Calcium Channel Blocker Nicardipine Research Articles

Investigating the mechanism of action of ginkgolides and bilobalide on absence seizures in male WAG/Rij rats.

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6mg/kg. In interaction groups, 6μg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10μg), CNQX (1μg), and nicardipine (50 μg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p=.028), C (p=.046), and bilobalide (p=.043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p=.046), CNQX (p=.043), and nicardipine (p=.046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

A randomized, single ascending dose safety, tolerability and pharmacokinetics study of NicaPlant® in aneurysmal subarachnoid hemorrhage patients undergoing clipping

IntroductionAneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Post-hemorrhagic vasospasm with neurological deterioration is a major concern in this context. NicaPlant®, a modified release formulation of the calcium channel blocker nicardipine, has shown vasodilator efficacy preclinically and a similar formulation known as NPRI has shown anti-vasospasm activity in aSAH patients under compassionate use. Research questionThe study aimed to assess pharmacokinetics and pharmacodynamics of NicaPlant® pellets to prevent vasospasm after clip ligation in aSAH. Material and methodsIn this multicenter, controlled, randomized, dose escalation trial we assessed the safety and tolerability of NicaPlant®. aSAH patients treated by clipping were randomized to receive up to 13 NicaPlant® implants, similarly to the dose of NPRIs previous used, or standard of care treatment. ResultsTen patients across four dose groups were treated with NicaPlant® (3–13 implants) while four patients received standard of care. 45 non-serious and 13 serious adverse events were reported, 4 non-serious adverse events and 5 serious adverse events assessed a probable or possible causal relationship to the investigational medical product. Across the NicaPlant® groups there was 1 case of moderate vasospasm, while in the standard of care group there were 2 cases of severe vasospasm. Discussion and conclusionThe placement of NicaPlant® during clip ligation of a ruptured cerebral aneurysm raised no safety concern. The dose of 10 NicaPlant® implants was selected for further clinical studies.

Opposing Responses of the Calcium Channel Blocker Nicardipine to Vascular Stiffness in the Elastic and Muscular Arteries in Rabbits.

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.

In vitro and in vivo testing of a novel local nicardipine delivery system to the brain: a preclinical study.

The management of patients with aneurysmal subarachnoid hemorrhage (aSAH) remains a highly demanding challenge in critical care medicine. Despite all efforts, the calcium channel antagonist nimodipine remains the only drug approved for improving outcomes after aSAH. However, in its current form of application, it provides less than optimal efficacy and causes dose-limiting hypotension in a substantial number of patients. Here, the authors tested in vitro the release dynamics of a novel formulation of the calcium channel blocker nicardipine and in vivo local tolerance and tissue reaction using a chronic cranial window model in mice. To characterize the release kinetics in vitro, dissolution experiments were performed using artificial cerebrospinal fluid over a time period of 21 days. The excipients used in this formulation (NicaPlant) for sustained nicardipine release are a mixture of two completely degradable polymers. A chronic cranial window in C57BL/6 mice was prepared, and NicaPlant slices were placed in proximity to the exposed cerebral vasculature. Epifluorescence video microscopy was performed right after implantation and on days 3 and 7 after surgery. Vessel diameter of the arteries and veins, vessel permeability, vessel configuration, and leukocyte-endothelial cell interaction were quantified by computer-assisted analysis. Immunofluorescence staining was performed to analyze inflammatory reactions and neuronal alterations. In vitro the nicardipine release profile showed an almost linear curve with about 80% release at day 15 and full release at day 21. In vivo epifluorescence video microscopy showed a significantly higher arterial vessel diameter in the NicaPlant group due to vessel dilatation (21.6 ± 2.6 µm vs 17.8 ± 1.5 µm in controls, p < 0.01) confirming vasoactivity of the implant, whereas the venous diameter was not affected. Vessel dilatation did not have any influence on the vessel permeability measured by contrast extravasation of the fluorescent dye in epifluorescence microscopy. Further, an increased leukocyte-endothelial cell interaction due to the implant could not be detected. Histological analysis did not show any microglial activation or accumulation. No structural neuronal changes were observed. NicaPlant provides continuous in vitro release of nicardipine over a 3-week observation period. In vivo testing confirmed vasoactivity and lack of toxicity. The local application of this novel nicardipine delivery system to the subarachnoid space is a promising tool to improve patient outcomes while avoiding systemic side effects.

Mechanisms underlying the urotensin II-induced proliferation of and α-smooth muscle actin expression in human dermal fibroblasts

Objective To evaluate the effects of urotensin Ⅱ on cell proliferation of and α-smooth muscle actin (α-SMA) expression in normal human dermal fibroblasts (NFs) , and to explore their regulatory mechanisms. Methods NFs were isolated from foreskin tissues and subjected to primary culture in vitro. Reverse transcription PCR and Western blot analysis were performed to measure the mRNA and protein expression of urotensin Ⅱ and its receptor, respectively. Cell counting kit-8 (CCK-8) assay was conducted to estimate the proliferation of NFs, which were treated with urotensin Ⅱ at different concentrations of 0, 10-10, 10-9, 10-8, 10-7 and 10-6 mol/L for 0, 6, 12, 24 and 48 hours separately, and then the optimal concentration and duration of urotensin Ⅱ exposure were selected to be 10-8 mol/L and 24 hours respectively. Some cultured NFs were divided into 5 groups: control group receiving no treatment, UⅡgroup treated with 10-8 mol/L urotensin Ⅱ, UⅡ+ nicardipine group treated with 10-8 mol/L urotensin Ⅱ and the calcium channel blocker nicardipine at the concentration of 10-5 mol/L, UⅡ+ PD98059 group treated with 10-8 mol/L urotensin Ⅱ and the mitogen activated protein kinase (MAPK) inhibitor PD98059 at the concentration of 10-5 mol/L, and UⅡ+ cyclosporine group treated with 10-8 mol/L urotensin Ⅱ and the calcium-dependent protein kinase (CaM PK) inhibitor cyclosporine at the concentration of 10-5 mol/L. After24-hour treatment, CCK-8 assay was conducted to evaluate the proliferation of NFs in the above groups, realtime fluorescence-based quantitative PCR and Western blot analysis were performed to determine the mRNA and protein expression of α-SMA respectively. Results Urotensin Ⅱ receptor was expressed in NFs, but urotensin Ⅱ was not. The proliferative activity of NFs significantly differed among the control group, UⅡ group, UⅡ+ nicardipine group, UⅡ+ PD98059 group and UⅡ+ cyclosporine group (the mean absorbance value at 405 nm: 1.036 ± 0.046, 1.405 ± 0.158, 1.121 ± 0.109, 1.192 ± 0.089 and 1.141 ± 0.056, respectively; F = 9.587, P < 0.01) , and the UⅡ group showed significantly higher proliferative activity of NFs compared with the control group, UⅡ + nicardipine group, UⅡ + PD98059 group and UⅡ + cyclosporine group (q = 8.263, 6.355, 4.774 and 5.912, respectively, all P < 0.05) . There were significant differences in the mRNA and protein expression of α-SMA among the 5 groups (F = 6.351, 7.045, both P < 0.01) , and the mRNA and protein expression of α-SMA was significantly higher in the UⅡ group than in the other 4 groups (all P < 0.05) . Conclusion UrotensinⅡ may induce the proliferation of and α-SMA expression in NFs through calcium channels, MAPK and CaM PK pathways. Key words: Urotensins; Fibroblasts; Cell proliferation; Actins; Cicatrix; Receptor, urotensins

Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats.

Left-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction. Thirty-seven-week-old SHRs were randomized in four groups receiving either saline, the selective 5-HT2BR antagonist RS-127445 (1 mg/kg per day), a calcium channel blocker nicardipine (6 mg/kg per day), or RS-127445 + nicardipine. During the 14 weeks of treatment period, cardiac function and blood pressure were monitored by echocardiography and tail-cuff. Finally, electrocardiograms and invasive hemodynamics were obtained before blood collection. Heart was analyzed for morphology and mRNA expression. A complementary study evaluated the cardiac and vascular effects of serotonin on wild-type and mice knockout for the 5-HT2BR (Htr2B) and/or the 5-HT2AR (Htr2A). Despite the left ventricular 5-HT2BR overexpression, 5-HT2BR blockade by RS-127445 did not affect left ventricular hypertrophy and fibrosis in SHRs. This antagonist did not improve diastolic dysfunction, neither alone nor in combination with nicardipine, although it induced plasma brain natriuretic peptide decrease. Moreover, RS-127445 amplified subendocardial fibrosis and favored left ventricular dilatation. Finally, a subendocardial left ventricular fibrosis was induced by chronic serotonin in wild-type mice, which was increased in Htr2B animals, but prevented in Htr2A and Htr2A/2B mice, and could be explained by a contribution of the endothelial 5-HT2BRs to coronary vasodilatation. This work is the first to identify a cardioprotective function of the 5-HT2BR in an integrated model of diastolic dysfunction with preserved ejection fraction.

Altered L-type Ca2+ channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice.

We determined the contribution of vascular large conductance Ca2+-activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

Anti-neuroinflammatory effects of the calcium channel blocker nicardipine on microglial cells: implications for neuroprotection.

Background/ObjectiveNicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved.Methodology/Principal FindingsIn the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo.Conclusion/SignificanceThe present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases.

The long chain fatty acid oleate activates mouse intestinal afferent nerves in vitro

Vagal afferents innervating the gastrointestinal tract serve an important nutrient-sensing function, and these signals contribute to satiety. Detection of nutrients occurs largely through the release of mediators from specialized enteroendocrine cells within the mucosa of the gastrointestinal tract. The signaling pathways leading to vagal afferent activation are not clear; however, previous in-vivo studies have implicated a role for cholecystokinin (CCK). We used an in vitro intestinal afferent extracellular recording preparation to study the effect of luminal perfusion of the long chain fatty acid oleate on mouse intestinal afferent activity. Oleate activated intestinal afferents in a concentration-dependent fashion, with an EC50 value of approximately 25 mmol/L. The L-type calcium channel blocker nicardipine attenuated the effect of oleate. Vagotomy resulted in a significant (>60%) reduction of the responses to both oleate and CCK. The CCK-1 receptor antagonist lorglumide nearly abolished responses to CCK and oleate. Our experiments therefore suggest that oleate activates intestinal afferents, with vagal afferents primarily involved; however, nonvagal fibres also contribute. The activation is dependent on CCK release, likely via activation of L-type channels on mucosal enteroendocrine cells, finally resulting in activation of CCK-1 receptors on the afferent terminals.

Inhibitory effect of nicardipine on rotenone-induced apoptosis in SH-SY5Y human neuroblastoma cells

Previous studies have demonstrated that calcium channel blockers have protective effects on damaged brains. In the present study, the protective effect of the calcium channel blocker nicardipine against rotenone‑induced apoptosis in SH‑SY5Y human neuroblastoma cells was investigated, focusing on mitogen‑activated protein kinases (MAPKs) and caspase (CASP)‑mediated apoptotic events. Nicardipine was found to decrease rotenone‑induced apoptosis through 4,6‑diamidino‑2‑phenylindole staining and the terminal deoxynucleotidyl transferase‑mediated dUTP nick end‑labeling assay. In addition, nicardipine was identified to inhibit rotenone‑induced elevation of intracellular Ca2+ concentration measured using the Fluo‑4 AM fluorescent dye. Rotenone increased phosphorylation of c‑Jun NH2‑terminal kinase (JNK) and p38 MAPK, whereas nicardipine blocked these increases. Nicardipine also prevented downregulation of B‑cell CLL/lymphoma 2 and upregulation of Bcl2‑associated X protein by rotenone. Furthermore, nicardipine abrogated cleavage of CASP9 and 3 and poly (ADP‑ribose) polymerase‑1 by rotenone and CASP3 enzyme activity in rotenone‑treated cells. These results indicate that nicardipine exerts a protective effect against rotenone‑induced apoptosis in SH‑SY5Y cells, inhibiting phosphorylation of JNK and p38 MAPK and activation of CASPs.

Effect of calcium channel blocker Nicardipine on secretion of cytokines and prostaglandin E2 in traumatic brain injury in rats

Effect of calcium channel blocker Nicardipine on secretion of cytokines and prostaglandin E2 in traumatic brain injury in rats

Contractile response of human omental arteries to endothelin.

The effects of endothelin have been studied in isolated arterial segments (0.8-1 mm in external diam.) of human omental arteries obtained during the course of abdominal operations (15 patients, 7 men and 8 women). Paired segments, one normal and the other de-endothelized, were mounted for isometric recording of tension in organ baths. Endothelin produced concentration-dependent contractions with an EC50 value of 5.4 x 10(-9) M. Removal of endothelium did not affect significantly endothelin-induced contractions (EC50, 6.7 x 10(-9) M). Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10(-6) M) diminished but did not abolish responses to endothelin. These results indicate that endothelin exerts powerful contractile effects on human isolated omental arteries which are independent of the presence of an intact endothelial cell layer; this contraction cannot be explained solely by voltage-dependent calcium channels.

Endothelin action on goat cerebral arteries

Cumulative application of endothelin-1 (human) markedly constricted goat isolated cerebral arteries in a concentration-dependent manner. Contractile responses were not affected by removal of endothelial cells. Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10(-7) M) failed to abolish responses to endothelin. The results suggest that the endothelium-independent constriction of cerebral arteries produced by endothelin cannot be explained solely by voltage-dependent calcium channels. The contractile responses are likely to be mediated by stimulation of specific receptors for this peptide.

Augmentation of 3-methylcholanthrene-induced bioactivation in the human hepatoma cell line HepG2 by the calcium channel blocker nicardipine

The abilities of the dihydropyridine calcium channel blocker nicardipine (Nic) to induce cytochrome P450 1 family enzymes (CYP1s) and to enhance the 3-methylcholanthrene (MC)-mediated induction of CYP1s and formation of MC-DNA adduct were examined in the human hepatoma cell line HepG2. The results from real time RT-PCR analysis demonstrated that Nic could induce CYP1 mRNAs and enhance the MC-mediated induction of the CYP1 mRNAs. The luciferase-reporter gene assay using the HepG2-A10 cell line, which has been previously established for the screening of aryl hydrocarbon receptor (AhR) activators, also indicated the augmentation of MC-mediated activation of AhR (induction of luciferase) by Nic, although Nic showed limited capacity for the activation of AhR. Furthermore, the results from the Western blot analysis of CYP1s, the enzyme activity assay, and the assay for MC-DNA adduct formation indicated that Nic could enhance the MC-mediated induction of CYP1s, especially CYP1A1. Furthermore, the intracellular accumulation level of [(3)H]MC after treatment of HepG2 cells with [(3)H]MC significantly increased in the presence of Nic. The present findings demonstrate that Nic can enhance the MC-mediated induction of CYP1s, especially CYP1A1, and the formation of MC-DNA adduct in HepG2 cells. Furthermore, the augmentation of the MC-mediated bioactivation by Nic is demonstrated to occur mainly through an increase in intracellular accumulation of MC.

Acute Antihypertensive Therapy in Pregnancy-Induced Hypertension: Is Nicardipine the Answer?

Hypertensive disorders in pregnancy constitute one of the most frequent medical complications during gestation. Unfortunately, maternal and perinatal mortality remains significant worldwide in this population. Not infrequently, patients with severe preeclampsia will need parenteral agents to achieve rapid blood pressure control to avoid end-organ damage. During the last decades, new antihypertensive medications have become available for management of hypertensive crisis. One of these agents is the calcium channel blocker nicardipine. Nicardipine has been used extensively in different clinical settings including neurosurgery, cardiothoracic surgery, transplant medicine, and internal medicine patients. Minimal data exist in the literature regarding the use of this medicine during pregnancy. The purpose of this article is to review the pharmacological properties of nicardipine, the available literature regarding its use during pregnancy, and potential interactions with other medicines used commonly in preeclampsia, as well as potential side effects directly affecting the peripartum period.

Further Investigation Into the Mechanism of Tachykinin NK2 Receptor– Triggered Serotonin Release From Guinea-Pig Proximal Colon

The effects of the monoamine oxidase A (MAO-A) inhibitor clorgyline, the L-type calcium-channel blocker nicardipine, the syntaxin inhibitor botulinum toxin type C, and the potent thiol-oxidant phenylarsine oxide (PAO) on the selective tachykinin NK(2)-receptor agonist [beta-Ala(8)]-neurokinin A(4-10) [betaAla-NKA-(4-10)]-evoked 5-hydroxytryptamine (5-HT) outflow from colonic enterochromaffin (EC) cells was investigated in vitro using isolated guinea-pig proximal colon. The betaAla-NKA-(4-10)-evoked outflow of 5-HT from clorgyline-treated colonic strips was markedly higher than that from clorgyline-untreated colonic strips. The betaAla-NKA-(4-10)-evoked 5-HT outflow from the clorgyline-treated colonic strips was sensitive to nicardipine or botulinum toxin type C. Moreover, PAO concentration-dependently suppressed the betaAla-NKA-(4-10)-evoked 5-HT outflow from the clorgyline-treated colonic strips. The suppressant action of PAO was reversed by the reducing agent dithiothrietol, but was not blocked by the protein tyrosine kinase inhibitor genistein. These results suggest that the tachykinin NK(2) receptor-triggered 5-HT release from guinea-pig colonic EC cells is mediated by syntaxin-related exocytosis mechanisms and that colonic mucosa MAO-A activity has the important function of modulating the tachykinin NK(2) receptor-triggered 5-HT release. It also appears that PAO-mediated sulfhydryl oxidation plays a role in modulating the tachykinin NK(2) receptor-triggered 5-HT release through a mechanism independent of inhibition of protein tyrosine phosphatase activity.

Mechanisms of Strain-Mediated Mesenchymal Stem Cell Apoptosis

Mechanical conditioning of mesenchymal stem cells (MSCs) has been adopted widely as a biophysical signal to aid tissue engineering applications. The replication of in vivo mechanical signaling has been used in in vitro environments to regulate cell differentiation, and extracellular matrix synthesis, so that both the chemical and mechanical properties of the tissue-engineered construct are compatible with the implant site. While research in these areas contributes to tissue engineering, the effects of mechanical strain on MSC apoptosis remain poorly defined. To evaluate the effects of uniaxial cyclic tensile strain on MSC apoptosis and to investigate mechanotransduction associated with strain-mediated cell death, MSCs seeded on a 2D silicone membrane were stimulated by a range of strain magnitudes for 3 days. Mechanotransduction was investigated using the stretch-activated cation channel blocker gadolinium chloride, the L-type voltage-activated calcium channel blocker nicardipine, the c-jun NH(2)-terminal kinase (JNK) blocker D-JNK inhibitor 1, and the calpain inhibitor MDL 28170. Apoptosis was assessed through DNA fragmentation using the terminal deoxynucleotidyl transferase mediated-UTP-end nick labeling method. Results demonstrated that tensile strains of 7.5% or greater induce apoptosis in MSCs. L-type voltage-activated calcium channels coupled mechanical stress to activation of calpain and JNK, which lead to apoptosis through DNA fragmentation. The definition of the in vitro boundary conditions for tensile strain and MSCs along with a proposed mechanism for apoptosis induced by mechanical events positively contributes to the development of MSC biology, bioreactor design for tissue engineering, and development of computational methods for mechanobiology.

PROSPECTIVE RANDOMIZED COMPARISON OF SAFETY AND EFFICACY OF NICARDIPINE AND NITROPRUSSIDE DRIP FOR CONTROL OF HYPERTENSION IN THE NEUROSURGICAL INTENSIVE CARE UNIT

The calcium channel blocker nicardipine (NC) is effective for acute control of hypertension. However, efficacy and safety in neurosurgical patients have not been evaluated. We sought to compare NC with the most commonly used agent, sodium nitroprusside (SNP), in patients with subarachnoid or intracerebral hemorrhage. We performed a prospective randomized comparison of the safety and efficacy of NC and SNP in patients with subarachnoid or intracerebral hemorrhage. We assessed the number of dose adjustments per patient day, proportion of time within set blood pressure parameters, use of additional medications for blood pressure control, clinical outcome, and drug-related complications. Two hundred patients were screened and 163 patients were randomized, including 89 in the SNP group and 74 in the NC group. In 107 patients, intravenous blood pressure control was started; 60 of these patients received SNP and 47 received NC. When analyzed by intent to treat, patients randomized to NC had fewer dose adjustments per day: 5.7 versus 8.8 in the nitroprusside group (P = 0.0012, Wilcoxon rank-sum test). There were fewer additional medications per day to maintain blood pressure control in the NC group: 1.4 versus 1.9 for SNP (P = 0.043, Wilcoxon rank-sum test). Blood pressure control was similar (NC, 66% of the time within parameters; SNP, 69%). "As-treated" analysis maintained the apparent advantage of NC. When used for control of hypertension in patients with subarachnoid or intracerebral hemorrhage, NC and SNP were both safe and effective, but patients on an NC drip required fewer dose adjustments and fewer additional medications.

Nicardipine inhibits human conjunctival fibroblastic proliferation, migration and attachment in vitro

Abstract Purpose: To evaluate the effect of the calcium channel blocker nicardipine (NIC) on fibroblastic proliferation, migration, attachment and cell viability on human conjunctival fibroblasts in vitro Methods: Human conjunctival fibroblasts were incuvated in a humidified incubator (37ºC‐5%CO2), plus the doses of NIC to be tested. Fibroblastic proliferation at 18, 24 and 48 h was evaluated with a colorimetric assay based on the cleavage of the tetrazolium salt WST‐1 by mitochondrial dehydrogenases in viable cells. Cell viability was evaluated at 4 h with the WST‐1 asssay and with trypan blue (TB) staining. Migration was determined in a artificial wound made in a confluent fibroblast monolayer. Cell free areas were monitored with digitallized images at 0, 18, 24 and 48 h. Fibroblastic attachment was evaluated at 24 h with the WST‐1 asssay. Groups: 9 controls and 9 NIC concentrations (10‐4, 7.5x10‐5, 5x10‐5, 2.5x10‐5, 10‐5, 7.5x10‐6, 10‐6, 10‐7 and 10‐8 M). Each experiment was carried out in triplicate and repeated 4 times Results: NIC &lt; or = 10‐5 M showed cell viability &gt;98% with TB and &gt;99% with WST‐1 at 4 h. DI50=1.018x10‐4 M. NIC &gt; or = 10‐5 M at 18 h, and NIC &gt; or = 7.5x10‐6 M at 24 and 48 h showed significantly less proliferation than control groups. DI50 in 7.5x10‐5‐5x10‐5 M rank. NIC &gt; or = 10‐5 M showed significantly larger cell‐free areas at 18, 24 and 48 h. NIC &lt; or = 7.5x10‐6 M didn´t showed differences among the control groups. NIC &gt; or = 7.5x10‐6 M inhibited fibroblastic attachment in &gt;23% at 24 h. DI50=1.107x10‐3 M Conclusions: NIC have a significant inhibitory effect in vitro on conjunctival fibroblastic wound healing process with potential applicability in ophthalmic surgery

Effect of Calcium Channel Blocker Nicardipine on Brain Edema in Rats

The aim of the present study was to examine the therapeutic effect of nicardipine on diffuse brain injury. Male Wistar adult rats were subjected to a diffuse brain injury. Nicardipine, as a calcium channel blocker was injected intravenously 15 min following induction of injury at doses of 10 or 20 μg kg-1. Quantitative measurements of water content, as index of brain edema and Evans Blue (EB) content as index of blood brain barrier permeability were determined using standard procedures. The histological examination was done by hematoxylin-eosin staining. The results indicated that there were no significant differences in the percent of water content between nicardipine treated, trauma alone and trauma + vehicle groups. The content of EB was significantly lower in nicardipine-treated groups in comparison with trauma and trauma + vehicle groups. There was no difference between nicardipine and other groups in histological verification. The present data indicated that nicardipine could have a protective effect on vascular permeability after brain injury. © 2007 Asian Network for Scientific Information.