Antireproductive effect of the calcium channel blocker amlodipine in male rats.

The purpose of the present study was to investigate whether treatment of male rats with the calcium antagonist amlodipine, used in the treatment of hypertension and angina, interferes with the reproductive function of male rats. Amlodipine treatment (0.04 mg amlodipine besylate/rat/day for 30 days) decreased plasma follicle-stimulating hormone and testosterone but not luteinizing hormone or prolactin concentrations (measured by double-antibody radioimmuno-assay). A significant reduction (23%) was observed in sperm density (sperm suspension collected from the cauda epididymidis) as well as in the amount of mature spermatids (14%) and Sertoli cells (9%) counted in seminiferous tubule cross-sections (400 x magnification). The results reveal the deleterious effects of subacute amlodipine treatment on the reproductive function of male rats.     

The effect of inhaled salmeterol on methacholine responsiveness in subjects with asthma up to 12 hours.

The duration of the protective effect of 50 and 100 micrograms of inhaled salmeterol against methacholine-induced bronchoconstriction was compared with that of 200 micrograms of inhaled salbutamol in 12 patients with asthma with a baseline FEV1 of at least 70% and a provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) greater than or equal to 8 mg/ml. The study was placebo controlled, double blind, randomized, and crossover. The bronchodilating effect was no longer significant 4 hours after inhalation of salbutamol, whereas the effect was still present 12 hours after administration of 50 and 100 micrograms of salmeterol. All active treatments caused PC20 to increase at 1 hour (p less than 0.05). PC20 (milligrams per milliliter) thus reached 3.7 +/- 0.8 after placebo, 13.8 +/- 3.0 after 50 micrograms of salmeterol, 23.2 +/- 4.7 after 100 micrograms of salmeterol, and 13.9 +/- 3.4 after 200 micrograms of salbutamol. The protective effect of 200 micrograms of salbutamol was no longer significant at 4 hours, whereas both doses of salmeterol protected against methacholine challenge up to 12 hours after inhalation (p less than 0.01). An increased incidence of tremor (2/12) and palpitations (2/12) was recorded after inhalation of 100 micrograms of salmeterol. We conclude that inhalation of 50 or 100 micrograms of salmeterol causes a long-lasting bronchodilatation and protects against methacholine-induced bronchoconstriction for at least 12 hours.     

The contribution of mast cells to the late-phase of allergic asthma in rats

Introduction: Mast cells are thought to be the main cause of an immediate asthmatic response, but their contribution to the late-phase of asthma is unknown.Objective: To prove the contribution of preactivated mast cells to the late phase of allergic asthma by advanced activation.Methods: Mast cell function in the late-phase of asthma was studied. Rats (wild, +/+ and mast cell deficient, Ws/Ws) were challenged with OVA to investigate the relationship between the contraction of airways and the population of inflammatory cells in the trachea.Result: During the entire asthmatic period, the contraction of the airway after OVA challenge in +/+ rats was enhanced significantly compared to Ws/Ws rats, especially in the late phase. The bronchoalveolar lavage fluid histamine in +/+, but not Ws/Ws, rats increased 5.3-fold in 30 min and 3.4-fold in 8 h after challenge, significantly. The number of mucosal mast cells in the tracheal epithelial layer in +/+ rats increased significantly 2.2-fold over controls at 8 h after challenge, as demonstrated by in situ hybridization.Conclusions: Mast cells may contribute to the late phase of asthmatic response by continuous mast cell activation and the mucosal mast cell number increased in the late phase of asthmatic response.Received 15 October 2004; returned for revision 21 December 2004; accepted by A. Falus 26 January 2005     

Protective effect of diltiazem (a calcium channel blocker) against cadmium-induced toxicity in mice.

Protective efficacy of diltiazem (a calcium channel blocker) has been studied against cadmium chloride (CdCl2) induced hematological and biochemical alterations in Swiss albino mice. CdCl2 (5 mg/kg b.wt.; i.p.) with or without prior treatment of diltiazem (100 mg/kg b. wt.; i.p.) was given to six-week old mice. Significant increase in the number of bone marrow cells as well as hematological parameters was observed in diltiazem pretreated CdCl2 intoxicated animals. A significant increase in lipid peroxidation (LPO) and acid phosphatase (ACP) level, and decrease in glutathione (GSH) and alkaline phosphatase (ALP) level in blood as well as liver were measured in CdCl2 intoxicated mice, while such values were near normal in DTZ pretreated animals. Furthermore, a significant increase in erythropoeitin (EPO) level was observed in diltiazem (DTZ) pretreated CdCl2 intoxicated animals as compared to CdCl2 alone treated animals. Thus, Diltiazem administration before cadmium intoxication protects bone marrow and hematological constituents in mice.     

Inhibition of lipid deposition in the hypercholesterolemic rat by clentiazem, a calcium channel blocker.

We studied the effects of clentiazem, a calcium channel blocker (1) on the accumulation of lipid in the aorta, (2) on the level of plasma lipids, and (3) on the number of adherent intimal monocytes and foam cells. Seventy Wistar rats were assigned to one of the following groups: (1) regular diet, (2) an atherogenic diet consisting of regular chow with 2% cholesterol, 1% cholic acid, and 0.5% thiouracil (CCT), (3) CCT supplemented with 5 mg/kg/day clentiazem, and (4) CCT with 25 mg/kg/day clentiazem. Animals were sacrificed after 6 or 12 weeks of diet. Aortas were studied by light microscopy after staining with oil red O (ORO) and/or hematoxylin. ORO staining was quantified in both abdominal and thoracic regions of the aorta. The aortas of the clentiazem groups demonstrated significantly less ORO staining than CCT diet controls in thoracic aorta after 6 weeks and abdominal aorta after 12 weeks. There was no significant difference in the plasma lipid concentrations. The clentiazem-treated groups had fewer numbers of adherent monocytes and foam cells. We conclude that clentiazem inhibits lipid deposition in cholesterol-fed rats without lowering plasma lipid concentrations and that the number of intimal monocytes and foam cells is decreased in the presence of this calcium antagonist.     

Antiepileptic effects of IOS-1.1212, a new calcium channel blocker

Research Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Institute of Organic Synthesis, Latvian Academy of Sciences, Riga. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 112, No. 10, pp. 362–365, October, 1991.     

Thickening of the adrenal zona glomerulosa in dogs induced by oxodipine, a calcium channel blocker.

Subchronic effects of oxodipine, a calcium channel blocker affecting the adrenal gland of the dog, are described. Thirteen wk of treatment at a high dose (24 mg/kg/day) of oxodipine resulted in drug-induced thickening of the zona glomerulosa and increased stimulation of its secretory activity. It is postulated that subchronic administration of oxodipine at this dosage resulted in a decrease in blood pressure, with uninterrupted stimulation of the adrenal zona glomerulosa to release aldosterone, causing an increase in the width of this portion of the gland involving cellular hyperplasia. Support for this indirect effect is found in the increased presence of renin granules in the juxtaglomerular apparatus.     

The effect of inhaled allergen on circulating basophils in atopic asthma.

There is increasing evidence for the role of basophils in the allergen-induced late asthmatic response (LAR). To study the effect of inhaled allergen on basophil function in subjects with asthma, ex vivo basophil spontaneous histamine release (SHR) in peripheral blood and plasma histamine was measured before and 2, 5, 10, and 15 minutes, and 2, 4, 6, and 8 hours after allergen bronchial challenge (allergen study day) in six subjects with atopic asthma. Allergen inhalation induced an early response and LAR consisting of a mean (+/- SD) 32.5% (+/- 7.9%) and 28.8% (+/- 7.7%) fall in FEV1, respectively. As a control for the effects of bronchoconstriction, on another occasion, methacholine challenge was performed to produce a mean 33.4% (+/- 3.4%) fall in FEV1 during the early response and no LAR, and blood was obtained to measure basophil histamine release (HR) and plasma histamine. There was a small, but significant (p less than 0.05), rise in median SHR from 4.6% to 6.1% of total basophil histamine after allergen but not after methacholine inhalation. HR remained high after allergen inhalation during the 8 hours of study, whereas it demonstrated a steady, significant, decrease between 4 to 8 hours after methacholine inhalation. No significant changes in plasma histamine were recorded on either allergen or methacholine study days. On a third occasion, SHR was measured after challenge with physiologic saline to control for any effects of methacholine on SHR, and a decrease in HR was recorded during the day similar to HR observed after methacholine challenge. These studies suggest an enhancing effect of inhaled allergen on SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of responses to pollen extract in subjects with allergic asthma and nonasthmatic subjects with allergic rhinitis

We compared pulmonary responses with inhaled pollen-antigen extract in eight subjects with allergic asthma and eight nonasthmatic subjects with allergic rhinitis. Lower respiratory tract sensitivity to antigen was determined from dose-response curves using SGaw and FEV₁ measurements to quantitate responses. We found no difference in antigen sensitivity in terms of SGaw between the two groups (p > 0.05). Hay fever subjects required almost eight times more antigen to produce a 20% fall in FEV₁, although there was considerable overlap between the two groups. After antigen challenge there were significant increases in lung volumes in asthmatic subjects (RV, +78.6%; FRC, +33.6%; TLC, +12.6%) which were not significantly different from rhinitis subjects (RV, +98.3%; FRC, +39.1%; TLC, +10.3%). Six rhinitis and five asthmatic subjects were rechallenged after pretreatment with atropine (2.5 mg aerosol). Atropine caused an initial increase in SGaw and FEV₁ but failed to alter sensitivity or volume responses in both groups. The effects of a maximum inspiration on physiologic responses to antigen were different in the two groups. Deep inspiration transiently improved SGaw and FRC toward prechallenge values in rhinitis subjects but the same maneuver had little effect in asthma subjects. Although only asthma subjects experience lower respiratory tract symptoms during periods of environmental pollen exposure, these two groups of subjects were indistinguishable on the basis of their immediate responses to inhaled antigen. This suggests that asthmatic symptoms during the pollen season are unrelated to the immediate effects of allergic reactions to pollen. This also suggests that these bronchial challenge responses represent a localized anaphylactic reaction, whereas naturally occurring asthma during the pollen season may represent a syndrome of increased airways reactivity which is perhaps related to antigen exposure.     

Pregnancy following discontinuation of a calcium channel blocker in the male partner

The fertility potential of human sperm populations can be assessedby the presence of head-directed mannose ligand receptors (mannose-specificlectin) and the occurrence of spontaneous acrosome reactionsafter incubation under capacitating conditions in vitro. Wehave reported previously on the interaction between anti-hypertensivemedications and their effects on these parameters of male fertilitypotential. In this report we document the effects of cessationof calcium ion channel blocker medication on male fertility.Motile spermatozoa from a 30 year old infertile patient on acalcium ion channel blocker as anti-hypertensive treatment hadsubnormal expression of mannose-specific lectin and did notexhibit spontaneous acrosome reactions. Three months followingdiscontinuation of the medications, complete recovery of boththe expression of head-directed mannose ligand receptors andthe acrosome reaction was documented, though sperm motilityand morphology remained unchanged. The couple had 2 years ofinfertility and previously failed to conceive through sevencycles of Pergonal/intra-uterine insemination. Conception occurredon the second Pergonal/intra-uterine insemination cycle afterthe husband discontinued calcium ion channel blocker medication.Calcium ion channel blockers may adversely affect sperm fertilizingpotential. Discontinuation of such medications enhances thechances for conception.     

The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects

Eight subjects with asthma inhaled on separate occasions leukotriene E4 (LTE4) (6.1 nmol, geometric mean), methacholine, and diluent, which produced an average 41.0%, 37.0%, and 3.3% decrease in specific airway conductance (SGaw), respectively. When the SGaw had recovered to baseline levels at 60 minutes after challenge, the provocative dose of inhaled histamine that produced a 35% decrease in SGaw (PD35) was determined. The histamine PD35 observed after inhalation of LTE4 was 0.46 mumol, and this was significantly less than the histamine PD35 observed after inhalation of methacholine (0.88 mumol; p less than 10(-4) and diluent (0.97 mumol; p less than 10(-5). Histamine responsiveness was also enhanced by a fiftyfold lower dose of LTE4 (p = 0.005), and the enhancement was less than that elicited by the higher dose of LTE4 in the same individuals (p = 0.02). The changes in histamine PD35 during a 1-week period after LTE4 and methacholine challenges were compared in four subjects with asthma. There was a time-dependent enhancement in histamine responsiveness that reached a maximal of 3.5-fold at 7 hours after LTE4. The enhancement had disappeared by 1 week. Similar changes were not observed after methacholine challenge, which elicited the same degree of bronchoconstriction as LTE4. Inhalation of LTE4 in five normal subjects that produced a mean 37.6% decrease in SGaw did not change histamine responsiveness for up to 7 hours. These findings suggest that LTE4 may play a role in the perpetuation of nonspecific airway hyperresponsiveness in bronchial asthma.     

Obtaining concomitant control of allergic rhinitis and asthma with a nasally inhaled corticosteroid

Allergic rhinitis (AR) and asthma coexist frequently and a dual treatment is recommended by prescribing topical nasal plus oral inhaled corticosteroids. The purpose of this study was to assess the efficacy of a nasally inhaled corticosteroid aiming at concomitant control of AR and asthma. A controlled trial was conducted among 60 patients with AR and asthma, aged 6-18 years, who were randomized into two groups. During 8 weeks, the experimental group (30 patients) received exclusively fluticasone propionate hydrofluoroalkane (FP-HFA) inhaled through the nose (mouth closed) using a large volume spacer attached to a face mask. The comparison group (30 patients) received a nasal spray of isotonic saline plus oral inhalation of FP-HFA through a mouthpiece attached to the same spacer. Clinical scores for AR and asthma, nasal inspiratory peak flow (NIPF), and spirometry were assessed by blinded observers. There was a significant improvement in AR scores and NIPF in the experimental group (P or= 0.20). Prebronchodilator FEV(1) (% predicted value) improved by 10% in both groups, comparing values at inclusion with those obtained at the end of follow up. Our results suggest that nasally inhaled FP-HFA through a spacer may control AR and asthma in children and adolescents. This approach is likely to result in higher compliance, lower costs, and fewer side effects.     

Effect of deep inspiration on airway conductance in subjects with allergic rhinitis and allergic asthma

We measured specific airway conductance ($\text{Gaw}\text{Vtg}$) in a body plethysmograph before and after a deep inspiratory maneuver in 8 subjects with allergic rhinitis and 8 subjects with allergic asthma. In hay fever subjects deep inspiration had no effect on $\text{Gaw}\text{Vtg}$ if it was performed in the control state; however, when methacholine-induced bronchoconstriction was present, deep inspiration transiently increased $\text{Gaw}\text{Vtg}$. In asthmatic subjects deep inspiration was followed by a transient fall in baseline $\text{Gaw}\text{Vtg}$ in the control state; however, when bronchoconstriction was present, deep inspiration was followed by small and variable changes in $\text{Gaw}\text{Vtg}$ in 7 subjects and marked improvement in $\text{Gaw}\text{Vtg}$ in 1 subject. In asthmatic subjects the bronchoconstrictor response to deep inspiration performed in the control state is thought to be due to reflex changes in bronchomotor tone mediated by cholinergic (vagal) nerve pathways. Like asthmatic subjects, hay fever subjects also possess cholinergic-mediated airway hyperreactivity compared with normals. Our results indicate that, in spite of their increased airway reactivity, hay fever subjects respond more like normal subjects than like asthmatic subjects after a deep inspiratory maneuver.     

The effect of aerosol distribution on airway responsiveness to inhaled methacholine in patients with asthma.

It has been demonstrated that airway deposition of inhaled aerosols is more heterogeneous in patients with asthma than in normal subjects. Nevertheless, the influence of abnormal airway deposition on responses to bronchoactive aerosols is poorly understood. We altered bronchopulmonary deposition heterogeneity of methacholine aerosol in nine asymptomatic patients with asthma by controlling inspiratory flow at high (approximately 60 L/min) versus low (approximately 12 L/min) rates on 2 study days and determined the effect on the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) (often used as a measure of airway responsiveness). Deposition uniformity was quantified from gamma-camera scans of the lungs in terms of the distribution of a technetium-labeled aerosol that was inhaled rapidly or slowly before the inhalation of methacholine. Increased deposition in an inner (large, central airways) versus an outer (peripheral airways and alveoli) zone of the right lung (inner/outer ratio, greater than 1) and higher values of skew (an index of deposition asymmetry) and kurtosis (an index of deposition range) indicated enhanced heterogeneity of deposition. Mean (+/- SD) inner/outer ratio was significantly higher during rapid inspiration compared to slow inspiration with 2.91 +/- 0.51 and 1.84 +/- 0.30, respectively (p less than 0.01). Mean skew and kurtosis were also significantly higher after rapid inspiration, with 1.12 +/- 0.35 and 3.86 +/- 1.25, respectively, compared to 0.74 +/- 0.36 and 2.64 +/- 0.77 after slow inhalation (p less than 0.01). Geometric mean PD20 methacholine was significantly reduced when the aerosol was inhaled rapidly, with 5.9 cumulative methacholine units compared to 15.7 units after slow inhalation (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of diabetic vascular calcification by nifedipine, a dihydropyridine-based calcium channel blocker

Vascular calcification is a common feature in advanced atherosclerosis and also a predictor of future cardiovascular events such as unstable angina and myocardial infarction, especially in diabetes. There is a growing body of evidence that advanced glycation end products (AGEs), senescent macroprotein derivatives formed at an accelerated rate in diabetes, exist within atherosclerotic lesions, thereby being implicated in the pathogenesis of accelerated atherosclerosis in diabetes. Indeed, we have previously shown that AGE - their receptor (RAGE) interaction could induce angiogenesis through autocrine production of vascular endothelial growth factor, suggesting its role for plaque formation and enlargement in diabetes. Furthermore, we have found that AGEs have the ability to induce the osteoblatic differentiation of pericytes, thus contributing to the development of vascular calcification as well. These observations suggest that the inhibition of AGE formation or blockade of the downstream signaling of RAGE may be a novel therapeutic target for the inhibition of vascular calcification in diabetic atherosclerosis. Since we, along with others, have shown that nifedipine inhibits glycation of low-density lipoprotein in vitro and blocks the AGE-induced RAGE expression in endothelial cells through its anti-oxidative properties, nifedipine could inhibit vascular calcification by blocking the AGE formation or the downstream signaling in diabetes. In this paper, we would like to propose the possible ways of testing our hypothesis. Does nifedipine treatment slow down the progression of coronary calcification in diabetic patients? If the answer is yes, is this beneficial effect of nifedipine superior to that of other DHPs with equihypotensive properties? Does nifedipine treatment decrease expression levels of AGEs and RAGE in diabetic atherosclerosis? Is the unique effect of nifedipine on vascular calcification correlated with its AGE or RAGE-suppressing properties? These prospective studies will provide further valuable information whether nifedipine could prevent vascular calcification in diabetic atherosclerosis by blockade the AGE-RAGE signaling in vascular wall cells.     

Genetic polymorphisms as biomarkers of sensitivity to inhaled sulfur dioxide in subjects with asthma.

BACKGROUND: Individuals with asthma are sensitive to inhaled sulfur dioxide (SO2); decrements in pulmonary function occur after exposure to low concentrations even for a short duration of time. There is a great amount of interindividual variation in response to SO2. OBJECTIVE: It was our objective to determine whether one of the following polymorphism locations linked with asthma is associated with the bronchial hyperresponsiveness to SO2 observed in some asthmatic patients: the beta2-adrenergic receptor, interleukin-4 (IL-4) receptor alpha subunit, Clara cell secretory protein (CC16), TNF-alpha gene promoter, and first intron of the lymphotoxin alpha (LT-alpha) gene. METHODS: Subjects were volunteers with physician-diagnosed asthma requiring regular asthma medication. Spirometry was performed before and after a 10-minute exposure to 0.5 ppm SO2. Subjects were classified as SO2 responders if forced expiratory volume in 1 second (FEV1) decreased > or = 12%. DNA obtained from buccal cell samples was analyzed for genetic polymorphisms. RESULTS: Of the 62 subjects (21 male and 41 female), 13 had a 12% or greater decrement in FEV1 after SO2 exposure (range + 19% to -49%). Response to SO2 was associated with the wild-type allele of the TNF-alpha promoter polymorphism (12 of 12 SO2 responders versus 28 of 46 nonresponders; P < .05) but with no other polymorphisms. Medication category and atopic status showed no association with SO2 sensitivity. CONCLUSIONS: The wild-type allele of the TNF-alpha promoter polymorphism may be associated with mechanisms of asthmatic sensitivity to inhaled SO2.     

The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma

Background:  IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma.
Methods:  Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation.
Results:  When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV₁%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively ( P  < 0.01). The degree of attenuation in the EAR [maxFEV₁% (mean ± SE) 26.5 ± 2.8% vs placebo 31.0 ± 2.8%, P  = 0.059] and LAR (15.6 ± 2.9% vs placebo 19.0 ± 2.9%, P  = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed.
Conclusions:  The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated.     

The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma

We have compared the effects of the leukotriene (LT) D4 antagonist L-649,923 and placebo on the airway response to antigen challenge in eight men with mild asthma known to have both an early and late response to inhaled antigen. Subjects ingested 1000 mg of L-649,923 or placebo in a randomized, double-blind protocol and, two hours later, inhaled the dose of antigen known to induce a 20% fall in FEV1. Pulmonary function (specific conductance, FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity) was measured at intervals before and up to 9 hours after antigen. FEV1 fell in one subject after L-649,923 ingestion. L-649,923 in the other seven subjects caused no change in baseline pulmonary function, a small reduction in the early response to antigen for FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity but not for specific airway conductance (six subjects only) and no effect on the late response. The mean maximum fall in FEV1 in the early response was 1.35 L after L-649,923 ingestion and 1.78 after placebo ingestion. This relatively small degree of protection by L-649,923 suggests either that L-649,923 is not a sufficiently potent antagonist to diminish the effect of endogenous LTD4 in vivo or that LTD4 does not play a major role in the airway response to antigen challenge.     

Calcium channels in embryonic chick skeletal muscle cells after cultivation with calcium channel blocker.

The effects of chronic treatment with calcium channel blockers were studied on the expression of voltage-dependent calcium channels (VDCCs) in chick skeletal muscle cells developing in culture. Myotubes were treated after 2 days in culture with either 20 microM D600 or 10 microM nifedipine, and measurements were made of the maximum rate of rise (M.R.R.) of the two components of action potential, operated by T- and L-type VDCCs, respectively. Treatment with either blocker reduced the M.R.R. of the action potential component operated by the L-type VDCC throughout the culture period examined. The M.R.R. of the T-type VDCC component, on the other hand, was unaffected by either treatment. The reduction in the M.R.R. of the L-type component in blocker-treated cells is thought to be due to the down-regulation of the expression of L-type VDCC. Thus, it appears that the expression of L-type VDCC in the chick skeletal muscle cells can be regulated by a function of L-type VDCC, which mediate the entry of Ca2+ into the cells. The physiological significance of the L-type VDCC, which expressed prominently early in the development of skeletal muscle cells, for the differentiation of excitability is discussed.