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Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation- contraction coupling in mice. Mice with forced skipping of exon 29 in the [Ca.sub.V]1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The [Ca.sup.2+]/[Cl.sup.- ] bi- channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that [Ca.sup.2+]/[Cl.sup.-] bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers., Introduction Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder characterized by myotonia, progressive weakness, heart block, gastrointestinal dysmotility, predisposition to malignancy, and other symptoms (1). Survival is limited [...]

Byline: S. Lakshmikanthcharan, Mohamed. Hisham, S. Chaitanya Juluri, Sivakumar. Nandakumar Almost one-third of the people suffering from epilepsy continue to have seizures in spite of using appropriate antiepileptics. Pharmacoresistance is [...]

ABSTRACT P-glycoprotein-mediated drug efflux can cause a multidrug resistance (MDR) phenotype that is associated with a poor response to cancer chemotherapy. Through bioassay-guided fractionation, active Stemona alkaloids were isolated from [...]

Many cardiac interventional procedures, such as coronary angioplasty, stenting, and thrombolysis, attempt to reintroduce blood flow (reperfusion) to an ischemic region of myocardium. However, the reperfusion is accompanied by a complex cascade of cellular and molecular events resulting in oxidative damage, termed myocardial ischemia-reperfusion (I/R) injury. In this study, we evaluated the ability of HO-4038, an N-hydroxypiperidine derivative of verapamil, on the modulation of myocardial tissue oxygenation ([Po.sub.2]), I/R injury, and key signaling molecules involved in cardioprotection in an in vivo rat model of acute myocardial infarction (MI). MI was created in rats by ligating the left anterior descending coronary artery (LAD) for 30 min followed by 24 h of reperfusion. Verapamil or HO-4038 was infused through the jugular vein 10 min before the induction of ischemia. Myocardial [Po.sub.2] and the free-radical scavenging ability of HO-4038 were measured using electron paramagnetic resonance spectroscopy. HO-4038 showed a significantly better scavenging ability of reactive oxygen radicals compared with verapamil. The cardiac contractile functions in the I/R hearts were significantly higher recovery in HO-4038 compared with the verapamil group. A significant decrease in the plasma levels of creatine kinase and lactate dehydrogenase was observed in the HO-4038 group compared with the verapamil or untreated I/R groups. The left ventricular infarct size was significantly less in the HO-4038 (23 [+ or -] 2%) compared with the untreated I/R (36 [+ or -] 4%) group. HO-4038 significantly attenuated the hyperoxygenation (36 [+ or -] 1 mmHg) during reperfusion compared with the untreated I/R group (44 [+ or -] 2 mmHg). The HO-4038-treated group also markedly attenuated superoxide production, increased nitric oxide generation, and enhanced Akt and Bcl-2 levels in the reperfused myocardium. Overall, the results demonstrated that HO-4038 significantly protected hearts against I/R-induced cardiac dysfunction and damage through the combined beneficial actions of calcium-channel blocking, antioxidant, and prosurvival signaling activities. nitroxide; Akt; oxygenation

In this study we tested the hypothesis that ventricular homeostasis of L-type [Ca.sup.2+] current ([I.sub.Ca,L]) minimally involves regulation of the main pore-forming [alpha]-subunit (Cav1.2) and auxiliary proteins that serve as positive or negative regulators of [I.sub.Ca,L]. We treated animals for 24 h with verapamil (Ver, 3.6 mg * [kg.sup.-1] [day.sup.-1]), isoproterenol (Iso, 30 mg * [kg.sup.-1] * [day.sup.-1]), or Iso + Ver via osmotic minipumps. To test for alterations of [Ca.sup.2+] channel complex components we performed real-time PCR and Western blot analysis on ventricle. In addition, cardiac myocytes (CMs) were dispersed and current was recorded in the whole cell configuration to evaluate [I.sub.Ca.L] Surprisingly, 24- to 48-h Ver increased Cav1.2 mRNA and protein and [I.sub.Ca.L] current (Ver 11 [+ or -] 1pA/pF vs. control 7 [+ or -] 0.5pA/pF; P < 0.01). [I.sub.Ca,L] from CMs in Ver mice showed no change in whole cell capacitance. To examine the in vivo effects of a physiologically relevant [Ca.sup.2+] channel agonist, we treated mice with Iso. Twenty-four-hour Iso infusion increased heart rate; Cav1.2- and [Ca.sub.v][[beta].sub.2] mRNA levels were constant, but the [Ca.sup.2+] channel subunit mRNA Rem was increased twofold. Cells isolated from 24-h Iso hearts showed no change in basal [I.sub.Ca,L] density and diminished responsiveness to acute 1 [micro]M Iso. To further examine the homeostatic regulation of the [Ca.sup.2+] channel, we treated animals for 24 h with Iso + Ver. The influence of Iso + Ver was similar that of to Iso alone on [Ca.sup.2+] channel mRNAs and [I.sub.Ca,L], with the exception that it prevented the increase in Rem seen with Iso treatment. Long-term [Ca.sup.2+] channel blockade induces an increase of Cav1.2 mRNA and protein and significantly increases [I.sub.Ca,L]. calcium channel blockade; ventricle; electrocardiogram; electrophysiology

Byline: E. R. Sharifullina (1), R. A. Afzalov (1), M. V. Talantova (1), F. Vyskochil (1), R. A. Giniatullin (1) Keywords: verapamil; cholinoreceptors; desensitization; calcium channels Abstract: Experiments on the frog sartorius muscle were used to study the effects of the L-type calcium channel blocker verapamil on endplate currents. Verapamil had no effect on the amplitudes of miniature and multiple-quantum endplate currents, the synchronicity of transmitter secretion, or repeat activity in nerve endings. Verapamil had no effect on the decay of miniature currents, but accelerated that of multiple-quantum currents. This effect was sharply increased after inhibition of cholinesterase activity. In conditions of inhibited cholinesterase activity, verapamil depressed currents during rhythmic stimulation. This depression was more marked in synapses with high quantal compositions and in conditions of membrane depolarization. Thus, the sensitivity of neuromuscular junction calcium channels to verapamil was unrelated to the release of transmitter from the motor nerve ending either at physiological levels of secretion or when secretion was potentiated by potassium channel blockers. At the postsynaptic level, the effect of verapamil was insignificant in relation to cholinoreceptors in the resting and active states, though verapamil could cooperatively enhance the transition of postsynaptic receptors into the desensitized state in conditions of prolonged transmitter action. Author Affiliation: (1) Department of Normal Physiology, Kazan', State Medical University, 49 Butlerov Street, 420012, Kazan', Russia Article History: Registration Date: 10/10/2004

Byline: Shazia Afridi (1), Chris M. Bacon (2), Jonathan Bowling (3), Peter J. Goadsby (1) Author Affiliation: (1) Headache Group Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK (2) Department of Histopathology, University College London Hospitals, London, UK (3) Department of Dermatology, University College London Hospitals, London, UK Article History: Registration Date: 01/01/2004 Received Date: 27/06/2003 Accepted Date: 18/09/2003

Verapamil, a drug that blocks the influx of calcium into cardiac muscle cells, is commonly prescribed as an antiarrhythmic agent. This drug is considered quite safe and lacking in side effects, but occasional reports of verapamil overdose have been published. A case is described of a previously healthy 33-year-old white male who was hospitalized 20 minutes after ingesting 52 verapamil tablets (80 milligrams per tablet) in a suicide attempt. He was initially treated with gastric lavage, injection of activated charcoal (to complex with the drug, rendering it inactive) and ipecac (to induce vomiting). The patient's cardiovascular status began to deteriorate, and analysis of blood chemistry indicated high glucose levels, significant hypokalemia (low potassium levels), and verapamil levels 10 to 40 times higher than therapeutic levels. Various types of drug therapy were attempted to no avail. Transvenous pacing electrodes were inserted to electrically drive the heart, but the ventricle could not be induced to contract reliably. Two hours after verapamil ingestion, the patient had no pulse; the thorax was opened, and electrical stimulation was applied directly to the heart in an effort to induce contraction; this was not successful. Despite all efforts, the patient died within three hours of overdose. There have been a total of 15 case reports of verapamil overdosage; this is the first to report dramatic decreases in potassium levels. Decreased potassium may have contributed to the toxic effects of the drug by altering the electrical properties of the conduction system of the heart. If this is so, administration of potassium supplements should prove beneficial in treating verapamil overdose. (Consumer Summary produced by Reliance Medical Information, Inc.)

Byline: F. Margaret Shanthi, Kalpana. Ernest, Prema. Dhanraj Background : The calcium channel blocker, verapamil stimulates procollagenase synthesis in keloids and hypertrophic scars. Aim : To study the effect of [...]

Ventricular tachycardia (VT), rapid heart rate produced by pathology of the ventricle, is a serious problem that is often associated with improper filling of the heart chambers and severely impaired hemodynamic (blood flow patterns) functioning. One irregularity that is seen clinically is wide QRS tachycardia, which may be associated with a stable hemodynamic situation. Wide QRS refers to a relatively increased length of electrical activity (greater than 0.14 seconds) in the phase identified on an electrocardiogram as the QRS complex, which reflects the muscular contraction of the ventricle. A generally held misconception, which in turn has led to misdiagnosis, is that VT must lead to circulatory collapse. To examine the association of hemodynamic stability in patients with wide QRS tachycardia, 20 consecutive patients were examined. Eighty-five percent of patients were found to have VT. As a result of this study, until proven otherwise, patients with wide QRS tachycardia should be regarded as being in VT and appropriate therapy for this condition should be instituted. Failure by physicians to understand that a wide QRS tachycardia is associated with ventricular difficulties may lead to improper treatment that can severely and adversely affect a patient's condition. Electrophysiologic testing has been shown to be of particular value in establishing this diagnosis., ABSTRACT: Hemodynamic stability during wide QRS tachycardia is commonly, albeit erroneously, taken as evidence for a supraventricular mechanism. To determine the magnitude for potential misdiagnosis in applying this notion clinically, we analyzed 20 consecutive cases of regular wide QRS tachycardia in conscious adult patients (mean age, 64 years). The most common heart disease was atherosclerotic (75%), with an associated history of remote myocardial infarction in 73% of the cases. Tachycardia was sustained for a mean of 4.8 hours prior to medical evaluation, with a mean rate of 186 beats per minute and mean systolic blood pressure of 111 mm Hg. A diagnosis of ventricular tachycardia (VT) was established in 17 cases (85%). In the patients with VT, atrioventricular dissociation was recognized on the 12-lead electrocardiogram in 38%, with Wellens&apos; morphological features favoring the diagnosis in 73%. Following conversion to sinus rhythm, electrophysiological testing in 17 patients reproduced the clinical arrhythmia in 94% (with a replication rate of 100% in 15 patients with VT), with at least one additional unsuspected VT morphology induced in 53% of patients with VT. Thus, VT should be considered the most likely cause of regular wide QRS tachycardia in the conscious adult patient, especially with a history of remote myocardial infarction. Recognition of this simple principle and careful examination of the 12-lead electrocardiogram may help to prevent the misapplication of pharmacotherapy in the vast majority of these patients.

Verapamil, a drug that blocks the distribution of calcium into cardiac muscle cells (calcium channel blocker, or calcium antagonist), is commonly prescribed as an antiarrhythmic agent. A side effect of verapamil administration can be hypotension (excessively low blood pressure). A common strategy for preventing verapamil-induced hypotension is pretreatment with calcium. Calcium pretreatment has on occasion been reported to result in relatively minor side effects, such as flushing and a feeling of warmth. A case is reported, apparently the first published incident, in which severe arrhythmia and atrioventricular nodal block (AV block), interruption of the electrical conduction system of the heart, occurred following calcium pretreatment preceding verapamil administration. A 45-year-old woman who had previously been in good health was admitted to the hospital with a 12-hour history of abnormally rapid, fluttering heartbeat. Propranolol (a beta adrenergic receptor blocking agent) was ineffective in normalizing her heart beat, and 1 gram of calcium was administered over a two-minute period in preparation for verapamil treatment. Immediately, the patient reported an intense burning sensation, lightheadedness, and her face and hands became dusky. Blood pressure and heart rate dropped significantly; electrocardiogram revealed electrical abnormalities in the conduction system of the heart. Within two minutes, in the absence of any intervention, heart rate and blood pressure began to return to normal, color improved, and the patient reported an improvement in symptoms. She was admitted to the coronary care unit for overnight observation and discharged the next day. This is the first report of severe cardiac slowing and arrhythmia resulting from calcium treatment. Lower doses, administered over a prolonged period (longer than two minutes) may be just as effective as higher doses, and would result in fewer adverse side effects. (Consumer Summary produced by Reliance Medical Information, Inc.)