In the heart, neuropeptide Y (NPY) released during stimulation of the sympathetic nerve attenuates vagal-evoked bradycardia for a prolonged period. The inhibitory action of NPY is proposed as being Y2 receptor mediated. In rat and mouse, anaesthetised with sodium pentobarbitone, the selective Y2 receptor antagonist BIIE0246 reduced the inhibition of cardiac vagal activity evoked by a Y2 agonist, N-acetyl [Leu28, 31] NPY 24-36. BIIE0246 also reduced the inhibitory effect on vagal action evoked by stimulation of the sympathetic nerve. Deletion of the receptor in Y2 receptor-knockout mice abolished all NPY mediated inhibition of cardiac vagal-evoked bradycardia. These findings strongly support the proposal that NPY released during stimulation of the sympathetic nerve acts via Y2 receptors on the vagus nerve to decrease the slowing effect on the heart evoked by vagal stimulation. Examination of the structural components within NPY, using NPY, related PP peptides and structurally altered analogs, showed proline residues in the N-terminal polyproline region of NPY were found to influence the level of presynaptic activity while residues in the PP fold region further enhanced activity. NPY fragments, as long or longer than 3-36 NPY, possessed full inhibitory activity whereas short C-terminal analogs, such as 24-36 did not. The two leucine residues in agonist N-acetyl [Leu28, 31] NPY 24-36 was found to alter the structure and enhance the amphipathic nature of the a-helix in the shortened fragment. Arginine residues in the helix were also found to be important for activity. The leucine residues in N-acetyl [Leu28, 31] NPY 24-36 are proposed to stabilise the molecule producing an over all linear conformation. Although the conformation adopted by NPY at the receptor is unknown, it is plausible to suggest that the interaction between the proline residues and the a-helix stabilise the molecule in the same way that leucine substitution does in N-acetyl [Leu28, 31] NPY 24-36. Results obtained in Y2 receptor-knockout mice infer by their faster heart rates, an inhibitory role for the receptor in regions of the brain able to effect sympathetic outflow to the heart. Therefore knowledge of the structural requirements required of agonists and antagonists for Y2 receptor activation is likely to be of practical significance in drug design for the treatment of diseases affecting both parasympathetic and sympathetic innervation of the heart.

Thesis (Ph. D.)--University of New South Wales, 2003. / Also available online.

Heart rate was found to be significantly lower in unrestrained diving muskrats than in those which were forced to dive. The response in the unrestrained animal represents a heart rate of about 9% of the resting rate and is similar to the cardiac responses recorded in freely diving pinnipeds. Apnea and bradycardia were initiated by water lapping the nares of the conscious animal. Anaesthesia abolished this narial reflex to submersion. In anaesthetized muskrats water was drawn into the nasal cavity causing transient apnea and prominent bradycardia by stimulating receptors located principally in the glottal and pharyngeal areas. Nerve blockade by reversible cooling and section demonstrated that these nasal receptors are innervated by the maxillary and inferior, laryngeal nerves. In the conscious animal trigeminal neurotomy failed to affect the course of the response confirming that the muskrat has a number of external sensory mechanisms capable of initiating the diving reflexes. Respiratory activity was shown to have a marked effect on heart rate when the muskrat was at rest and when water was passed through the nares. Cardioacceleration during nasal stimulation resulted from a central component and from neural input originating in fast adapting pulmonary receptors. Artificial ventilation not only increased heart rate but often tended to restore normal respiratory activity. Pulmonary deafferentation by steaming eliminated the Hering-Breuer reflex to maintained lung inflation as well as the cardioacceleration seen in response to artificial ventilation during nasal stimulation. The loss of the Hering-Breuer reflex occurred first suggesting that different receptors are involved. Lung deflation per se caused a reflex bradycardia but it appears that this does not potentiate the narial reflex since nasal bradycardia was not reduced when lung inflation was maintained. Central and peripheral components arising from respiratory activity have their greatest effect during the recovery period. Elimination of the carotid bodies delayed but did not abolish chemoreceptor driven bradycardia demonstrating that these are the most chemosensitive units but not the only ones responding to changes in blood gas tensions. No role however, has been found for the arterial baroreceptors. The barostatic reflex brought on by drug induced hypertension was triggered at a lower pressure than that found in the seal but it appears that this pressure would not be exceeded in the muskrat if heart rate remained low during a dive. It is concluded that the cardiac response to submersion in the muskrat results from at least three reflex arcs. These reflexes originate from the nares, the lungs and from peripheral chemoreceptors. Although the chemoreceptors act to maintain the prevailing diving responses, it is likely that the external narial reflex accounts for almost all of the cardiovascular adjustment brought about in normal foraging dives since these are usually of short duration. The chemoreflex could play a significant role in dives exceeding one minute by prompting the animal to resurface when oxygen stores are depleted. / Science, Faculty of / Zoology, Department of / Graduate

Cardiac performance, angiogenesis and growth was investigated during early chicken development. Heart rate, and thus arterial pulse pressure and cardiac output, were altered with the bradycardic drug ZD7288. Heart rates at 72 h of development of control embryos and those dosed with chicken Ringer were not different at 171 bpm. Acute and chronic application of ZD7288 caused significant bradycardia. Chronic dosing of Ringer and ZD7288 changed neither eye diameter nor development rate. Chronic dosing of ZD7288 did not significantly alter CAM vessel density close to the embryo (2, 3 and 4 mm) but at farther distances (5 and 6 mm) chronic dosing with both Ringer and ZD7288 decreased vessel density by 13 - 16%. Chronic dosing with ZD7288 also reduced body mass by 20%. Thus, lowered heart rate and cardiac output had little effect on vessel density or developmental stage, but did reduce embryo growth.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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Large inter-individual differences exist in the degree of bradycardia induced by breath-hold facial immersion. The purpose of this study was to examine baroreceptor sensitivity in subjects who exhibit a strong response and in those who exhibit a minimal response. Thirty-nine healthy volunteers. were screened with three trials of breath-hold facial immersion during mild steady-state cycling. The six subjects displaying the greatest bradycardia were selected as responders and the six showing the least as non-responders. Baroreceptor sensitivity was estimated in each subject by examination of the heart rate and blood pressure responses to a controlled Valsalva manoeuvre and to isometric handgrip exercise. Regression lines for changes in systolic blood pressure over time showed a flatter response in the responders both during isometric handgrip exercise (p<.05) and over the 25 s immediately following release (p<.01). One interpretation of these findings is that the non-responders are less able to maintain a resting level of arterial blood pressure. As well, regression lines for the change in diastolic blood pressure over the period 25 to 55 s post-release of isometric handgrip exercise had different slopes in the two groups (p<.05). A positive mean slope calculated for the responders and a negative mean slope calculated for the non-responders, when plotted with the average intercepts, suggested an undershoot in diastolic blood pressure upon release in the responders. This may represent an attempt to regain resting levels of arterial blood pressure through peripheral vasodilitation. Direct measures by arterial catheter, in a sub-sample of four subjects, suggested that the blood pressure overshoot during the recovery phase of the Valsalva manoeuvre may not have been large enough to demonstrate group differences in baroreceptor sensitivity. / Thesis / Master of Science (MS)

Mise en contexte : Les chémoréflexes laryngés (CRI) sont déclenchés suite au contact entre un liquide et la muqueuse laryngée. Chez un organisme mature, ces CRL sont responsables de mécanismes de protection des voies aériennes inférieures (VAI) tels que déglutitions, toux et réaction d'éveil afin d'éviter l'aspiration. Par contre, chez un organisme immature comme c'est le cas chez les nouveau-nés, ces CRL associent apnée, bradycardie, laryngospasme, hypertension et redistribution du débit sanguin. En période néonatale, ces CRL, déclenchés en réponse à un reflux gastro-oesophagien acide, sont tenus responsables d'apnées du prématuré, de malaises graves du nourrisson (ALTE) et probablement de quelques cas de mort subite du nourrisson (MSN). Malgré leur pertinence clinique évidente, la revue de la littérature permet de constater que de nombreuses questions persistent concernant les CRL, principalement parce que les conditions expérimentales des études antérieures ne reflètent pas ce qui est vu en clinique. Ainsi, les CRL ont été étudiés le plus souvent en utilisant des modèles anesthésiés, en utilisant l'eau distillée, en se servant d'une trachéotomie pour l'injection des solutions et finalement en ne prenant pas en compte les stades de conscience. Une meilleure compréhension des CRL, en particulier déclenchés par des solutions acides, est donc nécessaire. But du projet : Le but de ce travail est d'étudier les CRL chez l'agneau nouveau-né sans sédation en réponse à l'acide, en comparaison à l'eau distillée et au salin durant le sommeil calme.

Fundamento: A estimulação endocárdica convencional do ventrículo direito em ápice ou na região subtricuspídea ocasiona grande alargamento do QRS e importante dessincronização do miocárdio comprometendo a função ventricular. Com o surgimento da estimulação bifocal do VD e com a necessidade de estimulação cardíaca menos deletéria, a estimulação septal do VD tem sido cada vez mais utilizada. Eventualmente têm sido relatados limiares de estimulação mais altos e ondas R menores na estimulação septal. Objetivo: Comparar os parâmetros eletrofisiológicos das estimulações apical e septal, no mesmo paciente, para verificar se existem diferenças que possam interferir na escolha do ponto de estimulação. Este não é um estudo de ressincronização, porém tem o objetivo de contribuir na busca de uma estimulação ventricular monofocal menos deletéria. Casuística e métodos: Estudo prospectivo controlado. Foram incluídos 25 pacientes, com 67,2 ± 9 anos, 10 (40%) mulheres, 15 (60%) homens, com indicações clássicas de marca-passo por bradiarritmias. As etiologias foram Degenerativa em 9 (36%), Insuficiência coronária em 8 (32%), Doença de Chagas em 7 (28%), e Valvopatia em 1 (4%) pacientes. Foram utilizados eletrodos de fixação ativa tanto no ápice e região subtricuspídea, como no septo IVD. Foram medidos e comparados os limiares de comando, impedância e onda R uni e bipolares no momento do implante (medida direta) e após seis meses de evolução (medida por telemetria). Resultados: No implante, as médias dos limiares de comando septais x apicais foram respectivamente 0,73 x 0,74V (unipolar) e 0,73 x 0,78V (bipolar). As médias das ondas R septais x apicais foram 10 x 9,9mV (unipolar) e 12,3 x 12,4mV (bipolar). As médias das impedâncias septais x apicais foram 579 x 621? (unipolar) e 611 x 629? (bipolar). Todas as diferenças entre parâmetros septais e apicais com teste t-pareado bicaudal foram não significativas (p > 0,1). Após seis meses do implante, as médias dos limiares de comando septais x apicais foram respectivamente 0,5 x 0,72V (unipolar) e 0,71 x 0,87V (bipolar). As médias das ondas R septais x apicais foram 11,4 x 9,5mV (unipolar) e 12 x 11,2mV (bipolar). As médias das impedâncias septais x apicais foram 423 x 426? (unipolar) e 578 x 550? (bipolar). As diferenças entre parâmetros septais e apicais após 6 meses com teste t-pareado bicaudal foram não significativas (p > 0,05), exceto quanto às médias dos limiares de estimulação unipolares septal x apical (p=0,02) com menores limiares septais. 27, Conclusão: Este estudo mostrou que não existem diferenças expressivas entre parâmetros eletrofisiológicos de estimulação septal e apical, quando comparadas no mesmo paciente. Estes dados sugerem que em relação aos parâmetros de estimulação não há restrições para a escolha da estimulação septal em ventrículo direito. Este estudo não tem o objetivo de testar a ressincronização ventricular, porém contribui na escolha de uma estimulação monofocal ventricular direita mais fisiológica e menos deletéria. / Background: The conventional endocardial pacing in right ventricular apex or subtricuspid area causes significant QRS enlargement and important left ventricular desynchronization with ventricular function damage. By the introduction of RV bifocal pacing and the need of a less deleterious ventricular stimulation right ventricular septal pacing has been increasingly used. However, despite rare, some authors have reported high pacing thresholds and low R wave in septal pacing. Objective: To compare the electrophysiological parameters of the apical and septal stimulation in the same patient, seeking for any difference that could affect the choice of the pacing point. This is not a resynchronization study however it has the aim to search for for a better monofocal ventricular pacing. Materials and methods: Prospective controlled study of 25 symptomatic patients (67.2 ± 9 years old, 10 [40%] female, 15 [60%] male) having permanent atrial fibrillation with high degree AV block and classical pacemaker indication. The etiologies were 9 (36%) aging, 8 (32%) coronary disease, 7 (28%) Chagas disease and 1 (4%) valvar cardiopathy. There were used active fixation leads both in septal and in apical locations. The generators were Biotronik Philos II DR and Entovis DR. There were measured and compared pacing thresholds, impedance and R wave uni and bipolar during implantation (direct measurement) and after six months of follow-up (telemetry measurement). Results: During implantation, the septal vs apical mean pacing threshold were respectively 0.73 vs 0.74V (unipolar) and 0.73 vs 0.78V (bipolar). Mean R wave septal vs apical were 10 vs 9.9 mV (unipolar) and 12.3 vs 12.4mV (bipolar). The mean impedance septal vs apical were 579 vs 621? (unipolar) and 611vs 629? (bipolar). All septal vs apical comparisons were non-significant (p > 0.1, two-tailed paired t-test). After six months the mean pacing threshold septal vs apical were respectively 0.5 vs 0.72V (unipolar) and 0.71 vs 0.87V (bipolar). The mean R wave septal vs apical were 11.4 vs 9.5mV (unipolar) and 11.2 vs 12mV (bipolar). The mean impedance septal vs apical were 423 vs 426? (unipolar) and 578 vs 550? (bipolar). Only the unipolar septal vs apical mean threshold had significant difference (p = 0.02) with lower septal value. Conclusion: This study showed no significant difference between electrophysiological septal and apical pacing parameters when the 29 comparison is done in the same patient. By this way there are no restrictions for the right ventricular septal pacing. Despite being a non-resynchronization study it may contribute for chosen a less deleterious right ventricular monofocal pacing.

Fundamento: A estimulação endocárdica convencional do ventrículo direito em ápice ou na região subtricuspídea ocasiona grande alargamento do QRS e importante dessincronização do miocárdio comprometendo a função ventricular. Com o surgimento da estimulação bifocal do VD e com a necessidade de estimulação cardíaca menos deletéria, a estimulação septal do VD tem sido cada vez mais utilizada. Eventualmente têm sido relatados limiares de estimulação mais altos e ondas R menores na estimulação septal. Objetivo: Comparar os parâmetros eletrofisiológicos das estimulações apical e septal, no mesmo paciente, para verificar se existem diferenças que possam interferir na escolha do ponto de estimulação. Este não é um estudo de ressincronização, porém tem o objetivo de contribuir na busca de uma estimulação ventricular monofocal menos deletéria. Casuística e métodos: Estudo prospectivo controlado. Foram incluídos 25 pacientes, com 67,2 ± 9 anos, 10 (40%) mulheres, 15 (60%) homens, com indicações clássicas de marca-passo por bradiarritmias. As etiologias foram Degenerativa em 9 (36%), Insuficiência coronária em 8 (32%), Doença de Chagas em 7 (28%), e Valvopatia em 1 (4%) pacientes. Foram utilizados eletrodos de fixação ativa tanto no ápice e região subtricuspídea, como no septo IVD. Foram medidos e comparados os limiares de comando, impedância e onda R uni e bipolares no momento do implante (medida direta) e após seis meses de evolução (medida por telemetria). Resultados: No implante, as médias dos limiares de comando septais x apicais foram respectivamente 0,73 x 0,74V (unipolar) e 0,73 x 0,78V (bipolar). As médias das ondas R septais x apicais foram 10 x 9,9mV (unipolar) e 12,3 x 12,4mV (bipolar). As médias das impedâncias septais x apicais foram 579 x 621? (unipolar) e 611 x 629? (bipolar). Todas as diferenças entre parâmetros septais e apicais com teste t-pareado bicaudal foram não significativas (p > 0,1). Após seis meses do implante, as médias dos limiares de comando septais x apicais foram respectivamente 0,5 x 0,72V (unipolar) e 0,71 x 0,87V (bipolar). As médias das ondas R septais x apicais foram 11,4 x 9,5mV (unipolar) e 12 x 11,2mV (bipolar). As médias das impedâncias septais x apicais foram 423 x 426? (unipolar) e 578 x 550? (bipolar). As diferenças entre parâmetros septais e apicais após 6 meses com teste t-pareado bicaudal foram não significativas (p > 0,05), exceto quanto às médias dos limiares de estimulação unipolares septal x apical (p=0,02) com menores limiares septais. 27, Conclusão: Este estudo mostrou que não existem diferenças expressivas entre parâmetros eletrofisiológicos de estimulação septal e apical, quando comparadas no mesmo paciente. Estes dados sugerem que em relação aos parâmetros de estimulação não há restrições para a escolha da estimulação septal em ventrículo direito. Este estudo não tem o objetivo de testar a ressincronização ventricular, porém contribui na escolha de uma estimulação monofocal ventricular direita mais fisiológica e menos deletéria. / Background: The conventional endocardial pacing in right ventricular apex or subtricuspid area causes significant QRS enlargement and important left ventricular desynchronization with ventricular function damage. By the introduction of RV bifocal pacing and the need of a less deleterious ventricular stimulation right ventricular septal pacing has been increasingly used. However, despite rare, some authors have reported high pacing thresholds and low R wave in septal pacing. Objective: To compare the electrophysiological parameters of the apical and septal stimulation in the same patient, seeking for any difference that could affect the choice of the pacing point. This is not a resynchronization study however it has the aim to search for for a better monofocal ventricular pacing. Materials and methods: Prospective controlled study of 25 symptomatic patients (67.2 ± 9 years old, 10 [40%] female, 15 [60%] male) having permanent atrial fibrillation with high degree AV block and classical pacemaker indication. The etiologies were 9 (36%) aging, 8 (32%) coronary disease, 7 (28%) Chagas disease and 1 (4%) valvar cardiopathy. There were used active fixation leads both in septal and in apical locations. The generators were Biotronik Philos II DR and Entovis DR. There were measured and compared pacing thresholds, impedance and R wave uni and bipolar during implantation (direct measurement) and after six months of follow-up (telemetry measurement). Results: During implantation, the septal vs apical mean pacing threshold were respectively 0.73 vs 0.74V (unipolar) and 0.73 vs 0.78V (bipolar). Mean R wave septal vs apical were 10 vs 9.9 mV (unipolar) and 12.3 vs 12.4mV (bipolar). The mean impedance septal vs apical were 579 vs 621? (unipolar) and 611vs 629? (bipolar). All septal vs apical comparisons were non-significant (p > 0.1, two-tailed paired t-test). After six months the mean pacing threshold septal vs apical were respectively 0.5 vs 0.72V (unipolar) and 0.71 vs 0.87V (bipolar). The mean R wave septal vs apical were 11.4 vs 9.5mV (unipolar) and 11.2 vs 12mV (bipolar). The mean impedance septal vs apical were 423 vs 426? (unipolar) and 578 vs 550? (bipolar). Only the unipolar septal vs apical mean threshold had significant difference (p = 0.02) with lower septal value. Conclusion: This study showed no significant difference between electrophysiological septal and apical pacing parameters when the 29 comparison is done in the same patient. By this way there are no restrictions for the right ventricular septal pacing. Despite being a non-resynchronization study it may contribute for chosen a less deleterious right ventricular monofocal pacing.