENa at POD1 in the control group was higher than that in the nicardipine group and was increased compared with that after surgery. Using RIFLE criteria, 6 patients in the control group and 2 patients in the nicardipine group were classified as having acute kidney injury., Conclusions: Nicardipine increased Ccr and attenuated the increase in FENa at POD1 in patients undergoing spine surgery under deliberate hypotension.

Background: Currently, a lack of published literature exists regarding the use of clevidipine in the neuroscience population. This agent may be preferred in some patients because of its short half-life, potentially leading to more narrow blood pressure (BP) control in comparison with other agents. The purpose of this study was to compare the difference in time to achieve target systolic blood pressure (SBP) goals with clevidipine versus nicardipine infusions in patients admitted to the neuroscience intensive care unit (NSICU) at our institution., Methods: A retrospective review was performed on patients receiving clevidipine or nicardipine infusions while in the NSICU between July 1, 2011 and June 30, 2014. Patients were matched based on indication for BP lowering and target SBP. Primary endpoints included time to target SBP and percentage of time within target BP range., Results: Of the 57 patients included in the study, the median time to target SBP was 30 min in the clevidipine group and 46 min in the nicardipine group (p = 0.13). The percentage of time spent within target BP range was 79 versus 78% (p = 0.64). Clevidipine administration resulted in significantly less volume administered per patient versus nicardipine (530 vs. 1254 mL, p = 0.02)., Conclusions: There were no statistically significant differences in acute BP management between the two agents; however, there was a trend toward shorter time to target and significantly less volume administered in the clevidipine group. Either agent should be considered a viable option in a NSICU population.

Background: The effectiveness of surgical pleth index (SPI) for managing nociception-antinociception balance during general anesthesia with vasodilators, including nicardipine has not been demonstrated. We aimed to compare the time course during surgery in SPI values in patients receiving nicardipine or remifentanil infusion during thyroidectomy., Methods: Forty patients undergoing thyroidectomy were randomly assigned to receive nicardipine (group N; n = 19) or remifentanil (group R; n = 21) along with induction (propofol, fentanyl, and rocuronium) and maintenance (50% desflurane/nitrous oxide in oxygen) anesthesia (goal bispectral index [BIS] ∼50). The infusion of nicardipine or remifentanil was started before the 1st incision and adjusted to keep mean blood pressure (MBP) within ±20% of the preoperative value. SPI, BIS, end-tidal desflurane concentration (EtDes), MBP, and heart rate were recorded at 2.5 minute intervals from the 1st incision to the end of surgery. Extubation and recovery times, pain score/rescue ketorolac consumption, and adverse events in postanesthesia care unit (PACU) were recorded., Results: The trend of SPI during surgery was comparable between the 2 groups (P = 0.804), although the heart rates in group N were significantly higher than those in group R (P = 0.040). The patient characteristics, trends of BIS, EtDes, and MBP during surgery, extubation and recovery times, and incidence of nausea/vomiting were comparable between the groups. Group N had significantly lower pain scores and rescue ketorolac consumption at PACU., Conclusion: SPI was comparable between patients receiving nicardipine or remifentanil infusion during thyroidectomy under general anesthesia, which suggests that the administration of nicardipine may confound the interpretation of SPI values during general anesthesia., Clinical Trial Registration: This trial was registered in the UMIN clinical trials registry (unique trial number: UMIN000019058; registration number: R000022028; principal investigator's name: Young Ju Won; date of registration: September 17, 2015).

Cilnidipine is a dihydropyridine derivative that inhibits N-type and L-type voltage-gated Ca 2+ channels (VDCCs). We recently reported that a selective N-type VDCC blocker attenuated the spinal long-term potentiation (LTP) of C-fiber-evoked field potentials recorded in the spinal dorsal horn of rats, which served as a model for examining synaptic function during central pain sensitization. In this study, we investigated the effects of cilnidipine on the changes related to neuropathic pain induced by nerve injury. Mechanical allodynia and hyperalgesia were evaluated by von Frey test and pin prick test, respectively. Spinal LTP of C-fiber-evoked field potentials were evaluated by in vivo electrophysiology. Intrathecally administrated cilnidipine attenuated mechanical allodynia and hyperalgesia in the spared nerve injury mouse model. Using in vivo electrophysiology in rats, cilnidipine (10µm) administered spinally inhibited the induction and maintenance of high-frequency stimulation-induced LTP of C-fiber-evoked field potentials, while basal C-fiber-evoked field potentials in naïve rats were unaffected. The basal C-fiber-evoked field potentials in nerve-injured rats were strongly inhibited by cilnidipine. Treatment with a specific N-type VDCC blocker, ω-conotoxin GVIA, which reportedly attenuates C-fiber-evoked field potentials both before and after the induction of LTP, attenuated mechanical allodynia and hyperalgesia in nerve-injured mice. By contrast, an L-type VDCC blocker, nicardipine attenuated only mechanical hyperalgesia, but not mechanical allodynia in nerve-injured mice, and also attenuated the established LTP of C-fiber-evoked field potentials in rats. These results suggested that N-type and L-type VDCC blockers may effectively alleviate the hyperalgesia and allodynia associated with neuropathic pain without affecting normal pain perception., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex-mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca 2+ channel inhibition by cilnidipine might have suppressed the parasympathetic nerve activity in vivo like those reported in the sympathetic nerve. Thus, cilnidipine may become a useful strategy for inhibiting coronary vasospasm-induced anginal attack.

Angelica acutiloba Kitagawa (Yamato Toki) is a herbal medicine known to exhibit various health effects. In this study, we used a rat model to examine the effects of two different Yamato Toki extracts on the blood flow response of the instep of the hind paw. Twelve-week- old male stroke-prone spontaneously hypertensive rats (SHRSP) were orally given 200 mg of a water extract of Yamato Toki (n=6), 200 mg of an ethanol extract of Yamato Toki (n = 6), 30 mg/kg of nicardipine (n = 6) as a positive control and saline (n = 6) as a negative control. Blood flow was monitored continuously for 0, 1, 3, 6 and 24 hours after treatment. Rats given 200 mg of the ethanol extract of Yamato Toki demonstrated significantly greater blood flow compared with control rats at I hour after treatment. An ethanol extract of Yamato Toki from Nara administrated orally can increase blood flow in SHRSP.

Study Objective: The objective of this study was to identify the effects of nicardipine on neuromuscular blockade of rocuronium, such as the onset time and intubation conditions, using a nicardipine dose that attenuates cardiovascular responses during endotracheal intubation., Design: Randomized, double-blinded, placebo-controlled clinical comparison was used as the design of this study, Setting: The study was conducted at the operating room of a university hospital., Patients: Participants of this study comprise 78 American Society of Anesthesiologists physical status 1 and 2 patients, aged 18 to 60 years who were undergoing elective surgery under general anesthesia., Interventions: The nicardipine group was given an intravenous bolus of 20 μg/kg nicardipine before tracheal intubation: the control group was given an intravenous bolus of a comparable volume of normal saline before tracheal intubation., Measurements: Using a TOF-Watch SX monitor, the time from the end of the injection of rocuronium to maximum depression of T1 (onset time) was measured. Intubation was performed 1 minute after rocuronium administration, and the status of the intubation conditions was assessed. The mean blood pressure and heart rate were each measured after endotracheal intubation. Rate pressure product values were also calculated., Main Results: Intubation conditions were clinically acceptable in 37 (94.9%) of 39 patients in group N compared with 29 (74.4%) of 39 in group C (P < .05). The onset time of rocuronium was significantly faster in group N than in group C (P < .05). The mean blood pressure was significantly lower in group N than in group C (P < .05). The heart rate was significantly higher in group N than in group C (P < .05). Rate pressure product values showed no significant difference between the two groups (P > .05)., Conclusions: Pretreatment with 20 μg/kg nicardipine improves intubation conditions, shortens the onset time of rocuronium, and attenuates cardiovascular responses to tracheal intubation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Organotypic tissue slices provide seminatural, three-dimensional microenvironments for use in ex vivo study of specific organs and have advanced investigative capabilities compared with isolated cell cultures. Several characteristics of the gastrointestinal tract have made in vitro models for studying the intestine challenging, such as maintaining the intricate structure of microvilli, the intrinsic enteric nervous system, Peyer's patches, the microbiome, and the active contraction of gut muscles. In the present study, an organotypic intestinal slice model was developed that allows for functional investigation across regions of the intestine. Intestinal tissue slices were maintained ex vivo for several days in a physiologically relevant environment that preserved normal enterocyte structure, intact and proliferating crypt cells, submucosal organization, and muscle wall composure. Cell death was measured by a membrane-impermeable DNA binding indicator, ethidium homodimer, and less than 5% of cells were labeled in all regions of the villi and crypt epithelia at 24 h ex vivo. This tissue slice model demonstrated intact myenteric and submucosal neuronal plexuses and functional interstitial cells of Cajal to the extent that nonstimulated, segmental contractions occurred for up to 48 h ex vivo. To detect changes in physiological responses, slices were also assessed for segmental contractions in the presence and absence of antibiotic treatment, which resulted in slices with lesser or greater amounts of commensal bacteria, respectively. Segmental contractions were significantly greater in slices without antibiotics and increased native microbiota. This model renders mechanisms of neuroimmune-microbiome interactions in a complex gut environment available to direct observation and controlled perturbation., (Copyright © 2016 the American Physiological Society.)

We previously reported that INS-1 cells expressing the intracellular II-III loop of the L-type Ca(2+) channel Cav1.2 (Cav1.2/II-III cells) are deficient in Ca(2+)-induced Ca(2+) release (CICR). Here we show that glucose-stimulated ERK 1/2 phosphorylation (GSEP) is slowed and reduced in Cav1.2/II-III cells compared to INS-1 cells. This parallels a decrease in glucose-stimulated cAMP accumulation (GS-cAMP) in Cav1.2/II-III cells. Influx of Ca(2+) via L-type Ca(2+) channels and CICR play roles in both GSEP and GS-cAMP in INS-1 cells since both are inhibited by nicardipine or ryanodine. Further, the Epac1-selective inhibitor CE3F4 abolishes glucose-stimulated ERK activation in INS-1 cells, as measured using the FRET-based sensor EKAR. The non-selective Epac antagonist ESI-09 but not the Epac2-selective antagonist ESI-05 nor the PKA antagonist Rp-cAMPs inhibits GSEP in both INS-1 and Cav1.2/II-III cells. We conclude that L-type Ca(2+) channel-dependent cAMP accumulation, that's amplified by CICR, activates Epac1 and drives GSEP in INS-1 cells., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers., Methods: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration., Results: Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO., Conclusion: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension.

Retinal blood flow insufficiency due to capillary loss induces hypoxia in the retina, leading to an abnormal angiogenesis, relating to ischemic retinopathy. To better understand the mechanism and process of retinal capillary regression, we examined the process of hyperoxia- and vascular endothelial growth factor receptor (VEGFR) inhibitor-induced retinal capillary regression in neonatal mice. We also investigated the effects of Ca(2+) channel blockers, amlodipine and nicardipine, on hyperoxia-induced capillary regression. The regression of capillaries adjacent to arteries began immediately after the mice were exposed to 80% oxygen on postnatal day 7. An apparent avascular zone was established within 24 h after the initiation of oxygen exposure, whereas capillaries in the retinal vascular front were not affected. Axitinib, an inhibitor of VEGFR tyrosine kinase, induced capillary regression throughout the retinal vasculature. High-concentration oxygen exposure affected the capillaries on the arterial side of the retinal circulation more preferentially than axitinib. The Ca(2+) channel blockers significantly delayed hyperoxia-induced capillary regression and changes in the capillaries on the arterial side. These results suggest that the decreased blood flow due to arterial constriction contributes to hyperoxia-induced capillary regression. Compounds that improve the retinal blood flow may prevent ischemia by preventing capillary loss., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Cardio-ankle vascular index (CAVI) has been developed for measurement of vascular stiffness from the aorta to tibial artery, which is clinically utilized for assessing the progress of arteriosclerosis. In this study, we established measuring system of the CAVI in rabbits, and assessed whether the index could reflect different pharmacological actions of nitroglycerin and nicardipine on the systemic vasculature. Rabbits were anesthetized with halothane, and the CAVI was calculated from the well-established basic equations with variables obtained from brachial and tibial blood pressure and phonocardiogram. Nicardipine (1, 3 and 10 μg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and heart-ankle pulse wave velocity (haPWV). Meanwhile, no significant change was detected in the CAVI at the low or middle dose, which reflects the defining feature of the CAVI that is independent of blood pressure. The index increased at the high dose. Nitroglycerin (2, 4 and 8 μg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and haPWV. Meanwhile, the CAVI was decreased during the nitroglycerin infusion, which may reflect its well-known pharmacological action dilating conduit arteries. These results suggest that the CAVI differentiates the properties of these vasodilators in vivo., (Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: The main aims of rapid sequence induction (RSI) are prompt and adequate muscle relaxation for tracheal intubation and hemodynamic stability during and after intubation. The purpose of the present study was to investigate the effects of nicardipine and esmolol on the action of rocuronium and intubation conditions during RSI., Methods: Adult patients (n = 82) were randomly allocated to one of three groups. One minute prior to the induction of sevoflurane-based general anesthesia, patients received 20 μg/kg of nicardipine (N group; n = 27) or 0.5 mg/kg of esmolol (E group; n = 27), or 5 ml of saline (C group; n = 28). Patients were assessed according to intubation conditions, the onset time of rocuronium, mean arterial pressure (MAP), and heart rate (HR) during RSI., Results: The intubation conditions and score were significantly better in the C and N groups than in the E group (P < 0.001). The onset time of rocuronium was shortened in the N group and prolonged in the E group when compared to the C group (P < 0.001). A significant attenuation in the increase of MAP immediately after intubation was observed in the N group as compared with the C and E groups (P < 0.008). HR was significantly lower in the E group than in the N and C groups (P < 0.01)., Conclusion: Pretreatment with nicardipine for RSI improved intubation conditions and shortened the onset time of rocuronium and attenuated changes in MAP after intubation. Esmolol may disturb intubation conditions and the onset of action of rocuronium, despite being effective in alleviating responses of HR after RSI.

Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta.

Nifedipine and nicardipine are both calcium channel inhibitors, used off-label as tocolytics in preterm labour. Their use is related to their relaxing effects on uterin muscle by L-type voltage dependent calcium channels blockade. This article describes pharmacological effects, pharmacokinetics properties and tolerance of these drugs. It also discusses serious adverse effects, such as pulmonary edema, reported with both nifedipine and nicardipine in preterm labour., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Models of basal ganglia (BG) function posit a dynamic balance between two classes of striatal projection neurons (SPNs): direct pathway neurons (dSPNs) that facilitate movements, and indirect pathway neurons (iSPNs) that repress movement execution. Two main modulatory transmitters regulate the output of these neurons: dopamine (DA) and acetylcholine (ACh). dSPNs express D1-type DA, M1-and M4-type ACh receptors, while iSPNs express D2-type DA and M1-type ACh receptors. Actions of M1-, D1-, and D2-receptors have been extensively reported, but we still ignore most actions of muscarinic M4-type receptors. Here, we used whole-cell recordings in acutely dissociated neurons, pharmacological tools such as mamba-toxins, and BAC D(1 or 2)-eGFP transgenic mice to show that activation of M4-type receptors with bath applied muscarine enhances Ca(2+)-currents through CaV1-channels in dSPNs and not in iSPNs. This action increases excitability of dSPNs after both direct current injection and synaptically driven stimulation. The increases in Ca(2+)-current and excitability were blocked specifically by mamba toxin-3, suggesting mediation via M4-type receptors. M4-receptor activation also increased network activity of dSPNs but not of iSPNs as seen with calcium-imaging techniques. Moreover, actions of D1-type and M4-type receptors may add to produce a larger enhancement of excitability of dSPNs or, paradoxically, oppose each other depending on the order of their activation. Possible implications of these findings are discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

The binding of GnRH to its receptor initiates signaling cascades in gonadotropes, which result in enhanced LH and FSH biosynthesis and secretion. This process is necessary for follicular maturation and ovulation. Calcium influx activates MAPKs, which lead to increased transcription of LH and FSH genes. Previous research suggests that two MAPK signaling pathways, ERK and jun-N-terminal kinase, are activated by either calcium influx through L-type calcium channels or by global calcium signals originating from intracellular stores, respectively. Here we continued this investigation to further elucidate molecular mechanisms transducing GnRH receptor stimulation to ERK activation. Although it is known that GnRH activation of ERK requires calcium influx through L-type calcium channels, direct evidence supporting an underlying local calcium signaling mechanism was lacking. Here we used a combination of electrophysiology and total internal reflection fluorescence microscopy to visualize discrete sites of calcium influx (calcium sparklets) in gonadotrope-derived αT3-1 cells in real time. GnRH increased localized calcium influx and promoted ERK activation. The L-type calcium channel agonist FPL 64176 enhanced calcium sparklets and ERK activation in a manner indistinguishable from GnRH. Conversely, the L-type calcium channel antagonist nicardipine inhibited not only localized calcium sparklets but also ERK activation in response to GnRH. GnRH-dependent stimulation of L-type calcium channels was found to require protein kinase C and a dynamic actin cytoskeleton. Taken together, we provide the first direct evidence for localized L-type calcium channel signaling in αT3-1 cells and demonstrate the utility of our approach for investigating signaling mechanisms and cellular organization in gonadotropes.

We have recently shown that in mouse ventricular myocytes, t-tubules can be quickly and tightly sealed during the resolution of hyposmotic shock of physiologically relevant magnitude. Sealing of t-tubules is associated with trapping extracellular solution inside the myocytes but the ionic homeostasis of sealed t-tubules and the consequences of potential transtubular ion fluxes remain unknown. In this study we investigated the dynamics of Ca(2+) movements associated with sealing of t-tubules. The data show that under normal conditions sealed t-tubules contain Ca(2+) at concentrations below 100μM. However, blockade of voltage-dependent Ca(2+) channels with 10μM nicardipine, or increasing extracellular concentration of K(+) from 5.4mM to 20mM led to several fold increase in concentration of t-tubular Ca(2+). Alternatively, the release of Ca(2+) from sarcoplasmic reticulum using 10mM caffeine led to the restoration of t-tubular Ca(2+) towards extracellular levels within few seconds. Sealing of t-tubules in the presence of extracellular 1.5mM Ca(2+) and 5.4mM extracellular K(+) led to occasional and sporadic intracellular Ca(2+) transients. In contrast, sealing of t-tubules in the presence of 10mM caffeine was characterized by a significant long lasting increase in intracellular Ca(2+). The effect was completely abolished in the absence of extracellular Ca(2+) and significantly reduced in pre-detubulated myocytes but was essentially preserved in the presence of mitochondrial decoupler dinitrophenol. This study shows that sealed t-tubules are capable of highly regulated transport of Ca(2+) and present a major route for Ca(2+) influx into the cytosol during sealing process., (Copyright © 2014 Elsevier Ltd. All rights reserved.)