Calcium Channel Alpha Research Articles

Assessment of Prescribing Pattern of Antihypertensive Medications in Elderly Hypertensive

Introduction : In elderly hypertensive patients, blood pressure is over 140/90mmHg. Diuretics, renin angiotensin aldosterone system inhibitors, beta blockers, calcium channel blockers, alpha blockers and direct vasodilators are commonly prescribed to treat geriatric hypertensive patients. The choice of drugs for a particular patient changes at short intervals because of factors like changes in vascular compliance, efficacy, side effects, cost and launch of new drugs in pharmaceutical market. These facts indicate the need for assessment of prescribing pattern of antihypertensives. Objective: The prescribing pattern of antihypertensive medications was assessed in elderly patients who were suffering from hypertension. Methodology: It was a prospective observational study for six months carried out on in-patients who were admitted to general medicine units. The study protocol was approved by the human ethical committee. The patients of either sex and aged above 60 years and satisfying the study criteria such as diagnosed newly as suffering from hypertension as per Joint National Committee (JNC-7) guidelines and prescribed with antihypertensive medications were enrolled. The clinical, social and medication data was collected from the case records into a specialised patient profile form to analyze prescribing pattern of medications. All the data was analyzed using descriptive statistics. Results and Discussion: Totally 93 prescriptions were collected from the study patients. The proportion of male to female patients was 53:46 and their mean age was 68.74 ± 8.6years. Of 93 prescriptions, 50 (53.76%) prescriptions were containing antihypertensive medications as monotherapy and 43 (46.23%) prescriptions were containing antihypertensive medications as combination drug therapy. Of 50 prescriptions that were containing single antihypertensive medications, amlodepine was frequently 26 (52%) found prescribed among others. The results obtained in our study were similar to the study results conducted by Mohammed A et al. Among 43 prescriptions that were containing combination of antihypertensive medications, telmisartan+ hydrochlorothiazide were the drug combinations that were frequently 22 (51.16%) found prescribed among others.The results obtained in our study were similar to the study results conducted by Arshad HM et al. This combination was reported as fixed dose combinations used in hospitals in for treating patients enrolled in other studies. Conclusion: The medications such as amlodipine and telmisartanand hydrochlorothiazide are frequently prescribed as monotherapy and combination therapy respectievely to treat elderly patients suffering from hypertension.

Medical expulsive treatment in pediatric urolithiasis.

The frequency of stone disease in childhood ranges between 0.1-5 percent. Stone disease occurs as a result of enviromental, metabolic, anatomical, infectious and nutritional factors. Percutaneous nephrolitotomy, uretherorenoscopy, laparoscopic surgery, open surgery and extracorporeal shock wave lithothripsy are treatment alternatives for stone disease during childhood. However, these methods are not completely innocent. Some complications may occur after these procedures. These procedures are generally not cost- effective. Even invasive procedures have high success rates, so medical expulsive treatment modalities have become an alternative for a group of patients. Nonsteroidal anti- inflammatory drugs, antimuscarinic drugs, phospodiesterase type 5 inhibitors, steroids, calcium channel blockers and alpha blockers are treatment alterneatives used for this modality in the literature. The drug is chosen according to the location, size, and composition of the stone, recent technology, cost, surgeon's experience and surgeon's and the parents' preferences. In this review article the following topics will be discussed such as "Why medical expulsive treatment is needed during childhood? Which drug should be chosen for which stone type? How long should a treatment of urolithiasis last?

Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

An Anusual Cause of Secondary Hypertension in a Young Man

Mr F.P., a 33-y/o man consulted after 3 months of general status alteration with a loss of 7 kgs and nocturnal sweats. His blood pressure was controlled up to 190/110 mmHg. Clinical examination by general pratictioner was considered as normal. Bitherapy by calcium channel blockers and alpha blockers was given.

In search of the protein kinase A phosphorylation sites on the human cardiac L-type calcium channel alpha subunit

In search of the protein kinase A phosphorylation sites on the human cardiac L-type calcium channel alpha subunit

CACNA1C risk variant affects reward responsiveness in healthy individuals.

The variant at rs1006737 in the L-type voltage-gated calcium channel (alpha 1c subunit) CACNA1C gene is reliably associated with both bipolar disorder and schizophrenia. We investigated whether this risk variant affects reward responsiveness because reward processing is one of the central cognitive-motivational domains implicated in both disorders. In a sample of 164 young, healthy individuals, we show a dose-dependent response, where the rs1006737 risk genotype was associated with blunted reward responsiveness, whereas discriminability did not significantly differ between genotype groups. This finding suggests that the CACNA1C risk locus may have a role in neural pathways that facilitate value representation for rewarding stimuli. Impaired reward processing may be a transdiagnostic phenotype of variation in CACNA1C that could contribute to anhedonia and other clinical features common to both affective and psychotic disorders.

Effect of Histone Deacetylase Inhibitor JNJ-26481585 in Pain

Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1β increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.

Total flavonoids from Ganshanbian (Herba Hyperici Attenuati) effect the expression of CaL-α1C and KATP-Kir6.1 mRNA of the myocardial cell membrane in myocardial ischemia-reperfusion arrhythmia rats

ObjectiveTo observe the impact of total flavonoids from Ganshanbian (Herba Hyperici Attenuati) on the expression of vascular smooth muscle membrane L-type calcium channel alpha1 C subunit (CaL-α1C) and ATP-sensitive K+ channel (KATP)-Kir6.1 mRNA, and explore the mechanisms of the antiarrhythmic effect of Ganshanbian (Herba Hyperici Attenuati) total flavonoids. MethodsThe treatment group was fed total flavonoids from Ganshanbian (Herba Hyperici Attenuati) for 7 days by gavage with 100 mg · kg−1 · d−1. The blank control group and model control group were given the same amount of normal saline for 7 d. Arrhythmias were induced by performing a myocardial ischemia-reperfusion and electrocardiogram was observed. Reverse transcription-polymerase chain reaction was used to detect the expression of CaL-α 1Cand KATP-Kir6.1 mRNA in the myocardial cell membrane of all groups of rats. ResultsTotal flavonoids from Ganshanbian (Herba Hyperici Attenuati) can delay the appearance of myocardial ischemia reperfusion arrhythmias, shorten the duration of myocardial ischemia reperfusion arrhythmias, reduce heart rate, reduce cell membrane expression of CaL-α1C mRNA and enhance the expression of KATP-Kir6.1 mRNA in myocardial ischemia-reperfusion arrhythmic rats. ConclusionTotal flavonoids from Ganshanbian (Herba Hyperici Attenuati) can alleviate arrhythmias by affecting the expression of L-type calcium channels and ATP-sensitive K+ channels.

PM376 Direct phosphorylation of the human cardiac L-type calcium channel alpha subunit by cAMP-dependent protein kinase alters function

PM376 Direct phosphorylation of the human cardiac L-type calcium channel alpha subunit by cAMP-dependent protein kinase alters function

Co-localization of L-type voltage dependent calcium channel alpha 1D subunit (Cav1.3) and calbindin (CB) in the mouse central nervous system

Previous study has shown that the co-localization of calbindin (CB) with L-type voltage dependent Ca2+ channel (VDCC) alpha 1C subunit (Cav1.2) in the rat insulinoma 1046-38 (RIN) beta cells may play an important regulatory role in Ca2+ influx and exocytosis of insulin granules. In the present study, L-type voltage dependent Ca2+ channel (VDCC) and calbindin (CB) were demonstrated in different regions of the mouse central nervous system (CNS). Double labeling immunofluorescence staining showed a co-localization of Cav1.3 and CB. The co-localization of Cav1.3 and CB in certain brain regions such as the hippocampus suggests their important roles in neuroplasticity. The relative high percentages of co-localization of Cav1.3 with CB in the laminae II of the dorsal horn of the spinal cord indicate that the regulation mechanism of nociceptive transmission may be related with both VDCC and Ca2+ binding protein.

Abstract 353: Clinical Significance of Low Normal Serum Potassium Concentrations in the Diagnosis of Aldosterone Producing Adenoma

Introduction The number of PA patients is gradually increasing, because screening has been become active in general clinicians. Plenty of patients with PA, however, still have been undiagnosed and threatened by cardiovascular morbidities. Especially, patients with Aldosterone Producing Adenoma(APA) should be screened as early as possible to prevent from them. Therefore, we believed that useful marker not to miss APA has been hoped by general clinicians. Recent studies showed that serum potassium (sK) showed significantly lower in APA than in primary hypertension (PH), although the prevalence of hypokalemia is getting lower than previous in PA patients. In the present study, we retrospectively investigated to find the optimal cut-off value (CV) of sK among all hypertensive patients referred to our hospital for detecting APA, on the hypothesis that it might be significantly lower in APA than in PH instead of the administration of any hypertensive agents. Patients All 169 patients undergone adrenal vein sampling and diagnosed with APA by pathological exams after surgery were recruited. PA was screened by elevated value of ARR (&gt;20; PAC in ng/dl and PRA in ng/ml/hr) at baseline, and diagnosis was confirmed by the elevated ARR(&gt;20) after loading captopril. PH (n=194) was defined as below 20 of baseline ARR and ruled out other secondary hypertensions. Study protocol Patients were compared their parameters in each combination of agents shown as next. 1. All agents. 2. Only ACE-I and/or ARB were essentially included. 3. Diuretics and beta blockers were included in addition to agents of Study 2. In each study, Calcium channel blockers and alpha blockers were optionally allowed. ROC curve analysis was performed for each study. Results 1. The best CV was 28.1 in ARR. The sensitivity (SE) and specificity (SP) were 86% and 85%, respectively. 2. The best CV was 3.7mM in sK. SE and SP were 83% and 98%, respectively. 3. The best CV was 3.8mM in sK. SE and SP were 79% and 91%, respectively. In each study, the rate of above 140 mM in serum sodium (sNa) was 98%(165 of 169), 97%(29 of 30), and 98%(65 of 66), respectively. Conclusion For effective detection of APA, we propose that patients whose sK are below 3.8mM and sNa are above 140mM with ACE-I/ARB treatments should be referred to special clinicians.

Evidence-based pharmacological management of chronic neuropathic pain

Neuropathic pain (NP) is a chronic, debilitating symptomatology of lesions/injuries of the central and peripheral nervous system. As per pooled estimates, the prevalence is 7-8% in the general population; however, the prevalence varies with different neuropathic conditions. The aetiology can range from peripheral neuropathic conditions viz. peripheral diabetic neuropathic pain (PDNP), post-herpetic neuralgia (PHN), trigeminal neuralgia, HIV- associated polyneuropathy, cervical radiculopathy to central neuropathic conditions, viz. central post-stroke pain, spinal cord injury and the neuropathic pain associated with multiple sclerosis. Apart from the symptomatic perception of pain, neuropathic pain affects the cognitive and emotional aspects of the affected individual. The pain, being debilitating and resistant to over-the-counter analgesics, diminishes the quality of life, disrupts sleep and leads to psychiatric complications such as comorbid anxiety and depression. The management is palliative and involves drugs, psychological intervention, stimulations and nerve-blocking techniques. This review concentrates on the pharmacological therapeutic options available and focuses on the selection of the agent/s in accordance with the evidence. The first-line treatment includes the tricyclic antidepressants ([ TCAs]; amitriptyline, nortriptyline), selective serotonin norepinephrine inhibitors ([SNRIs]; duloxetine, venlafaxine), calcium channel alpha 2 - delta ligands (pregabalin, gabapentin), carbamazepine and oxcarbazepine. Lidocaine plasters are first-line options for specific focal conditions such as post-herpetic neuralgia. The second-line therapy includes the opioid analgesics and tramadol. The choice of drug selection should complement the patient’s age, type of neuropathic condition, tolerability to an agent, comorbid condition and cost-effectiveness. Management must be individualized with a realistic and composite goal of making the pain tolerable and improving the cognitive and emotional well-being.

Determining the Site of Phosphorylation on the Human Cardiac L-type Calcium Channel Alpha Subunit by cAMP-Dependent Protein Kinase

Determining the Site of Phosphorylation on the Human Cardiac L-type Calcium Channel Alpha Subunit by cAMP-Dependent Protein Kinase

Application of pregabalin in controlling postherpetic neuralgia

Postherpetic neuralgia (PHN) refers to a painful condition that persists for 4 weeks after the rash of shingles has gone away.The incidence of PHN is age-related.PHN may feel like a burning pain,electric shock,knifelike pain,paresthesia,etc.It often affects the quality of life of patients from the aspects of sleep,emotion,and so on.Pregabalin,a new type of gamma-aminobutyric acid receptor agonist,can control PHN via binding to the calcium channel alpha 2-delta type 1 subunit in the central nervous system,altering the conformation of alpha 2-delta subunit,and thereby restoring the calcium channel to nearly normal level.Both flexible- and fixed-dose of pregabalin for 4 to 12 weeks have been reported to be markedly effective for the control of PHN and improvement of patients' quality of life.Long-term pregabalin exhibits good tolerability and few drug interactions. Key words: Pregabalin; Neuralgia, postherpetic; Research

Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational 'hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.

Treatment of central sensitization in patients with ‘unexplained’ chronic pain: what options do we have?

Introduction: Central sensitization accounts for chronic ‘unexplained’ pain in a wide variety of disorders, including chronic whiplash-associated disorders, temporomandibular disorders, chronic low back pain, osteoarthritis, fibromyalgia, chronic fatigue syndrome and chronic tension-type headache among others. Given the increasing evidence supporting the clinical significance of central sensitization in those with unexplained chronic pain, the awareness is growing that central sensitization should be a treatment target in these patients.Areas covered: This article provides an overview of the treatment options available for desensitizing the CNS in patients with chronic pain due to central sensitization. It focuses on those strategies that specifically target pathophysiological mechanisms known to be involved in central sensitization. In addition, pharmacological options, rehabilitation and neurotechnology options are discussed.Expert opinion: Acetaminophen, serotonin-reuptake inhibitor drugs, selective and balanced serototin and norepinephrine-reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, N-methyl-d-aspartate (NMDA)-receptor antagonists, calcium-channel alpha(2)delta (a2δ) ligands, transcranial magnetic stimulation, transcutaneous electric nerve stimulation (TENS), manual therapy and stress management each target central pain processing mechanisms in animals that – theoretically – desensitize the CNS in humans. To provide a comprehensive treatment for ‘unexplained’ chronic pain disorders characterized by central sensitization, it is advocated to combine the best evidence available with treatment modalities known to target central sensitization.

Pharmacologic Management of Chronic Pain

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel α2-δ ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.

Traitements pharmacologiques actuels, recommandations et perspectives

Over the last few years, an international consensus has been reached for the treatment of chronic neuropathic pain. On the basis of randomized clinical trials, medications recommended for neuropathic pain include antidepressants (tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine), calcium channel alpha 2-delta ligands (i.e., gabapentin and pregabalin), topical lidocaine and opioids. The recommendations for clinical practice proposed by the French Society of Pain include a therapeutic algorithm and criteria for referral patient to a pain clinic by general practitioners. Current therapeutic perspectives include the development of drugs acting on novel targets as well as the pharmacological prevention of postoperative neuropathic pain.

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Cloning and characterization of voltage‐gated calcium channel alpha1 subunits in Xenopus laevis during development

Voltage-gated calcium channels play a critical role in regulating the Ca2+ activity that mediates many aspects of neural development, including neural induction, neurotransmitter phenotype specification, and neurite outgrowth. Using Xenopus laevis embryos, we describe the spatial and temporal expression patterns during development of the 10 pore-forming alpha1 subunits that define the channels' kinetic properties. In situ hybridization indicates that CaV1.2, CaV2.1, CaV2.2, and CaV3.2 are expressed during neurula stages throughout the neural tube. These, along with CaV1.3 and CaV2.3, beginning at early tail bud stages, and CaV3.1 at late tail bud stages, are detected in complex patterns within the brain and spinal cord through swimming tadpole stages. Additional expression of various alpha1 subunits was observed in the cranial ganglia, retina, olfactory epithelium, pineal gland, and heart. The unique expression patterns for the different alpha1 subunits suggests they are under precise spatial and temporal regulation and are serving specific functions during embryonic development.