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At least 19 recordsLinked to original sources
PubMed2000

Fendiline increases [Ca2+]i in Madin Darby canine kidney (MDCK) cells by releasing internal Ca2+ followed by capacitative Ca2+ entry.

The effect of fendiline, a documented inhibitor of L-type Ca2+ channels and calmodulin, on Ca2+ signaling in Madin Darby canine kidney (MDCK) cells was investigated using fura-2 as a Ca2+ probe. Fendiline at 5-100 microM significantly increased [Ca2+]i concentration-dependently. The [Ca2+]i rise consisted of an initial rise and a slow decay. External Ca2+ removal partly inhibited the Ca2+ signals induced by 25-100 microM fendiline by reducing both the initial rise and the decay phase. This suggests that fendiline triggered external Ca2+ influx and internal Ca2+ release. In Ca(2+)-free medium, pretreatment with 50 microM fendiline nearly abolished the [Ca2+]i rise induced by 1 microM thapsigargin, an endoplasmic reticulum Ca2+ pump inhibitor, and vice versa, pretreatment with thapsigargin prevented fendiline from releasing internal Ca2+. This indicates that the internal Ca2+ source for fendiline overlaps with that for thapsigargin. At a concentration of 50 microM, fendiline caused Mn2+ quench of fura-2 fluorescence at the 360 nm excitation wavelenghth, which was inhibited by 0.1 mM La3+ by 50%, implying that fendiline-induced Ca2+ influx has two components separable by La3+. Consistently, 0.1 mM La3+ pretreatment suppressed fendiline-induced [Ca2+]i rise, and adding La3+ during the rising phase immediately inhibited the signal. Addition of 3 mM Ca2+ increased [Ca2+]i after preincubation with 50-100 microM fendiline in Ca(2+)-free medium. However, 50-100 microM fendiline inhibited 1 microM thapsigargin-induced capacitative Ca2+ entry. Pretreatment with 40 microM aristolochic acid to inhibit phospholipase A2 inhibited 50 microM fendiline-induced internal Ca2+ release by 48%, but inhibition of phospholipase C with 2 microM U73122 or inhibition of phospholipase D with 0.1 mM propranolol had no effect. Collectively, we have found that fendiline increased [Ca2+]i in MDCK cells by releasing internal Ca2+ in a manner independent of inositol-1,4,5-trisphosphate (IP3), followed by external Ca2+ influx.

Animals↗
PubMed1987

The effect of fendiline on cAMP metabolism and activity of the isolated uterus of the rat.

Increasing concentrations of fendiline inhibit various types of muscle activation (KCl, oxytocin and electrical stimulation), as well as spontaneous rhythmic activity of the isolated uterus of the rat. Contrary to verapamil and nifedipine, fendiline in micromolar concentrations (from 1.5 to 15.5 mumol) affects various types of muscle activation almost to the same degree. Fendiline probably influences a common pathway in calcium metabolism in all types of muscle activation. The relaxant effect of fendiline does not depend on cAMP, being even associated with a significant decrease of the level of this nucleotide during electrical stimulation of the isolated uterus of the rat. Fendiline may have its place in the therapy of premature delivery and abortion, particularly because it exhibits lower selectivity in relation to the type of activation of the smooth muscle. Fendiline induces a stronger inhibition of the tonic than of the phasic component of contraction produced by oxytocin and KCl. Fendiline is more active against the oxytocin-induced contraction, probably due to an additional action on the fast Na+ channels. These findings indicate that KCl and oxytocin act through different calcium channels (voltage and receptor calcium channels). Our experiments in which fendiline inhibited more strongly the tonic than the phasic component of KCl-produced contraction also confirm the hypothesis on the existence of voltage calcium channels (or subtypes of one voltage calcium channel) in the isolated uterus of the rat. By adding calcium to the medium, almost all types of muscle activation are established, after the inhibitory action of fendiline, except its depressive action on the electrical stimulation of the isolated rat uterus. Calcium most effectively antagonizes the inhibitory effect of fendiline on spontaneous rhythmic activity. The finding that certain types of activation, after the inhibitory action of fendiline, occur to a different degree by addition of calcium to the medium, are also indirect confirmation of the existence of different calcium channels. Halothane, in a concentration of 1 vol %, did not change the relaxant action of fendiline during electrical stimulation and during spontaneous rhythmic activity.

Animals↗
PubMed2001

Fendiline-Induced Ca2+ movement in A10 smooth muscle cells.

The effect of fendiline, an anti-anginal drug, on cytosolic free Ca2+ levels ([Ca2+]i) in A10 smooth muscle cells was explored by using fura-2 as a Ca2+ indicator. Fendiline at concentrations between 10-50 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 of 20 microM. External Ca2+ removal reduced the Ca2+ signal by 75%. Addition of 3 mM Ca2+ increased [Ca2+]i in cells pretreated with fendiline in Ca2+-free medium. The 50 microM fendiline-induced [Ca2+]i increase in Ca2+-containing medium was inhibited by 10 microM of La3+, nifedipine, or verapamil. In Ca2+-free medium, pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete the endoplasmic reticulum Ca2+ store partly inhibited 50 microM fendiline-induced Ca2+ release; whereas pretreatment with 50 microM fendiline abolished 1 microM thapsigargin-induced Ca2+ release. Inhibition of phospholipase C activity with 2 microM U73122 did not alter 50 microM fendiline-induced Ca2+ release. Incubation with 50 microM fendiline for 10-30 min decreased cell viability by 10-20%. Together, the findings indicate that in smooth muscle cells fendiline induced [Ca2+]i increases. Fendiline acted by activating Ca2+ influx via L-type Ca2+ channels, and by releasing internal Ca2+ in a phospholipase C-independent manner. Prolonged exposure of cells to fendiline induced cell death.

Animals↗
PubMed2001

Dual effect of the antianginal drug fendiline on bladder female transitional carcinoma cells: mobilization of intracellular CA2+ and induction of cell death.

The effect of fendiline, an antianginal drug, on cytosolic free Ca2+ levels ([Ca2+]i) in populations of bladder female transitional carcinoma (BFTC) cells was explored using fura-2 as a Ca2+ indicator. Fendiline at concentrations between 3 and 200 micromol/l increased [Ca2+]i in a concentration-dependent manner and the signal saturated at 100 micromol/l. The [Ca2+]i signal was biphasic, with an initial rise and a slow decay. Ca2+ removal inhibited the Ca2+ signal by about half in peak amplitude. Adding 3 mmol/l Ca2+ increased [Ca2+]i in cells pretreated with 100 micromol/l fendiline in Ca2+ -free medium, suggesting that fendiline induced Ca2+ influx via capacitative Ca2+ entry. In Ca2+ -free medium, pretreatment with 1 micromol/l thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete the endoplasmic reticulum Ca2+ store inhibited most of the 100 micromol/l fendiline-induced internal Ca2+ release; and conversely, pretreatment with 100 micromol/l fendiline partly inhibited 1 micromol/l thapsigargin-induced Ca2+ release. This indicates that the major internal Ca2+ store of fendiline-induced [Ca2+]i increases is located in the endoplasmic reticulum. The Ca2+ release induced by 100 micromol/l fendiline may be partly mediated by inositol 1,4,5-trisphosphate, because the [Ca2+]i increase was inhibited by 50% by inhibiting phospholipase C with 2 micromol/l U73122. Fendiline (100 micromol/l) decreased cell viability by 12-44% after being added to cells for 2- 30 min. Together, the findings indicate that in BFTC cells, fendiline exerts a dual effect: mobilization of intracellular Ca2+ and induction of cell death.

Anti-Arrhythmia Agents↗
PubMed2001

Fendiline, an anti-anginal drug, increases intracellular Ca2+ in PC3 human prostate cancer cells.

BACKGROUND: The effects of the anti-anginal drug fendiline on intracellular Ca2+ concentrations ([Ca2+]i) in human PC3 prostate cancer cells were examined. METHODS: [Ca2+]i was measured using the fluorescent dye fura-2. RESULTS: Fendiline (0.5-100 microM) increased [Ca2+]i in a concentration-dependent manner. Ca2+ removal partly inhibited the Ca2+ signals. In Ca2+-free medium, pretreatment with 100 microM fendiline inhibited most of the [Ca2+]i increase induced by 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor), and pretreatment with thapsigargin abolished the fendiline-induced [Ca2+]i increases. Adding 3 mM Ca2+ increased [Ca2+]i in cells pretreated with 0.5-200 microM fendiline in Ca2+-free medium. Pretreatment with 1 microM U73122 to block the formation of inositol-1.4.5-trisphosphate (IP3) did not alter fendiline-induced internal Ca2+ release. CONCLUSIONS: The anti-anginal drug fendiline induced internal Ca2+ release and external Ca2+ entry. Because prolonged increases in [Ca2+]i may lead to cell injury and death, the long-term effect of fendiline on the function of prostate cancer cells should be investigated.

Adenosine Triphosphate↗
PubMed1993

Fendiline inhibits L-type calcium channels in guinea-pig ventricular myocytes: a whole-cell patch-clamp study.

1. Fendiline, a diphenylalkylamine type of antianginal drug, was examined for its effects on L-type calcium channels in guinea-pig ventricular myocytes by the whole-cell patch-clamp technique. 2. Fendiline (0.3-100 microM) applied extracellularly inhibited the calcium channel current (ICa) in a concentration- and time-dependent manner. The IC50 of fendiline was 17.0 +/- 2.43 microM and the Hill slope was 1.39 +/- 0.23. 3. Inhibition of ICa by fendiline appeared with an onset of less than 3 s. 4. Fendiline inhibited ICa at all the membrane potentials tested and shifted the current-voltage curve upwards. The overall calcium channel conductance (gCa) of the cell was reduced and conductance-voltage curve was shifted to the left in the presence of fendiline. 5. Isoprenaline (0.5-1 microM), a beta-adrenoceptor agonist, partially reversed the inhibitory effect of fendiline on ICa. 6. It is suggested that fendiline applied extracellularly blocks L-type calcium channels and reduces calcium channel conductance of the cell. The calcium channels thus inhibited are, nevertheless, still available for beta-adrenoceptor stimulation.

Animals↗
PubMed1976

[Pharmacological Properties of Fendiline in Cardiac and Smooth Muscle (author's transl)].

The pharmacological properties of fendiline N-(1-phenylethyl [1])-3,3 - diphenylpropylamine-hydrochloride; Sensit, were investigated in the isolated guinea pig heart and in isolated circular smooth muscle strips of bovine coronary arteries, pulmonary arteries and trachea. 1. Fendiline dose dependently increased coronary flow by up to 200% but, different from verapamil, did not inhibit contraction. 2. Fendiline dose dependently relaxed coronary strips and, more powerfully, tracheal and pulmonary arterial strips. 3. In cardiac muscle, fendiline was almost completely retained for a prolonged period of time. In the smooth muscle tissues under study, fendiline accumulated twenty-fold above the concentration present in the organ bath. 4. In paced hearts, fendiline non-competitively inhibited the positive inotropic effect of isoprenaline in doses that did not significantly depress the amplitude of isotonic contractions. 5. In the guinea pig heart, adenosine uptake becomes progressively inhibited when coronary flow increases. This "washout" effect was definitely counteracted by fendiline and by NaNO2, but was augmented by papaverine, hexobendine and dipyridamol. The counteraction of the "washout effect" by fendiline as well as by NaNO2 is most likely due to the opening of additional (previously closed) capillaries.

Adenosine↗
PubMed1991

Effects of the calmodulin antagonists fendiline and calmidazolium on aggregation, secretion of ATP, and internal calcium in washed human platelets.

Ca2(+)-calmodulin dependent phosphorylation of myosin is essential for the induction of platelet shape change and subsequent reactions. Therefore, we studied the effects of the calmodulin antagonists fendiline and calmidazolium on the thrombin-induced aggregation, secretion of ATP, and increases in the intracellular free calcium concentration ([Ca2+]i) in washed human platelets in the absence and presence of extracellular Ca2+. In Ca2+ free medium, fendiline (10-100 microM) and calmidazolium (3-30 microM) concentration-dependently inhibited aggregation. The effect of fendiline could be partly reversed by extracellular Ca2+ and higher thrombin concentrations. Furthermore, aggregations induced by the calcium ionophore ionomycin and by the protein kinase C-activator 4-beta-phorbol 12-myristate 13-acetate were inhibited by fendiline, although to a smaller degree than the thrombin-induced aggregation. Thrombin-induced secretion of ATP was attenuated by low concentrations of fendiline (1-3 microM) and calmidazolium (1 microM) but enhanced by higher concentrations (10-30 and 3-10 microM, respectively), independently of extracellular Ca2+. Fendiline (1-10 microM) did not affect [Ca2+]i in resting and thrombin-stimulated platelets. At higher concentrations (30-100 microM), it induced increases in [Ca2+]i in unstimulated platelets and attenuated the response to thrombin in Ca2+ free medium, whereas thrombin-induced Ca2+ influx was markedly enhanced. Similar results were obtained with calmidazolium (1-3 microM). These stimulating effects on ATP secretion and on [Ca2+]i of fendiline and calmidazolium may be attributed to interactions with platelet membranes by which the permeability of small cations is increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2002

The anti-anginal drug fendiline elevates cytosolic Ca(2+) in rabbit corneal epithelial cells.

The effect of the anti-anginal drug fendiline on intracellular free Ca(2+) levels ([Ca(2+)](i)) in a rabbit corneal epithelial cell line (SIRC) was explored using fura-2 as a fluorescent Ca(2+) indicator. At a concentration above 1 microM, fendiline increased [Ca(2+)](i) in a concentration-dependent manner with an EC(50) value of 7 microM. The [Ca(2+)](i) response consisted of an immediate rise and an elevated phase. Extracellular Ca(2+) removal decreased half of the [Ca(2+)](i )signal. Fendiline induced quench of fura-2 fluorescence by Mn(2+) (50 microM), suggesting the presence of Ca(2+) influx across the plasma membrane. This Ca(2+) influx was abolished by La(3+) (50 microM), but was insensitive to dihydropyridines, verapamil and diltiazem. Fendiline (10 microM)-induced store Ca(2+) release was largely reduced by pretreatment with thapsigargin (1 microM) (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+). Conversely, pretreatment with 10 microM fendiline abolished thapsigargin-induced Ca(2+) release. Fendiline (10 microM)-induced Ca(2+) release was not altered by inhibiting phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). Cumulatively, this study shows that fendiline induced concentration-dependent [Ca(2+)](i )increases in corneal epithelial cells by releasing the endoplasmic reticulum Ca(2+) in a phospholipase C-independent manner, and by causing Ca(2+) influx.

Animals↗
PubMed1999

Inhibition by fendiline of the transient outward current in rat ventricular cardiomyocytes.

The effects of fendiline on the transient outward current (Ito) were investigated in rat ventricular cardiomyocytes. Extracellularly applied fendiline reduced peak and steady-state current amplitude of Ito; the inactivation of Ito was accelerated by the drug, which reflects onset of block. The described effects were concentration dependent: half-maximal effects were achieved at approximately 3 microM fendiline. Intracellularly applied fendiline (3 microM) did not affect Ito within 5 min. The steady-state current amplitude of Ito was more efficiently suppressed by the drug at 22 +/- 1 degrees C than at 36 +/- 1 degrees C. The recovery of Ito was analyzed by the application of twin depolarizing voltage pulses, interrupted by variable pulse intervals. In the presence of fendiline, recovery of Ito was about twofold slower than that under control conditions, independent of the drug concentration used, which reflects offset from block. Concentration-dependent onset but concentration-independent offset of block suggest that the described time constants correspond to voltage-dependent net binding and unbinding, respectively, of fendiline at its receptor sites. It is proposed that fendiline binds extracellularly at positive potentials to Ito channels in their open state and dissociates from the channels at rest.

Animals↗
PubMed1992

Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.

1. The modulation of L-type calcium channel current (ICa) by fendiline, a diphenylalkylamine type of calcium channel blocker was investigated on guinea-pig ventricular myocytes by use of the whole-cell patch-clamp technique. 2. Fendiline-induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f infinity) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor. 3. When the 1,4-dihydropyridine agonist (4R, 4S)-Bay K 8644 was added in presence of 30 microM fendiline a further reduction of ICa instead of the expected stimulatory effect was observed. 4. A similar 'paradoxical' inhibition of ICa was produced by the pure agonist enantiomer (4S)-Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4-dihydropyridine receptor site for (4R)-Bay K 8644 during fendiline action. 5. The IC50 for fendiline was reduced to 3.0 +/- 0.1 microM (control value: 17.0 +/- 2.4 microM) and the Hill slope in its presence was increased to 1.90 +/- 0.1 (control value: 1.39 +/- 0.23) by 1 microM (4R, 4S)-Bay K 8644. 6. (4R,4S)-Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers. 7. The 'paradoxical' inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Basic mechanisms underlying prenylamine-induced 'torsade de pointes': differences between prenylamine and fendiline due to basic actions of the isomers.

The calcium antagonists prenylamine and fendiline both bind with rather low affinity to the dihydropyridine (nifedipine) binding site. As calmodulin (CaM) antagonists, they both inhibit CaM-dependent enzymes and relax smooth muscle preparation in nearly the same concentration range. If compared with other calcium antagonists, their action on smooth muscle develops rather slowly and cannot be inhibited by the calcium agonist Bay k 8644. In contrast, basic pharmacology reveals major differences of the actions of prenylamine and fendiline in heart muscle, indicating that, after all, the change in structure close to the asymmetric carbon strongly influences the molecular action of the compounds and their respective isomers. The negative inotropic effect of racemic prenylamine is rather independent of stimulation rate, whereas fendiline preferably depresses contraction at high rate stimulation. The negative inotropic potencies are determined by the (-)-isomers, but only in the case of prenylamine the isomeric ratio of 6 reveals a considerable stereoselectivity of action. In low concentrations and preferably at low rate stimulation, (+)-prenylamine exerts a strong positive inotropic effect. At low rate stimulation, total duration of transmembrane action potential is prolonged by (+/-)- and (+)-prenylamine, but discretely shortened by (+/-)- and (+)-fendiline. At high rate stimulation, it is shortened by (+/-)- and (-)-prenylamine, but prolonged (only) at the very final repolarization level by (+/-)- and (-)-fendiline. The positive inotropic action of prenylamine and the prolongation of action potential at low stimulation rate can be interpreted as a calcium agonistic side-effect due to the action of the (+)-isomer. It seems possible that, under the condition of low heart rate, prenylamine (as reported for the calcium agonist Bay k 8644) increases the potential-dependent transmembrane calcium current. In addition, it is argued that during the long-lasting action potential, a reactivation of the calcium current induces early after-depolarizations. These effects are postulated to represent the main mechanisms triggering torsade de pointes during therapy with prenylamine. Though fendiline, from a chemical point of view, rather resembles prenylamine, its pharmacological profile is different. In particular, in regard to electrophysiology, torsade de pointes are not expected to be induced by fendiline.

Animals↗
PubMed2001

Fendiline mobilizes intracellular Ca2+ in Chang liver cells.

1. The effects of the antianginal drug fendiline (N-[3,3-diphenylpropyl]-alpha-methyl-benzylamine) on intracellular free Ca2+ levels ([Ca2+](i)) in Chang liver cells were evaluated using fura-2 as a fluorescent Ca2+ indicator. 2. Fendiline (1-100 micromol/L) increased [Ca2+](i) in a concentration-dependent manner, with an EC50 of 25 micromol/L. 3. The [Ca2+](i) response was composed of an initial rise and a slow decay to a sustained phase. Removal of extracellular Ca2+ partly reduced the [Ca2+](i) signals. 4. Fendiline (10 micromol/L)-induced release of intracellular Ca2+ was reduced by 65% following pretreatment with 1 micromol/L thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete Ca2+ stored in the endoplasmic reticulum. 5. After pretreatment with 10 micromol/L fendiline in Ca2+-free medium for several minutes, addition of 3 mmol/L Ca2+ induced an increase in [Ca2+](i) of a magnitude four-fold greater than control. This increase in [Ca2+](i) was not reduced by 10 micromol/L SKF96365, econazole, nifedipine or verapamil. 6. Fendiline (10 micromol/L)-induced release of intracellular Ca2+ was not altered by inhibition of phospholipase C with 2 micromol/L 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino) hexyl)-1H-pyrrole-2,5-dione (U73122). 7. The results of the present study show that fendiline induces an increase in [Ca2+](i) in Chang liver cells by releasing stored Ca2+ in an inositol 1,4,5-trisphosphate-independent manner and by causing extracellular Ca2+ influx.

Calcium↗
PubMed2001

Effects of the antianginal drug fendiline on Ca2+ movement in hepatoma cells.

This study investigated the effect of the anti-anginal drug, fendiline, on intracellular free Ca2+ levels ([Ca2+]i) in HA/ 22 human hepatoma cells by using fura-2 as a fluorescent Ca2+ dye. Fendiline (1-100 microM) increased [Ca2+]i with an EC50 of 25 microM. Removal of extracellular Ca2+ reduced the [Ca2+]i signals by 51 +/- 5%. Fendiline (10 microM)-induced Ca2+ release was abolished by pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). Inhibition of phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122) did not alter 10 microM fendiline-induced Ca2+ release. Several other calmodulin antagonists, such as phenoxybenzamine (100-200 microM), trifluoperazine (5-50 microM), and fluphenazine-N-chloroethane (2-100 microM), had no effect on [Ca2+]i. Together, it was found that fendiline increased [Ca2+]i in human hepatoma cells by discharging Ca2+ from the endoplasmic reticulum in an inositol 1,4,5-trisphosphate-independent manner and by inducing Ca2+ entry. This effect of fendiline does not appear to be via antagonism of calmodulin.

Calcium↗
PubMed1977

The influence of the calcium antagonist fendiline on tone and motility of the guinea pig gut smooth muscle and the cAMP and cGMP concentrations of the isolated terminal ileum.

In various parts of the guinea pig gastrointestinal tract the calcium antagonist N-(2-benzhydryl-ethyl)-N-(1-phenyl-ethyl)-amine hydrochloride (fendiline, Sensit) decreases the smooth muscle tone elevated by K+-induced depolarisation. This effect is antagonized by addition of extra-Ca++. The muscle relaxation is dos-dependent and amounts to 45-90% after 1-5 microng/ml fendiline. Proportionally to this effect the tissue concentration in cGMP is decreased whereas cAMP remains unchanged. After 54 micron/ml theophylline the cAMP level in the terminal ileum is increased significantly whereas cGMP does not change. Theophylline has no influence on the relaxing effect of 1 microng/ml fendiline. By contrast, the increase in cAMP after theophylline is prevented by fendiline. These findings are explained by the antagonistic effect of fendiline to Ca++, which activates the guanylate cyclase and inhibits the adenylate cyclase. Furthermore, fendiline seems to prevent the binding of theophylline to guinea pig ileal phosphodiesterase. It is discussed that cGMP plays a physiological role in controlling the intestinal smolth muscle tone and motility.

Animals↗
PubMed2001

The anti-anginal drug fendiline increases intracellular Ca(2+) levels in MG63 human osteosarcoma cells.

The effect of fendiline, an anti-anginal drug, on cytosolic free Ca(2+) levels ([Ca(2+)](i)) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca(2+) indicator. Fendiline at concentrations between 1 and 200 microM increased [Ca(2+)](i) in a concentration-dependent manner and the signal saturated at 100 microM. The Ca(2+) signal was inhibited by 65+/-5% by Ca(2+) removal and by 38+/-5% by 10 microM nifedipine, but was unchanged by 10 microM La(3+) or verapamil. In Ca(2+)-free medium, pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) to deplete the endoplasmic reticulum Ca(2+) store inhibited fendiline-induced intracellular Ca(2+) release. The Ca(2+) release induced by 50 microM fendiline appeared to be independent of IP(3) because the [Ca(2+)](i) increase was unaltered by inhibiting phospholipase C with 2 microM U73122. Collectively, the results suggest that in MG63 cells fendiline caused an increase in [Ca(2+)](i) by inducing Ca(2+) influx and Ca(2+) release in an IP(3)-independent manner.

Calcium↗
PubMed2000

Frequency- and time-dependent effects of fendiline on action potentials of guinea pig papillary muscle.

The action of fendiline on cardiac electrical activity was investigated in guinea pig papillary muscle by monitoring frequency- and time-dependent changes in membrane potential, action potential (AP) configuration and conduction velocity. Isolated guinea pig papillary muscles driven at 0.1 to 3 Hz showed a concentration-dependent reduction of +Vmax, overshoot, and AP duration at -20mV (APD20) in the presence of fendiline (1-320 microM), reflecting inhibition of Na+ and L-type Ca2+ channels, respectively. No significant change in resting potential and AP duration at 90% repolarization (APD90) were observed. Inhibition of +Vmax and APD20 was more prominent at higher frequency of stimulation (2 Hz) than at lower ones (0.2 Hz), demonstrating frequency-dependent block of Na+ and Ca2+ channels including an open channel block. A good relationship between changes in +Vmax and APD20 suggested some commonality in the mechanism of inhibition of Na+ and Ca2+ channels by fendiline. Time-dependence of effects of fendiline, observed in presence of bolus dose (200 microM), showed an earlier onset of inhibition of +Vmax and APD20, particularly at higher frequencies. Missed beats and conduction block also appeared earlier in preparations driven at higher frequency. These findings suggest a frequency-dependent (and open channel) block of Na+ and Ca2+ channels by fendiline, leading to inhibition of fast and slow conduction in addition to its reported inactivated Ca2+ channel block.

Action Potentials↗
PubMed1998

Open state block by fendiline of L-type Ca++ channels in ventricular myocytes from rat heart.

The effects of fendiline on L-type Ca++ currents [ICa(L)] were investigated in rat ventricular cardiomyocytes using the patch-clamp technique both in the whole-cell disrupted-patch and in the cell-attached configuration. For comparison, the effects of verapamil were also investigated. Both compounds depressed the magnitude of whole cell ICa(L), verapamil being about 15 times more potent than fendiline. Verapamil did not change the time course of the current, whereas fendiline accelerated its decay when either Ca++ or Ba++ ions were used as charge carriers. In the presence of the Ca++ agonist BayK8644 (10 microM), the potency ratio of fendiline/verapamil was inverted. BayK8644 (10 microM) also reversed the potency ratio of verapamil/fendiline in smooth muscle, with respect to changes in tension induced by K+ (48 mM). In single channel recordings at 0.1 Hz, in the presence of BayK8644 (1 microM) and using Ba++ ions as the charge carrier, fendiline (1 microM) reduced mean open time by 34% and channel availability by 8%; the ensemble average current of Ca++ channels was reduced by 43%. In the same experimental conditions, verapamil (1 microM) was ineffective. These results can be explained by the assumption that fendiline blocks Ca++ channels preferentially in the open state, in contrast to verapamil which blocks preferentially inactivated Ca++ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗