Ionic transfer in cardiac muscle. An explanation of cardiac electrical activity

The evidence has been reviewed which suggests that the upstroke of the action potential in heart muscle is due to the entry of sodium ions. This conclusion is based on the failure of the upstroke to occur if 90 per cent of the sodium is replaced by sucrose, and the demonstration of a reduction in amplitude of the rising phase of the action potential with each decrement in extracellular sodium concentration or an increase in amplitude with increasing extracellular sodium concentration. In addition, the demonstration of a change in membrane resistance of one-hundred-fold at the time of the rising phase suggests increased permeability of the membrane at this time.The voltage-clamp studies in the squid giant axon clearly show an inward movement of current during the rising phase, which disappears when choline replaces sodium in the perfusing bath.The resting membrane potential resembles the model of a potassium and chloride concentration cell, since calculations based on measured concentrations across the membrane agree fairly closely with measured potentials. Furthermore, the membrane resting potential is altered in a predictable manner by changed extracellular potassium and chloride concentration, but is not appreciably affected by changing sodium concentration. Since the skeletal muscle membrane appears to be freely permeable to chloride, and only sparingly so to potassium, and since potassium permeability is selectively altered during the electrical cycle, the chloride ionic concentration gradient is probably dependent on the transmembrane potential, and, therefore, is passive. The current carried by the chloride ion in cardiac fibers is small.Little is known of the factors which alter membrane permeability or affect the transfer rates during recovery, but it is apparent that sodium is removed from the cell after the rising phase and is replaced by potassium to restore membrane resting potential.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32171/1/0000226.pd

The use of potassium in the treatment of heart disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32003/1/0000045.pd

An experimental study of the electromotive forces of the heart

Propagated wavefronts were produced by mechanical stimulation at points located deeply within the myocardium, and the external field so produced was measured by electrodes located within a radius of 10 mm. from the centrally stimulated point. In 104 experiments in 10 dogs the external field so produced was negligible until propagation reached either the epicardial or endocardial surfaces. If it is assumed that propagated intramural activity is temporarily a closed electromotive surface, then the data presented suggest that there is a uniform difference in potential across this surface. Since there is no fundamental difference in the wavefront characteristics of closed electromotive surfaces and those which present boundaries on the epicardial or endocardial surfaces, these data strongly suggest that there is a uniform difference in potential across all propagated wavefronts in normal ventricular muscle.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32059/1/0000103.pd

Clinical evaluation of glucagon by continuous infusion in the treatment of low cardiac output states

A continuous infusion of glucagon in an average dose of 4 mg. per hour over several days produced distinct improvement in the clinical state of 12 of 16 patients. Improvement was noted by an increase in blood pressure and urinary output and decrease in dyspnea, pulmonary rales, diaphoresis, and peripheral edema when present. Serum potassium must be carefully monitored. The rise in blood glucose has not been a clinical problem. No cardiac arrhythmias were induced by glucagon, and as cardiac function improved, the heart rate usually decreased. Nausea was the most frequent side effect, but no toxic effects or tachyphylaxis were observed. Long-term therapy with glucagon infusion is both safe and highly efficacious in selected patients with severe cardiovascular disease states and is the treatment of choice in cardiac decompensation secondary to beta-blocking agents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32778/1/0000151.pd

A clinical trial of antazoline in the treatment of arrhythmias

Antazoline is a comparatively safe and effective antiarrhythmic drug in many situations, for both the conversion and prevention of arrhythmias. It appeared to be most effective in the abolition of ventricular tachycardia, possibly helpful in 2 cases of cardiac arrest due to ventricular fibrillation and beneficial in the prevention of atrial and ventricular premature beats. It was useful and deserves further trial in the prevention of paroxysmal ventricular tachycardia. It was almost ineffective in the conversion and prophylaxis of atrial flutter and atrial fibrillation but appeared to be of value in the prevention of paroxysmal atrial tachycardia.There was a high incidence of mild side effects, mostly of the gastrointestinal type, some of which were prevented by taking the drug with meals or with an antacid preparation. No irreversible or serious side actions were encountered, but diarrhea, central nervous system symptoms and chills and fever necessitated stopping the drug in a small percentage of patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32096/1/0000146.pd

P50, the Small Subunit of DNA Polymerase Delta, Is Required for Mediation of the Interaction of Polymerase Delta Subassemblies with PCNA

Mammalian DNA polymerase δ (pol δ), a four-subunit enzyme, plays a crucial and versatile role in DNA replication and various DNA repair processes. Its function as a chromosomal DNA polymerase is dependent on the association with proliferating cell nuclear antigen (PCNA) which functions as a molecular sliding clamp. All four of the pol δ subunits (p125, p50, p68, and p12) have been reported to bind to PCNA. However, the identity of the subunit of pol δ that directly interacts with PCNA and is therefore primarily responsible for the processivity of the enzyme still remains controversial. Previous model for the network of protein-protein interactions of the pol δ-PCNA complex showed that pol δ might be able to interact with a single molecule of PCNA homotrimer through its three subunits, p125, p68, and p12 in which the p50 was not included in. Here, we have confirmed that the small subunit p50 of human pol δ truthfully interacts with PCNA by the use of far-Western analysis, quantitative ELISA assay, and subcellular co-localization. P50 is required for mediation of the interaction between pol δ subassemblies and PCNA homotrimer. Thus, pol δ interacts with PCNA via its four subunits

Evaluation of propranolol and quinidine in the treatment of quinidine-resistant arrhythmias

Combining propranolol and quinidine should improve the antiarrhythmic action of quinidine by blocking beta adrenergic receptors, an action helpful in cases of arrhythmias associated with anesthetic agents, digitalis and stress. To test this hypothesis, 60 patients with paroxysmal arrhythmias resistant to quinidine and 17 with chronic atrial fibrillation were given propranolol alone or in combination with quinidine (or procainamide) and followed up 1 to 17 months. Patients with severe aortic valve disease, severe mitral insufficiency, acute myocardial infarction or obstructive airway diseases were excluded from this study. The condition of 13 of 19 patients with paroxysmal atrial or nodal tachycardia was improved. In paroxysmal ventricular tachycardia combined therapy or propranolol alone was effective in 11 of 14 patients. Paroxysmal atrial flutter or fibrillation was suppressed in 11 of 16 patients, with a 75 percent or greater reduction in attacks. Prophylaxis of chronic atrial fibrillation terminated by drugs or by electroshock was effective in 9 of 11 patients (15 trials) followed up for 7 months. Sustained atrial fibrillation was terminated with propranolol, 40 to 160 mg, and quinidine sulfate, 1.2 to 1.6 g/day, in 41 percent of patients, a result no better than with propranolol alone. Propranolol slowed the ventricular rate in normal sinus rhythm as well as in atrial fibrillation and flutter. Significant slowing, although it was less in magnitude, occurred with the combination of propranolol and quinidine. It is concluded that propranolol potentiates quinidine and allows effective prophylaxis of atrial, nodal and ventricular arrhythmias in quinidine-resistant patients. Diarrhea was the only side effect peculiar to the combination of drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33712/1/0000224.pd

Mechanisms of onset and termination of abnormal cardiac rhythm studied by constant monitoring,

Digitalis accelerated the rate in atrial flutter resulting in atrial fibrillation, whereas the addition of quinidine slowed the atrial rate producing either asystole or interference dissociation. In some patients receiving both digitalis and quinidine, the atrial rate showed less of a tendency to slow or actually increased, resulting in atrial fibrillation followed by normal sinus rhythm. This suggests an overriding effect of digitalis.Since the spontaneous termination of atrial flutter occurred in unknown circumstances that usually slowed the atrial rate and asystole was observed, this suggests that asystole is not a toxic effect of quinidine.Atrial flutter, fibrillation, and atrial premature beats began more commonly in the P-T cycle than in the T-P cycle. Since atrial recovery is more likely incomplete during the P-T cycle, this favors reentry as the underlying mechanism in the patient studied.Atrial and nodal tachycardia begin with an irregular sequence of premature beats before a stable tachycardia is established. There is usually a significant slowing of the rate prior to termination of the abnormal rhythm. Sinus arrest with ventricular escape is the usual method of termination, regardless of the form of therapy used. Bursts of rapid ventricular rhythm resembling ventricular tachycardia were seen only after the use of pressor agents.Atrial tachycardia with block treated with digitalis shows an initial atrial slowing but, as the dose of digitalis was raised in one patient, abrupt increases in atrial rate occurred until the rhythm terminated. This is a mechanism similar to that seen in the digitalis-induced termination of atrial flutter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33279/1/0000671.pd

3D structures of individual mammalian genomes studied by single-cell Hi-C

The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes. We have calculated the first 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. This has allowed us to study genome folding down to a scale of <100 kb and to validate the structures. We show that the structures of individual topological-associated domains and loops vary very substantially from cell-to-cell. By contrast, A/B compartments, lamin-associated domains and active enhancers/promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. Through studying pluripotency factor- and NuRD-regulated genes, we illustrate how single cell genome structure determination provides a novel approach for investigating biological processes