Addition Of Nicardipine Research Articles

Direct investigations of the effects of nicardipine on calcium channels of astrocytes by Atomic Force Microscopy

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.

MICA enhances sensitivity to cisplatin in patients with extensive small cell lung cancer via downregulation of ABCG2.

Immunotherapy utilizing natural killer cell-activated receptor natural-killer group-2 member D ligands (NKG2DLs) has had preclinical success in the treatment of small cell lung cancer. The present study aimed to investigate the association between NKG2Ls and chemoresistance. The mRNA expression of six NKG2DLs associated with progression-free survival time (PFS) and first-line chemotherapy were assessed in the present study. Major histocompatibility complex class I polypeptide-related sequence A (MICA)-overexpressing NCI-H446 cell line was constructed, and the mRNA expression levels of 11 genes associated with chemotherapy sensitivity were determined. The results demonstrated that MICA was positively and significantly associated with PFS. Furthermore, MICA expression was 1.6 times higher in patients with prolonged PFS compared with the rapid chemoresistance group. ATP binding cassette subfamily G member 2 (ABCG2) mRNA expression was associated with chemotherapy resistance and significantly downregulated in the cell line overexpressing MICA. Moreover, following addition of nicardipine (an ABCG2 inhibitor), chemotherapeutic sensitivity increased in the MICA-overexpressing cell line. Taken together, the results of the present study suggested that MICA may enhance the chemosensitivity of patients with extensive small cell lung cancer by downregulating ABCG2.

Hydrogen peroxide-induced Ca 2+ responses in CNS pericytes

Objective: The aims of the present study were to elucidate the interaction of reactive oxygen species (ROS) and Ca 2+ response in central nervous system (CNS) pericytes. Methods: The intracellular Ca 2+ concentration was measured using fluorescent Ca 2+ indicator, fura-2, in cultured CNS pericytes. Results: Hydrogen peroxide evoked a dose-dependent increase in cytosolic Ca 2+, which was completely inhibited by catalase. Removal of external Ca 2+ or addition of nicardipine (1 μM) during application of hydrogen peroxide did not affect Ca 2+ response. Incubation of the cells in Ca 2+ free solution did not abolish but slightly reduced Ca 2+ response by hydrogen peroxide. Ca 2+ response to hydrogen peroxide was not altered by the depletion of intracellular Ca 2+ by thapsigargin (1 μM). Pretreatment of the cells with tyrosine kinase inhibitor genistein (100 μM) or tyrphostin A47 (30 μM) significantly reduced Ca 2+ increase by hydrogen peroxide. Conclusions: These results indicate that hydrogen peroxide evokes Ca 2+ increase predominantly by release from intracellular Ca 2+ store, which may be regulated by tyrosine kinases.

Differential Involvement of Intracellular Ca2+ in 1-Methyl-4-phenylpyridinium- or 6-Hydroxydopamine-Induced Cell Viability Loss in PC12 Cells

1-Methyl-4-phenylpyridinium (MPP(+)) or 6-hydroxydopamine (6-OHDA) caused a nuclear damage, the mitochondrial membrane permeability changes, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in PC12 cells. Nicardipine (a calcium channel blocker), EGTA (an extracellular calcium chelator), BAPTA-AM (a cell permeable calcium chelator) and calmodulin antagonists (W-7 and calmidazolium) attenuated the MPP(+)-induced mitochondrial damage and cell death. In contrast, the compounds did not reduce the toxicity of 6-OHDA. Treatment with MPP(+ )or 6-OHDA evoked the elevation of intracellular Ca(2+) levels. Unlike cell injury, addition of nicardipine, BAPTA-AM and calmodulin antagonists prevented the elevation of intracellular Ca(2+) levels due to both toxins. The results show that the MPP(+)-induced formation of the mitochondrial permeability transition seems to be mediated by elevation of intracellular Ca(2+) levels and calmodulin action. In contrast, the 6-OHDA-induced cell death seems to be mediated by Ca(2+)-independent manner.

Nicardipine and Itraconazole Inhibited Transcellular Transport of Digoxin

The inhibitory effects of nicardipine, nifedipine and itraconazole on P-glycoprotein-mediated transport of [3H]digoxin were examined using LLC-PK1 and LLC-GA5-COL150 cells, a porcine kidney epithelial LLC-PK1 cell line transformed with MDRI cDNA from man which results in overexpression of P-glycoprotein on the apical membrane. Basal-to-apical transport of [3H]digoxin in LLC-GA5-COL150 cells was higher than in LLC-PK1 cells; apical-to-basal transport was markedly lower in LLC-PK1 cells and even lower in LLC-GA5-COL150 cells. This is consistent with the possibility that [3H]digoxin is transported by P-glycoprotein. Co-administration of nicardipine or itraconazole markedly inhibited the basal-to-apical transport of [3H]digoxin in LLC-GA5-COL150 cells, and apical-to-basal transport also increased. The effect of nifedipine was less marked than that of nicardipine or itraconazole. Intracellular accumulation of [3H]digoxin after apical application in LLC-GA5-COL150 cells was 2.3 times less than in LLC-PK1 cells, and was increased by the addition of nicardipine or itraconazole, consistent with their inhibitory effects on transcellular transport. Following basal application of [3H]digoxin, its intracellular accumulation in LLC-GA5-COL150 cells was, unexpectedly, comparable with that in LLC-PK1 cells, and was hardly affected by the addition of nicardipine or itraconazole. In conclusion, it has been shown that nicardipine and itraconazole inhibited transport of digoxin, which is presumably mediated by P-glycoprotein. This explains their effects observed in clinical use.

Direct inhibitory effect of nicardipine on basolateral K+ channels in human colonic crypts.

The most abundant basolateral K+ channels in human colonic crypt cells have a low conductance (23 pS), respond to increases in intracellular Ca2+ and cAMP, and have been implicated in intestinal electrogenic Cl- secretion. The effect of nicardipine on the activity of these K+ channels was examined by patch-clamp recording in the cell-attached and excised inside-out configurations from the basolateral membrane of single crypts isolated from biopsied samples of human distal colon. During cell-attached recordings, addition of 2 micromol/l nicardipine to crypts pretreated with 200 micromol/l dibutyryl cAMP decreased single-channel open probability by 87%, but in parallel studies nicardipine had no effect on the intracellular Ca2+ concentration. Using inside-out patches from crypts pretreated with dibutyryl cAMP (bathed in 1.2 mmol/l Ca2+), the addition of increasing concentrations of nicardipine (200 nmol/l, 2 micromol/l and 20 micromol/l) decreased single-channel open probability in a concentration-dependent manner (IC50 0.47 micromol/l). In additional experiments using stripped rat distal colonic mucosa mounted in conventional Ussing chambers, serosal addition of nicardipine at increasing concentrations (ranging from 200 nmol/l to 20 micromol/l) produced a concentration-dependent inhibition of dibutyryl-cAMP-stimulated electrogenic Cl- secretion (IC50 2 micromol/l). Taken together, these results indicate that nicardipine has a direct inhibitory action on 23-pS basolateral K+ channels in human intestinal crypt cells, which is likely to decrease cAMP-stimulated electrogenic Cl- secretion. These basolateral K+ channels may provide a focal point for the development of new strategies in the treatment of secretory diarrhoeal diseases.

The Effect of Nicardipine on Renal Functions following 72-Hour Cold Ischemia

The aim of the study was to investigate the cytoprotective effect of a calcium channel blocker, nicardipine, on altered renal function due to cold ischemia for 72 h. The experiments were performed on isolated perfused kidneys from adult rabbits. Kidneys were perfused with either standard Euro-Collins (EC) solution (n = 7) or EC containing nicardipine (n = 6) and then incubated with the same preservation solutions in a beaker exposed to cold ischemia for 72 h at +4 degrees C. In the control group the same procedure was applied to untreated kidneys (n = 6) which were exposed to cold ischemia for 30 min. Vascular responses and urinary output to noradrenaline, angiotensin II, endothelin-1, acetylcholine and sympathetic stimulation were assessed as the functional activities of the kidney. The responses of the preserved kidneys were compared following cold ischemic conditions. The results indicate that the addition of nicardipine to EC solution protects the vascular endothelial regulatory function and urine excretion; therefore, dihydropyridine calcium channel blockers might be useful for kidney preservation.

Arginine vasopressin increases intracellular calcium ion concentration in isolated mouse collecting tubule cells: distinct mechanism of action through V2 receptor, but independent of adenylate cyclase activation.

The effects of arginine vasopressin (AVP*2) and its V2 receptor agonist, 1-deamino-8-D-AVP (dDAVP), on the intracellular calcium ion concentration ([Ca2+]i) in isolated collecting tubular cells of mouse kidney were examined using fluorescent indicator fura-2 and a superfusion system. Both AVP and dDAVP evoked a rapid, transient increase followed by a sustained elevation of [Ca2+]i in CCT, OMCT, and IMCT in a dose-dependent manner. In CCT, the increments in [Ca2+]i by dDAVP were lower than those induced by AVP at all concentrations (10(-10)-10(-6) M) of the agonists tested, while in OMCT and IMCT, the increments were comparable. The initial peak of the rise in [Ca2+]i induced by AVP and dDAVP in these collecting tubule segments was partially attenuated by about 40% and the second sustained elevation was largely abolished in the absence of Ca2+ in the superfusate. Further, the increments [Ca2+]i induced by AVP were not affected by the addition of nicardipine to the superfusate. The increases in [Ca2+]i evoked by AVP and dDAVP were not mimicked by cAMP or forskolin. Moreover, they were not affected by alpha-adrenergic stimulation with epinephrine, in the presence and absence of prazosin, conditions which inhibit AVP-dependent cAMP production. These results indicate that AVP increases [Ca2+]i in CCT, OMCT, and IMCT, probably through V2 receptors, but via a mechanism which is independent of adenylate cyclase activation. In addition, the rise in [Ca2+]i is due to both Ca2+ release from the intracellular stores and increased Ca2+ influx through Ca2+ channels insensitive to nicardipine.

THE ENHANCEMENT OF MYOCARDIAL PROTECTION THROUGH AN ACALCEMIC STORAGE SOLUTION CONTAINING NICARDIPINE, A POTENT CALCIUM CHANNEL BLOCKER

Adult rat ventricular myocytes were used as a model system for investigating the direct effects of nicardipine, a potent calcium-channel blocker, on preservation of the heart during periods of simple cold storage. Cells were stored at 4 degrees C for 24 hr with an acalcemic storage solution. The superfusate then was exchanged with hypoxic Tyrode solution (1.8 mmol/L CaCl2). After 2 hr of hypoxia at 20 degrees C, cells were reoxygenated and simultaneously warmed to 37 degrees C. The addition of nicardipine to both the storage solution and Tyrode solution resulted in the highest percentage of viable cells (70.5%). Using either the storage solution or Tyrode solution containing the compound, the percentages of viable myocytes were 51.9% and 52.2%, respectively. In the absence of the drug in either solution, the percentage was 38.0%. The effect of diltiazem, another potent calcium-channel blocker, was examined using the same experimental procedure. The addition of diltiazem to Tyrode solution elevated the viability of ventricular myocytes, but addition to the storage solution showed no cardioprotective effect. Moreover, the addition of 8-bromo cyclic GMP to the storage solution resulted in a cardioprotective effect. These results suggested that nicardipine exerts a direct effect on myocardial protection in hypothermic and acalcemic storage solution and that the pharmacological effect of nicardipine depends on a mechanism other than its calcium-channel blocking action.

Calcium channel effectors are potent non-competitive blockers of acetylcholine receptors

Nicardipine and other calcium channel effectors (CCEs) were studied for their effects on nicotinic acetylcholine receptor (nAChR) activity. While CCEs had no effect on frog (Rana pipiens) skeletal muscle contractions resulting from nerve stimulation or direct stimulation of the muscle, nicotinic agonist-induced contractures were blocked. Nicardipine did not affect nAChR single-channel open time or amplitude, corroborating data from endplate currents (EPCs); EPC amplitudes and decays were unaffected. All the CCEs tested, however, non-competitively blocked nAChRs. The block of nAChRs resulted in a shortened agonist-induced depolarization and thus a diminished contracture response. An increase in cultured mouse skeletal muscle (C-2) cell single-channel closed times was observed with the intracellular addition of nicardipine, verifying a direct block of nAChRs. Using single-channel analysis, nicardipine's site of action, or at least access to its site of action, was determined to be at the intracellular side of the receptor. A direct action of the CCEs on the nAChR was also shown by their ability to block phencyclidine (PCP) binding to Torpedo nobiliana membranes. All the CCEs blocked specific binding of [3H]-PCP to its binding site on the nAChR-channel complex, with bepridil and nicardipine being the most potent. These data are compatible with a model in which nicardipine and other CCEs, at concentrations which do not alter nAChR channel open time or conductance, block the effects of superfused nicotinic agonist on nAChRs either by stabilizing the formation of the nAChR desensitized state or by effecting a slow channel block.

An Evaluation of the Pharmacodynamics and Pharmacokinetics of Nicardipine Combined with Enalapril in Essential Hypertension

Recent observations suggest that calcium antagonists may enhance the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors. Twelve essential hypertensives who had blood pressures greater than 160/90 after a minimum of 6 weeks of monotherapy with the ACE inhibitor enalapril 20 mg daily received additional treatment with nicardipine 30 mg t.i.d. and placebo, each for 2 weeks, in a double-blind crossover study. The combination of nicardipine with enalapril was well tolerated. The addition of the first dose of nicardipine was associated with significant reductions (p less than 0.05) in blood pressure during the first 4 h: from a baseline of 165/99 to 128/80 (supine) at 2 h after nicardipine as compared with 167/101-146/90 following placebo. Two weeks of combined treatment with nicardipine and enalapril significantly reduced the predosing blood pressure, 12 h after the last dose of nicardipine (158/96 as compared with 172/106 with placebo), and there were further significant reductions in blood pressure during the subsequent dosage interval. The profile of plasma ACE inhibition and the pharmacokinetics of enalaprilat were unaffected by the addition of nicardipine. These results suggest that nicardipine and enalapril are an effective and well-tolerated antihypertensive combination.

Nicardipine for systemic hypertension: Effects on blood pressure and target organ function

Nicardipine has been shown to lower blood pressure in patients with uncomplicated hypertension as well as in patients with concomitant renal impairment, coronary artery disease or congestive heart failure. The decrease in blood pressure induced by nicardipine is related to a concurrent decrease in total peripheral vascular resistance. The antihypertensive actions of nicardipine are maintained during long-term administration without the development of tachyphylaxis. In patients receiving diuretics or β blockers, the addition of nicardipine has been shown to produce an additional decrease in blood pressure. The combined use of nicardipine and β blockers may be beneficial in the treatment of hypertension: the increase in peripheral vascular resistance during β blockade may be prevented by nicardipine-induced vasodilation; conversely, β blockers may prevent reflex tachycardia and other consequences of peripheral vasodilatation. Although nicardipine may increase the heart rate acutely, tachycardia does not occur during long-term therapy. Preliminary data suggest that nicardipine exerts potent antihypertensive effects in patients with renal insufficiency without altering renal parameters. In patients with normal renal function, nicardipine has been shown to cause acute natriuresis and an increase in renal blood flow and glomerular filtration rate. Nicardipine also has a favorable effect on peripheral and cerebral blood flow. Like other dihydropyridines, nicardipine appears to have an antiatherogenetic effect in the experimental model. Short-term therapy with nicardipine does not affect serum lipid levels. Results from several studies suggest that nicardipine is an effective antihypertensive agent that can be used as monotherapy or in combination with other drugs such as β blockers or diuretics. Nicardipine may also have a favorable effect on target organ function and on various circulatory parameters without causing adverse metabolic or biochemical consequences.

Addition of Nicardipine Further Reduces BP

Addition of Nicardipine Further Reduces BP

Nicardipine combined with enalapril in patients with essential hypertension

1 This study investigated the clinical usefulness and patient acceptability of adding nicardipine to the treatment of 12 patients with inadequate blood pressure control during monotherapy with the ACE inhibitor, enalapril. 2 After 6 weeks monotherapy with enalapril 20 mg daily, patients with BP greater than 150/90 mm Hg were given nicardipine 30 mg three times daily or placebo for 2 weeks, with crossover after another 2 week washout. 3 Patients were assessed after first dose and on steady state treatment for blood pressure, heart rate, plasma concentrations of enalapril and nicardipine and for ACE activity. 4 Blood pressure on the nicardipine-enalapril combination fell significantly from baseline (P < 0.05) and this was maintained for the 8 h of study. There was a small but significant transient rise in heart rate. 5 The addition of nicardipine did not alter the pharmacokinetics of enalapril, nor the enalapril-induced ACE activity inhibition. 6 Nicardipine and enalapril provided an effective and well-tolerated antihypertensive combination.

Mechanisms of relaxant action of nicardipine, a new Ca++-antagonist, on isolated dog cerebral and mesenteric arteries.

In helically-cut strips of cerebral and mesenteric arteries contracted with prostaglandin (PG) F2 alpha, carbocyclic thromboxane A2 (cTxA2) or K+, the addition of nicardipine caused a dose-related relaxation. Nicardipine-induced relaxation was greater in cerebral than in mesenteric arteries when contracted with PGF2 alpha and cTxA2, but did not appreciably differ in the arteries contracted with K+. Cerebral arteries contracted with hemolysate and PGF2 alpha relaxed in response to nicardipine to a similar extent. The contractile response to PGF2 alpha was attenuated by pretreatment with nicardipine, the attenuation being greater in cerebral than in mesenteric arteries. Ca++-induced contractions in cerebral and mesenteric arteries previously exposed to Ca++-free media and depolarized by excess K+ were attenuated by nicardipine to a similar extent. PGF2 alpha-induced contractions of cerebral arteries exposed to Ca++-free media were attenuated by nicardipine, whereas those of mesenteric arteries were unaffected. Attenuations by nicardipine of the Ca++-induced contraction in PGF2 alpha-treated cerebral arteries were greater than those seen in mesenteric arteries. It may be concluded that nicardipine produces a greater relaxation of cerebral arteries than mesenteric arteries, possibly due to a greater inhibition of the Ca++-influx and to a decrease in the release of Ca++ from intracellular storage sites in cerebral arteries. As far as the concentrations used are concerned, nicardipine appears to attenuate the inward movement of Ca++ across cell membrane in mesenteric arterial smooth muscle, but not the release of intracellularly stored Ca++.