In recent years there has been more focus on investigating sex differences across all medical fields, including cardiology. There are sex differences in disease presentation, treatment and baseline function. These differences are critical to understand in order to properly treat both men and women. Even with an increased focus on this field, research has a male bias and there is more work to be done. Cardiac conduction is a highly synchronized process. Electrical signals are passed cell to cell through two mechanisms, ephaptic coupling and gap junctional coupling. These methods of electrical communication rely on gap junctions, sodium channels and the perinexus. When conduction is disrupted it causes arrhythmias. When investigating these three critical determinants of cardiac conduction in guinea pig hearts, we determined that there are sex differences in two of three investigated determinants. It appears that females are more susceptible to sodium channel modulation while males are more susceptible to gap junction modulation. Understanding these differences is critical to clinical care. It has been shown that females have higher mortality following cardiothoracic surgery and the reason for this is unknown. During cardiothoracic surgery the heart is arrested and maintained by a fluid, cardioplegia solution. Cardioplegia solutions contain components that are known to modulate conduction. We investigated the sex differences in cardiac electrophysiology with a focus on cardiac conduction and components of a common cardioplegia solution; we determined that there are electrophysiologic sex differences in response to both magnesium and mannitol. The sex substrates in three of the major determinants of conduction (sodium channels, gap junctions and perinexal width) and the differences in the effects of cardioplegia components on males and females may help to explain the higher mortality of females post cardiothoracic surgery. / Master of Science / In recent years there has been more focus on investigating sex differences across all medical fields, including cardiology. There are sex differences in disease presentation, treatment and baseline function. These differences are critical to understand in order to properly treat both men and women. Even with an increased focus on this field, research has a male bias and there is more work to be done. Cardiac conduction is a highly synchronized process. Electrical signals are passed cell to cell through two mechanisms, ephaptic coupling and gap junctional coupling. These methods of electrical communication rely on gap junctions, sodium channels and the perinexus. When conduction is disrupted it causes arrhythmias. When investigating these three critical determinants of cardiac conduction in guinea pig hearts, we determined that there are sex differences in two of three investigated determinants. It appears that females are more susceptible to sodium channel modulation while males are more susceptible to gap junction modulation. Understanding these differences is critical to clinical care. It has been shown that females have higher mortality following cardiothoracic surgery and the reason for this is unknown. During cardiothoracic surgery the heart is arrested and maintained by a fluid, cardioplegia solution. Cardioplegia solutions contain components that are known to modulate conduction. We investigated the sex differences in cardiac electrophysiology with a focus on cardiac conduction and components of a common cardioplegia solution; we determined that there are electrophysiologic sex differences in response to both magnesium and mannitol. The sex substrates in three of the major determinants of conduction (sodium channels, gap junctions and perinexal width) and the differences in the effects of cardioplegia components on males and females may help to explain the higher mortality of females post cardiothoracic surgery.

Thesis--Copenhagen University. / Summary in Danish. Bibliography: p. 153-161.

Ventricular arrhythmias are difficult to study in man. The current experimental models are arrhythmias induced by electrical stimulation, coronary artery ligation or by subsequent reperfusion. An electrophysiological model will be useful for exploring the cellular mechanism of arrhythmias and for studying the mechanism of action of new anti-arrhythmic drugs. This project seeks to establish automaticity as a model for studying ventricular arrhythmias. Objectives 1. To review the literature on the mechanism of ventricular arrhythmias. 2. To explore ventricular automaticity induced by "reperfusion" after O₂ and substrate deprivation. 3 . To explore beta-adrenoceptor mediated ventricular automaticity. 4 . To evaluate possible new anti-arrhythmic drugs, carminomycin and ketanserin.

Stimulation of cardiac β-adrenoceptors is the primary mechanism by which cardiac output is increased to meet metabolic demands of the body. Recently, nicotinic acid adenine dinucleotide phosphate (NAADP), has been implicated as a novel component of the β-adrenoceptor signalling pathway. NAADP is thought to mobilise Ca²⁺ from acidic endolysosomal stores which then supplements sarcoplasmic reticulum Ca²⁺ load, leading to a positive inotropic effect. Recent progress in the field has been made with the identification of two-pore channel 2 (TPC2) as a candidate NAADP receptor. Isolated ventricular myocytes from mice lacking TPC2 proteins (Tpcn2^-/-) displayed blunted maximal responses to the β-adrenoceptor agonist isoprenaline. This blunted response was also evident in Langendorff-perfused Tpcn2^-/- hearts. Furthermore, a blunted response was observed in guinea pig ventricular myocytes which had been treated with bafilomycin A1, which disrupts the integrity of acidic endolysosomal stores. These data add to the body of evidence that NAADP signalling forms an important additional component of the β-adrenoceptor signalling pathway. Chronic activation of the β-adrenoceptor pathway is associated with certain disease states including heart failure and arrhythmias. Anandamide is an endogenous cannabinoid, ('endocannabinoid'), with similar properties to δ⁹-tetrahydrocannabinol (δ⁹-THC), the primary active constituent of Cannabis sativa. These compounds have widespread physiological effects through actions at cannabinoid CB₁ and CB₂ receptors, which are negatively coupled to adenylyl cyclases and are expressed in cardiac muscle. Exposure of guinea pig ventricular myocytes to anandamide resulted in a reduction in the amplitude of contractions and Ca²⁺ transients. This was associated with a reduction in action potential duration and amplitude of I_CaL. These effects of anandamide could not be prevented by cannabinoid receptor antagonists, and could not be mimicked by cannabinoid receptor agonists. An inhibition of IKs was also observed. Given the reported Gi-protein coupling of cannabinoid receptors, it may be expected that additional negative inotropic actions of anandamide might be observed when adenylyl cyclases are stimulated. However, the effects of anandamide to reduce amplitude of contraction and I_CaL were no greater in the presence of isoprenaline. Furthermore, the effects of anandamide were not prevented by pre-treatment of myocytes with pertussis toxin (PTX). This is in contrast to the actions of adenosine, which displayed clear PTX sensitive actions in the presence of isoprenaline. These data suggest that cannabinoid receptors are not involved in mediating the negative inotropic actions of anandamide. Another endocannabinoid, 2-arachidonoylglycerol, was without significant effect on action potentials or contractions in the absence or presence of isoprenaline. δ⁹-THC shared many of the actions of anandamide. It appears that anandamide and δ⁹-THC exert significant effects on cardiac muscle through direct modulation of ion channel function, although additional actions, for example, on the sarcoplasmic reticulum or myofilaments, cannot be ruled out.

No description available.

No description available.

The hippocampus contains more than 21 types of inhibitory interneurons that express different proteins and innervate different sub-domains of pyramidal cells to regulate the spatiotemporal integration of excitatory postsynaptic potentials (EPSPs) and to define temporal windows for spiking. Neurogliaform cells (NGFCs), form synapses on the distal tufts of pyramidal cell apical dendrites alongside excitatory inputs from the entorhinal cortex. NGFCs express neuronal nitric oxide synthase (nNOS), are often synaptically coupled, and fire rhythmically during theta oscillations in vivo. In this thesis, I describe a novel form of synaptic communication between these interneuron types, hereafter referred to as the firing induced suppression of inhibition (FSI). Specifically, I found that when a theta-associated activity patterns were evoked in NGFCs from rodent hippocampal slices, the cells exhibited a transient reduction in unitary IPSP amplitude. My data suggest that FSI requires the backpropagation of action potentials, calcium influx through L-type calcium channels, nNOS activity within the dendrites of interneurons, and the activation of NO-sensitive guanylyl cyclase (NOsGC) receptors that are present on presynaptic terminals. My results also demonstrate the physiological impact of this phenomenon by showing that when FSI occurs, the strength of incoming excitatory postsynaptic potentials onto NGFCs are transiently sharpened. Specifically, FSI indirectly increased the amplitude of EPSPs. Thus FSI may enhance spatial and temporal summation of excitatory inputs to NGFCs and regulate their inhibition of pyramidal cells.

Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects an estimated 33.5 million people worldwide. Despite its prevalence and economic burden, treatments remain relatively ineffective. Interventional treatments using catheter ablation have shown more success in cure rates than pharmacologic methods for AF. However, success rates diminish drastically in patients with more advanced forms of the disease. The focus of this research is to develop a mapping strategy to improve the success of ablation. To achieve this goal, I used a computational model of excitation in order to simulate atrial fibrillation and evaluate mapping strategies that could guide ablation. I first propose a substrate guided mapping strategy to allow patient-specific treatment rather than a one size fits all approach. Ablation guided by this method reduced AF episode durations compared to baseline durations and an equal amount of random ablation in computational simulations. Because the accuracy of electrogram mapping is dependent upon catheter-tissue contact, I then provide a method to identify the distance between the electrode recording sites and the tissue surface using only the electrogram signal. The algorithm was validated both in silico and in vivo. Finally, I develop a classification algorithm for the identification of activation patterns using simultaneous, multi-site electrode recordings to aid in the development of an appropriate ablation strategy during AF. These findings provide a framework for future mapping and ablation studies in humans and assist in the development of individualized ablation strategies for patients with higher disease burden.

The entorhinal cortex (EC) is a vital structure in the mammalian brain, implicated in the processes of learning and memory, and a possible site for the generation of seizures in temporal lobe epilepsy. Neurones in the EC are constantly bombarded with inhibitory and excitatory neurotransmitter. This background activity is thought to exert significant control on the excitability and function of neurones in cortical networks, with changes in the levels and proportion of background inhibition (IBg) and excitation (EBg) driving rhythmic oscillations in membrane potential, and even underlying the generation of epileptic seizures.

acase@tulane.edu / 1 / Jeremiah Hartner