Combination therapy of a TRPV2 agonist with a TNF inhibitor achieves sustained suppression of disease severity and reduced joint damage.

We aimed to compare a transient receptor potential vanilloid 2 (TRPV2) agonist with a TNF inhibitor, and to test the potential of their combination in collagen-induced arthritis (CIA) as a potential future strategy for rheumatoid arthritis (RA). Following the onset of CIA DBA1/j mice were started on treatment with either vehicle, etanercept (8 mg/kg three times a week), the TRPV2 agonist O1821 (20-30 mg/kg/day), or a combination of both. Mice were scored over a 61-day period. Synovial tissues were obtained for RNA sequencing. Mice on monotherapy with either O1821 or etanercept developed milder clinical disease. The O1821 protection was observed at an earlier time-point than in the etanercept group. The combination therapy group achieved a more robust and sustained reduction in disease severity than either monotherapy group. All treatment groups had reduced scores for synovial inflammation, synovial hyperplasia, and erosive changes, compared with controls, with the combination group achieving the most significant protection. RNA sequencing and pathway analyses of synovial tissues identified pathways and processes regulated by the TRPV2 agonist, such as chemotaxis and cytokine receptor signaling, including IL6R. The combination therapy affected additional pathways not seen in the monotherapy groups. In conclusion, the TRPV2 agonist achieved an overall similar reduction in arthritis severity and histology scores as etanercept, but the combination therapy achieved a more sustained disease control and more pronounced reduction in joint damage, suggesting a potential future option for improving disease control in RA. RNA sequencing analyses identified new pathways regulated by TRPV2, and also by the combination treatment.

The role of voltage-gated calcium channels in the mechanisms of anesthesia and perioperative analgesia.

PURPOSE OF REVIEW: A family of neuronal voltage-gated calcium channels (VGCCs) have received only recently a significant consideration regarding the mechanisms of anesthesia because VGCC inhibition may be important in anesthetic action by decreasing neuronal excitability and presynaptic excitatory transmission. The T-type VGCCs channels (T-channels), although rarely involved in synaptic neurotransmitter release, play an important role in controlling neuronal excitability and in generating spontaneous oscillatory bursting of groups of neurons in the thalamus thought to be involved in regulating the state of arousal and sleep. Furthermore, these channels are important regulators of neuronal excitability in pain pathway. This review will provide an overview of historic perspective and the recent literature on the role of VGCCs and T-channel inhibition in particular in the mechanisms of action of anesthetics and analgesics. RECENT FINDINGS: Recent research in the field of novel mechanisms of hypnotic action of anesthetics revealed significant contribution of the Ca V 3.1 isoform of T-channels expressed in the thalamus. Furthermore, perioperative analgesia can be achieved by targeting Ca V 3.2 isoform of these channels that is abundantly expressed in pain pathways. SUMMARY: The review summarizes current knowledge regarding the contribution of T-channels in hypnosis and analgesia. Further preclinical and clinical studies are needed to validate their potential for developing novel anesthetics and new perioperative pain therapies.

A comprehensive update on the ADMET considerations for α2δ calcium channel ligand medications for treating restless legs syndrome.

INTRODUCTION: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated. AREAS COVERED: The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options. EXPERT OPINION: α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.

Effects of clitorienolactones from Clitoria ternatea root on calcium channel mediating hippocampal long-term potentiation in rats induced chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common mechanism of acute brain injury due to impairment of blood flow to the brain. Moreover, a prolonged lack of oxygen supply may result in cerebral infarction or global ischemia, which subsequently causes long-term memory impairment. Research on using Clitoria ternatea root extract for treating long-term memory has been studied extensively. However, the bioactive compound contributing to its neuroprotective effects remains uncertain. In the present study, we investigate the effects of clitorienolactone A (CLA) and B (CLB) from the roots of Clitoria ternatea extract on hippocampal neuroplasticity in rats induced by CCH. CLA and CLB were obtained using column chromatography. The rat model of CCH was induced using two-vessel occlusion surgery (2VO). The 2VO rats were given 10 mg/kg of CLA and CLB orally, followed by hippocampal neuroplasticity recording using in vivo electrophysiological. Rats received CLA and CLB (10 mg/kg) significantly reversed the impairment of long-term potentiation following 2VO surgery. Furthermore, we investigate the effect of CLA and CLB on the calcium channel using the calcium imaging technique. During hypoxia, CLA and CLB sustain the increase in intracellular calcium levels. We next predict the binding interactions of CLA and CLB against NMDA receptors containing GluN2A and GluN2B subunits using in silico molecular docking. Our result found that both CLA and CLB exhibited lower binding affinity against GluN2A and GluN2B subunits. Our findings demonstrated that bioactive compounds from Clitoria ternatea improved long-term memory deficits in the chronic cerebral hypoperfusion rat model via calcium uptake. Hence, CLA and CLB could be potential therapeutic tools for treating cognitive dysfunction.

Case Series: Synergistic Effect of Gabapentin and Adjuvant Pregabalin in Neuropathic Pain.

Gabapentin and pregabalin both exert high affinity to the α2δ subunit of the voltage-gated calcium channels which inhibits excitatory neurotransmitter release. The synergistic mechanism was described in rats given combinations of gabapentin and pregabalin. In this case series, we described 2 cases which may illustrate the synergistic effect of gabapentin and pregabalin in treatment resistant neuropathic pain. Low dose pregabalin was added to therapeutic gabapentin to achieve appreciable pain reduction in one case and improved quality of life in another case. Further research with more enrollment and longer study duration may help elucidate the appropriate dosing and potential associated side effects.

Survival Outcomes of Calcium Channel Blocker Therapy in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Inhibitors: A Retrospective Study.

BACKGROUND: Non-cancer drugs are currently being repurposed for cancer treatment. Mounting evidence highlights the influence of calcium channels on tumorigenesis and progression. Hence, inhibition of calcium signaling may be a promising cancer treatment strategy. OBJECTIVE: In this study, we aimed to examine whether calcium channel blockers (CCBs) affect the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). DESIGN: We conducted a retrospective analysis. METHODS: In this study, conducted between January 2009 and June 2021, patients with NSCLC treated with erlotinib, or gefitinib for at least 1 week were enrolled and divided into 2 groups: CCBs-/EGFR-TKIs+ and CCBs+/EGFR-TKIs+, depending on whether they received CCB therapy. Progression-free survival (PFS) and overall survival (OS) were determined as the primary and secondary endpoints, respectively. RESULT: : The estimated median PFS and OS for the CCBs-/EGFR-TKIs+group were 7.70 and 12.17 months, respectively, and they were significantly different from those of the CCBs+/EGFR-TKIs+ group (10.43 and 18.07 months, respectively). CCB use was associated with improved PFS (adjusted hazard ratios [HR] 0.77, 95% confidence interval [CI]: 0.61-0.98; P = .035) and OS (adjusted HR 0.66, 95% CI: 0.51-0.84; P < .001). CONCLUSION: Calcium channels have been implicated in cancer pathogenesis. Our findings revealed the potential additive anticancer effects of CCBs when used concomitantly with EGFR-TKIs. However, study limitations, including the retrospective nature and small number of patients, necessitate large-scale prospective studies on the therapeutic potential of CCB as an adjunctive therapy with EGFR-TKIs in patients with NSCLC.

A pilot pharmacogenetic study of calcium channel blocker treatment of bipolar mania.

Common genetic variants located in calcium channel genes are important markers of genetic susceptibility for bipolar disorder (BD). Previous clinical trials with Calcium Channel Blocker (CCB) medication improved mood stability for some BD patients. We hypothesize that manic patients who carried calcium channel risk variants would differentially benefit from treatment with CCBs. In this pilot study, 50 BD patients (Chinese: 39; US: 11) who were hospitalized for manic episodes were given add-on CCB treatment. We determined genotypes for each patient. There was a significant decrease in the Young Mania Rating Scale (YMRS) after add-on medication treatment. Of note, two intronic variants of the Calcium Voltage-Gated Channel Subunit Alpha1 B (CACNA1B) were associated with treatment outcomes for manic patients: rs2739258 and rs2739260. BD rs2739258/rs2739260 AG-allele carriers had a better treatment response with add-on CCB than those carrying the AA or GG genotypes by survival analysis. Although these findings did not pass multiple testing correction, this study suggests that single-nucleotide polymorphisms (SNPs) residing in calcium channel genes could be predictors for response to add-on CCB treatment of bipolar mania patients, and that calcium channel genes may be involved in treatment responses for BD.

Immune challenges upregulate the expression of cannabinoid receptors in cultured human odontoblasts and gingival fibroblasts.

Odontoblasts and gingival fibroblasts play essential roles in the physiological and pathological processes of dental tissue. Cannabinoid receptors (CB1 and CB2) are involved in analgesia by modulating the función of calcium channels that inhibit the synthesis of some neurotransmitters. A better understanding of the physiology of these receptors would provide the possibility of using them as therapeutic targets in controlling dental pain. The aim of this study was to evaluate the presence and activity of cannabinoid receptors in human odontoblast-like cells (OLC) and human gingival fibroblasts (HGF). CB1 and CB2 transcription was analyzed by real-time PCR, proteins were detected by immunofluorescence, and functional cannabinoid receptors were evaluated by measuring intracellular calcium concentration after stimulation with cannabidiol (CBD) and pre-treatment with a CB1 antagonist, a CB2 inverse agonist and a TRPV1 antagonist. Transcripts for CB1 and CB2 were found in both odontoblasts and gingival fibroblasts. Cannabidiol induced an increase in [Ca2+]i in both cells types, but surprisingly, pre-treatment with selective cannabinoid antagonists attenuated this effect, suggesting a functional communication between specific cannabinoid receptors and other CBD target receptors. In conclusion, human odontoblasts and gingival fibroblasts express functional CB1 and CB2 cannabinoid receptors, which could be modulated to improve the treatment of pain or dental sensitivity.

Los odontoblastos y los fibroblastos gingivales desempeñan funciones esenciales en los procesos fisiológicos y patológicos de los tejidos dentales. Los receptores cannabinoides (CB1 y CB2) participan en la analgesia mediante la modulación de la función de canales de calcio que inhiben la síntesis de algunos neurotransmisores. Un mejor conocimiento de su fisiología abre la posibilidad de utilizar estos receptores como dianas terapéuticas en el control del dolor dental. Este trabajo tuvo como objetivo evaluar la presencia y la actividad de los receptores cannabinoides en células humanas similares a los odontoblastos (OLC) y en fibroblastos gingivales humanos (HGF). Se analizó la transcripción de CB1 y CB2 por PCR en tiempo real, la detección de las proteínas por inmunofluorescencia y se evaluaron los receptores cannabinoides funcionales midiendo las concentraciones de calcio intracelular, tras la estimulación con cannabidiol (CBD) y el pretratamiento con un antagonista de CB1, un agonista inverso de CB2 y un antagonista de TRPV1. Se encontraron mensajeros para CB1 y CB2 tanto en odontoblastos como en fibroblastos gingivales. El cannabidiol indujo un aumento de la [Ca2+]i en ambos tipos de células, pero sorprendentemente el pretratamiento con antagonistas cannabinoides selectivos atenuó este efecto, lo que sugiere una comunicación funcional entre receptores cannabinoides específicos y otros receptores diana del CBD. En conclusión, los odontoblastos humanos y los fibroblastos gingivales expresan receptores cannabinoides CB1 y CB2 funcionales, que podrían ser modulados para mejorar el tratamiento del dolor o la sensibilidad dental.

Antidiarrheal and antispasmodic activities of Trillium govanianum rhizomes extract: involvement of calcium channel blockade.

The antidiarrheal effect of methanolic extract of Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae) was studied at doses of 12.5, 25, and 50 mg/kg in different animal models of diarrhea including castor oil (6 mL/kg), magnesium sulfate (2 gm/kg), sodium picosulfate (2 mL/kg) and lactitol (0.25 mL/kg). The antispasmodic effect of T. govanianum was studied on isolated rabbit's jejunum, using acetylcholine as tissue stabiliser and verapamil as calcium channel blocker. T. govanianum attenuated the diarrhea by producing a significant decrease in the number and weight of stool, and an increase in stool latency time. T. govanianum completely inhibited both spontaneous as well as high potassium induced contractions of isolated rabbit's jejunum, which was analogous to verapamil. Moreover, T. govanianum produced a right shift in calcium concentration response curve, confirming its calcium channel blocking activity. These findings provide scientific ground to its medicinal use in diarrhea and gut spasms.

Orai3: Oncochannel with therapeutic potential.

Ion channels in particular Calcium (Ca2+) channels play a critical role in physiology by regulating plethora of cellular processes ranging from cell proliferation, differentiation, transcriptional regulation and programmed cell death. One such physiologically important and highly Ca2+ selective channel family is Orai channels consisting of three homologs Orai1, Orai2 and Orai3. Orai channels are responsible for Ca2+ influx across the plasma membrane in response to decrease in Endoplasmic Reticulum (ER) Ca2+ stores. STIM1/STIM2 proteins sense the reduction in ER Ca2+ levels and activate Orai channels for restoring ER Ca2+ as well as for driving cellular functions. This signaling cascade is known as Store Operated Ca2+ Entry (SOCE). Although Orai1 is the ubiquitous SOCE channel protein, Orai2 and Orai3 mediate SOCE in certain specific tissues. Further, mammalian specific homolog Orai3 forms heteromultimeric channel with Orai1 for constituting Arachidonic acid regulated Ca2+ (ARC) channels or arachidonic acid metabolite Leukotriene C4 (LTC4) regulated Ca2+ (LRC) channels. Literature suggests that Orai3 regulates Breast, Prostate, Lung and Gastrointestinal cancers by either forming Store Operated Ca2+ (SOC) or ARC/LRC channels in the cancerous cells but not in healthy tissue. In this review, we would discuss the role of Orai3 in these cancers and would highlight the potential of therapeutic targeting of Orai3 for better management and treatment of cancer. Finally, we will deliberate on key outstanding questions in the field that demand critical attention and further studies.

Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cardinal features of cognitive dysfunction in an individual. Recently, the blockade of mitochondrial calcium uniporter (MCU) exhibits neuroprotective activity in experimental animals. However, the therapeutic potential of MCU has not yet been established in the management of AD. Therefore, the present study explored the therapeutic potential of either Ruthenium red (RR), a MCU blocker, or Spermine, a MCU opener, on the extent of mitochondrial calcium accumulation, function, integrity and bioenergetics in hippocampus, pre-frontal cortex and amygdale of ICV-STZ challenged rats. Experimental AD was induced in male rats by intracerebroventricular injection of streptozotocin (ICV-STZ) on day-1 (D-1) of the experimental protocol at a sub-diabetogenic dose (3 mg/kg) twice at an interval of 48 h into both rat lateral ventricles. RR attenuated ICV-STZ-induced memory-related behavioral abnormalities in Morris water maze and Y-maze tests. RR also attenuated ICV-STZ-induced decrease in the level of acetylcholine and activity of choline acetyltransferase and, increase in the activity of acetylcholinestarase in memory-sensitive rat brain regions. Further, RR attenuated mitochondrial toxicity in terms of reducing mitochondrial calcium accumulation and improving the mitochondrial function, integrity and bioenergetics in memory-sensitive brain regions of ICV-STZ challenged rats. Furthermore, RR attenuated the percentage of apoptotic cells in ICV-STZ challenged rat brain regions. However, Spermine did not alter ICV-STZ-induced behavioral, biochemical and molecular observations in any of the brain regions. These observations indicate the fact that the MCU blockage could be a potential therapeutic option in the management of sporadic type of AD.

Treatment Algorithms for Systemic Sclerosis According to Experts.

OBJECTIVE: There is a lack of agreement regarding treatment for many aspects of systemic sclerosis (SSc). We undertook this study to generate SSc treatment algorithms endorsed by a high percentage of SSc experts. METHODS: Experts from the Scleroderma Clinical Trials Consortium and the Canadian Scleroderma Research group (n = 170) were asked whether they agreed with SSc algorithms from 2012. Two consensus rounds refined agreement; 62, 54, and 48 experts (36%, 32%, and 28%, respectively) completed the first, second, and third surveys, respectively. RESULTS: For treatment of scleroderma renal crisis, 81% of experts agreed (first-, second-, and third-line treatments were angiotensin-converting enzyme inhibitors, then adding calcium-channel blockers [CCBs], then adding angiotensin receptor blockers [ARBs], respectively). For pulmonary arterial hypertension (PAH), 81% of experts agreed (for mild PAH, treatments were phosphodiesterase 5 [PDE5] inhibitors, then endothelin receptor antagonists plus PDE5 inhibitors, then prostanoids, respectively; for severe PAH, prostanoids were first-line treatment). For mild Raynaud's phenomenon (RP), 79% of experts agreed (treatments were CCBs, then adding PDE5 inhibitors, then ARBs or switching to another CCB, respectively; after the third line of treatment, mild RP was deemed severe). For severe RP, the first- through fourth-line treatments were CCBs, then adding PDE5 inhibitors or prostanoids, then adding PDE5 inhibitors (if not added as second-line treatment) or prostanoids (if not added as second-line treatment), then switching to another CCB, respectively. For active treatment of digital ulcers, 66% of experts agreed (first- and second-line treatments were CCBs and PDE5 inhibitors, respectively). For interstitial lung disease, 69% of experts agreed (for induction therapy, treatments were mycophenolate mofetil [MMF], intravenous cyclophosphamide [IV CYC], and rituximab, respectively; for maintenance, first-line treatment was MMF). For skin involvement, 71% of experts agreed (for a modified Rodnan skin thickness score [MRSS] of 24, first- and second-line treatments were methotrexate [MTX] and MMF, respectively; for an MRSS of 32, first- through fourth-line treatments were MMF, MTX, IV CYC, and hematopoietic stem cell transplantation, respectively). For inflammatory arthritis, 79% of experts agreed (first- through fourth-line treatments were MTX, low-dose glucocorticoids, hydroxychloroquine, and rituximab or tocilizumab, respectively). Algorithms for cardiac and gastrointestinal involvement had ≥75% agreement. CONCLUSION: Total agreement for SSc algorithms was considerable. These algorithms may guide treatment.

Beneficial effect of cilnidipine on morning hypertension and white-coat effect in patients with essential hypertension.

Home blood pressure has a higher predictive power for cardiovascular events than office blood pressure, and there is a particularly close association between morning blood pressure at home and the incidence of cardiovascular events and mortality in the early morning. In this study, we evaluated the efficacy of a long-acting N-type and L-type calcium channel blocker, cilnidipine, in reducing morning blood pressure at home and in ameliorating the white-coat effect. Fifty-eight subjects diagnosed with both essential hypertension and morning hypertension (43 currently being treated, 15 new patients) were prescribed cilnidipine at a dosage of 10-20 mg per day for 8 weeks. After the addition of or a change to cilnidipine, the morning systolic blood pressure (SBP) was controlled to less than 135 mmHg in 25 (58%) out of the 43 patients currently receiving antihypertensive medication. The office SBP in 24 out of those 25 patients was also maintained under 140 mmHg. In the 15 newly treated patients, the morning SBP of 12 patients (80%) was controlled to less than 135 mmHg after administration of cilnidipine. At baseline, 17 patients showed a clear white-coat effect, in which the difference between office blood pressure and home blood pressure was 20/10 mmHg or more. The white-coat effect was depressed significantly after cilnidipine administration. These results suggest that cilnidipine may serve as a useful antihypertensive medication in the treatment of morning hypertension, and also attenuate the white-coat effect in patients with essential hypertension.

Orthostatic hypotension in a cohort of hypertensive patients referring to a hypertension clinic.

The prevalence of orthostatic hypotension (OH) in hypertensive patients ranges from 3 to 26%. Drugs are a common cause of non-neurogenic OH. In the present study, we retrospectively evaluated the medical records of 9242 patients with essential hypertension referred to our Hypertension Unit. We analysed data on supine and standing blood pressure values, age, sex, severity of hypertension and therapeutic associations of drugs, commonly used in the treatment of hypertension. OH was present in 957 patients (10.4%). Drug combinations including α-blockers, centrally acting drugs, non-dihydropyridine calcium-channel blockers and diuretics were associated with OH. These pharmacological associations must be administered with caution, especially in hypertensive patients at high risk of OH (elderly or with severe and uncontrolled hypertension). Angiotensin-receptor blocker (ARB) seems to be not related with OH and may have a potential protective effect on the development of OH.

Effect of lacidipine and nifedipine GITS on platelet function in patients with essential hypertension.

With the aim of evaluating the effects on blood pressure, platelet function and insulin sensitivity of the dihydropiridines lacidipine and nifedipine GITS, a parallel double-blind study was carried out in a group of 20 patients with mild to moderate essential hypertension. They received a placebo for 4 weeks; then were divided at random into two groups of 10 patients each. Nifedipine GITS, 30 mg and lacidipine, 4 mg, were given during 16 weeks of active treatment. Blood pressure and heart rate were measured at the clinic in supine, sitting and standing positions, 24 +/- 1 h after the last dose. After the placebo and active phases were carried out, a platelet aggregation test was performed to determine platelet malondialdehyde production and a tolerance to 100 g of glucose by measuring glucaemia and plasma insulin. Both drugs reduced systolic and diastolic blood pressure at the same level, however there were observable differences in the rate of reduction. The nifedipine GITS reduced supine systolic blood pressure by 25 mm Hg in the first week, while the lacidipine did so by 11 mm Hg. At the end of the study period nifedipine reduced supine systolic blood pressure by 28 mm Hg and lacidipine by 20 mm Hg. Heart rate was increased slightly but significantly in the nifedipine GITS group only in the standing position. Both drugs reduced platelet aggregation ex vivo only marginally but they modified the malondialdehyde production, indicating an action on the arachidonic acid metabolic pathway.

Calcium channel blockers: a potential cause of false-positive captopril renography.

PURPOSE: The purpose of the study was to review the causes of false-positive and false-negative captopril Tc-99m MAG3 renograms performed to evaluate renovascular hypertension at the authors' institution. METHODS: From May 2000 to January 2002, 77 patients were referred for evaluation of possible renovascular hypertension with captopril Tc-99m MAG3 renography. If the findings of the captopril study were abnormal, a baseline study was performed 3 days later. The captopril studies were retrospectively reviewed and correlated with available renal arteriography, magnetic resonance angiography, and duplex Doppler sonography studies and clinical follow-up. Renal artery stenosis greater than 70% on an arteriogram and 60% on Doppler studies or magnetic resonance angiography was considered positive for renovascular hypertension. RESULTS: There were five false-negative and four false-positive studies. The five patients who had the false-negative captopril studies underwent arteriography, which showed renal artery stenosis, and a stent was placed in two of them. The four false-positive captopril studies were proved by negative arteriograms in three and negative magnetic resonance angiography in one. Three patients with false-positive studies had bilateral renal function impairment after captopril and were taking calcium channel blockers at the time of the captopril study. One patient had a left nephrectomy and was also taking calcium channel blockers. CONCLUSION: Chronic intake of calcium channels blockers is a potential cause of bilateral symmetric false-positive captopril renography.

[Calcium antagonists and ischemic heart disease]. / Kalcium-antagonisták és ischaemiás szívbetegség.

The authors give a short account about the significance, basic rules in regulation of intracellular (cytosolic) calcium homeostasis, distribution of calcium channels in different organs and characteristics of L channels in cardiovascular system. The different types of calcium channel blockers (dihydropyridines, phenylalkilamines, benzothiazepines), their similarities, dissimilarities (cardio, -vascular selectivity) are discussed. Differences in calcium homeostasis, in sympathetic innervation between vascular smooth- and heart muscle in briefly disputed. The basic role of endothel cell dysfunction in development of ischemic heart disease, the possible mechanisms (potential anti-remodeling, antifissuring, antiischemic, cardioprotective, sympaticolytic effects) of different calcium antagonists in the treatment of patients with ischemic heart disease are reviewed. Potential adverse effects of calcium channel blockers (proischemic, proarrhythmic, procongestive, prohaemorrhagic effects) are also mentioned. Finally the up-date preventive and therapeutic indications of different calcium channel blockers in the clinical management of patients with stable, unstable angina pectoris, silent myocardial ischemia, vasospastic angina, acute myocardial infarction is shortly reported.