Modelling the characteristics of the baroreceptor

A dissertation submitted to the Faculty of Engineering and the Built Environment, University of Witwatersrand in fulfilment of the requirements for the degree of Master of Science in Engineering. 2017The baroreceptor is a stretch receptor which detects changes in pressure in arterial blood vessels. Baroreceptor nerves inform the brainstem of changes in blood pressure, which then influences sympathetic and parasympathetic nervous activity to counteract that change. Due to the relationship between essential hypertension, sympathetic nervous activity and the baroreflex, there is some debate in the literature about whether the baroreflex can act as a long-term controller of blood pressure. This debate has increased in recent years, due to the high prevalence of essential hypertension in all societies and the introduction of new technologies to counteract drug-resistance hypertension. The baroreflex has become a source of debate due to the complex physiological feedback control that regulates blood pressure and due to new stimulating electrical devices, which have shown promising results in reducing drug-resistant essential hypertension. system. This is done through a literature survey extending through experimental and modelling research, where selected mathematical models of the baroreceptor are then analysed and simulated to find the best performing model, so that they may be simulated for an extended frequency response than what would be experimentally possible. The purpose of this investigation is to determine, through simulation, what the sensor static and dynamic characteristics are. Through this characterisation of the sensor behaviour of the baroreceptor in the baroreflex control loop, it is then possible to infer whether the baroreflex can act as a long-term controller of blood pressure. An overview of experimental and analytical investigations on the baroreceptor over the last 70 years is summarised. This overview includes mathematical models, which predict experimental results. A subset of four models from Srinivasen et al., Bugenhagen et al., Beard et al. and Mahdi et al. are selected. These models are implemented in MATLAB and Simulink. The parameters and experimental conditions are integrated into the Simulink models, and the simulated results are compared to the reported experimental data. In this way, each mathematical model is evaluated using secondary data for its ability to simulate the expected behaviour. Thereafter, all simulated models are compared under the same input conditions (a 0-230 mmHg step input over 12 s). These results are used to select the best performing models, based on how well they were parameterised and validated for experimental tests. The best performing models are those of Beard et al. and Bugenhagen et al. They are tested for a wide range of artificial inputs at different frequencies, with sinusoidal inputs which have periods that range from 0.1 s to 10 days and have a 100 mmHg operating point with a 1 mmHg peak amplitude. All modelling techniques studied show that the baroreceptor firing response resets due to the rate of change in strain in the visco-elastic arterial wall. Both tested model frequency responses, although parameterised for different species and for different major vessels, show high sensitivity to inputs in range from 1 s to 1 min 36 s (0.01 Hz 1Hz), and very low sensitivity for changes that are longer than 16 min 36s (0.001 Hz). This extrapolated simulation suggests a zero gain near DC. The simulated frequency response of the best performing baroreceptor models, which were validated against short-term experimental data, indicate that the baroreceptor is only able to sense changes that happen in less than 1 min 16s. The critical analysis of all the simulated baroreceptor models show that this characteristic of the baroreceptor is caused by the visco-elastic layers of the arterial wall, and is likely in all baroreceptors regardless of type or species. It also indicates that under electrical stimulation of the baroreceptor, the input signal from the electrical device bypasses the baroreceptor nerve ending (which is embedded in the arterial wall) and that the electrical signal of the baroreceptor is bypassed by the new stimulated electrical signal of the device. Furthermore, if the sensor can only detect short-term changes, then it is unlikely that the baroreceptor can inform the brainstem on longterm changes to mean arterial blood pressure. Therefore, based on the models examined in this study, this suggests that the baroreceptor is unlikely to be involved in long-term blood pressure control. This analysis of the best performing model is presented to show the limitations of the baroreflex in long term control of blood pressure. It serves as a simulated experiment to rationalise the contentious debate around the role of the baroreflex in long term blood pressure control, and to allow for future improvements that can be made on the baroreceptor model to allow for more extended modelling on sor characteristics. An improvement that could be applied to the best performing baroreceptor models, implemented in this study, is to examine the effects of ageing and inter-species variability on carotid sinus dimensions and visco-elastic wall properties.CK201

Central neural mechanisms governing postural cardiovascular mechanisms

The results of the vestibular apparatus and cerebellum in orthostatic reflex control are summarized. Mechanisms within the brain which govern circulation reflexes and the consequences of disturbances in their function are also included

Sympatheticregulationofvascularfunctioninhealthanddisease

Thesympatheticnervoussystem(SNS)isknowntoplayapivotalroleinshort-andlong-termregulationofdifferentfunctionsofthecardiovascularsystem.Inthepastdecadesincreasingevidencedemonstratedthatsympatheticneuralcontrolisinvolvednotonlyinthevasomotorcontrolofsmallresistanearteriesbutalsoinmodulationoflargearteryfunction.Sympatheticactivityandvascularfunction,bothofwhicharekeyfactorsinthedevelopmentandprognosisofcardiovasculareventsanddisease,arelinkedatseverallevels.EvidencefromexperimentalstudiesindicatesthattheSNSiscriticallyinfluenced,atthecentralandalsoattheperipherallevel,bythemostrelevantfactorsregulatingvascularfunction,suchasnitricoxide(NO),reactiveoxygenspecies(ROS),endothelin(ET),therenin-angiotensinsystem.Additionally,thereisindirectevidenceofareciprocalrelationshipbetweenendothelialfunctionandactivityoftheSNS.Anumberofcardiovascularriskfactorsanddiseasesarecharacterizedbothbyincreasedsympatheticoutflowanddecreasedendothelialfunction.Inhealthysubjects,musclesympatheticnerveactivity(MSNA)appearstoberelatedtosurrogatemarkersofendothelialfunction,andanacuteincreaseinsympatheticactivityhasbeenassociatedwithadecreaseinendothelialfunctioninhealthysubjects.However,directevidenceofacause-effectrelationshipfromhumanstudiesisscanty.Inhumanslargearterystiffnesshasbeenassociatedwithincreasedsympatheticdischarge,bothinhealthysubjectsandinrenaltransplantrecipients.Peripheralsympatheticdischargeisalsoabletomodulatewavereflection.Ontheotherhand,largearterystiffnesscaninterferewithautonomicregulationbyimpairingcarotidbaroreflexsensitivity

The efficacy of antihypertensiye drugs in chronic intermittent hypoxia conditions

The authors would like to thank the Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) and CEDOC (Chronic Diseases Research Centre, Lisbon, Portugal). Lucilia N. Diogo is supported by an FCT fellowship (SFRH/BD/48335/2008; PTDC/SAU-TOX/112264/2009).Sleep apnea/hypopnea disorders include centrally originated diseases and obstructive sleep apnea (OSA). This last condition is renowned as a frequent secondary cause of hypertension (HT). The mechanisms involved in the pathogenesis of HT can be summarized in relation to two main pathways: sympathetic nervous system stimulation mediated mainly by activation of carotid body (CB) chemoreflexes and/or asphyxia, and, by no means the least important, the systemic effects of chronic intermittent hypoxia (CIH). The use of animal models has revealed that CIH is the critical stimulus underlying sympathetic activity and hypertension, and that this effect requires the presence of functional arterial chemoreceptors, which are hyperactive in CIH. These models of CIH mimic the HT observed in humans and allow the study of CIH independently without the mechanical obstruction component. The effect of continuous positive airway pressure (CRAP), the gold standard treatment for OSA patients, to reduce blood pressure seems to be modest and concomitant antihypertensive therapy is still required. We focus this review on the efficacy of pharmacological interventions to revert HT associated with CIH conditions in both animal models and humans. First, we explore the experimental animal models, developed to mimic HT related to CIH, which have been used to investigate the effect of antihypertensive drugs (AHDs). Second, we review what is known about drug efficacy to reverse HT induced by CIH in animals. Moreover, findings in humans with OSA are cited to demonstrate the lack of strong evidence for the establishment of a first-line antihypertensive regimen for these patients. Indeed, specific therapeutic guidelines for the pharmacological treatment of HT in these patients are still lacking. Finally, we discuss the future perspectives concerning the non-pharmacological and pharmacological management of this particular type of HT.publishersversionpublishe

A reversal of fate : unravelling the role of central 5-HT in cardiorespiratory control in neonatal and adult rodents

We seek to address the extent to which a specific loss of 5-hydroxytryptamine (5-HT) affects the control of respiration, arterial blood pressure (ABP) and heart rate (HR) across vigilance-states based on existing evidence suggesting that 5-HT defects increase the risk for Sudden Infant Death Syndrome (SIDS) and neurogenic hypertension. SIDS is the leading cause of infant mortality between 1 month and 1 year of age, occurs during sleep, and up to 70% of all SIDS cases have at least one 5-HT system abnormality. Neonatal rodents lacking central 5-HT exhibit severe apneas, and a reduced ABP and HR. Central 5-HT has been implicated in the etiology of neurogenic hypertension, presumably due to projections of 5-HT neurons within the midline raphe to vagal and presympathetic regions of the brain. However, data from studies examining the specific role of central 5-HT function is conflicting or inconclusive. Neurogenic hypertension accounts for more than 90% of all hypertensive cases and the normal fall in ABP that occurs during non-rapid eye movement sleep is absent in some patients with hypertension. Understanding the mechanisms associated with the development of hypertension is critical not only to lower blood pressure, but to lower its associated cardiovascular events. The purpose of this dissertation is to examine the role of central 5-HT in the control of ABP during sleep and reveal, mechanistically, the physiological role of 5-HT in the autonomic control of ABP in neonatal and adult rodents. The overarching hypothesis for this dissertation is that central 5-HT is required for the maintenance of ABP and autonomic tone at rest in both neonatal and adult rodents.Includes bibliographical reference

The mechanism and site of action of clonidine in the rat

The inactin anaesthetized rat shews cardiovascular reflex responses. Heat rate is under sympathetic but not vagal control.Clonidine reduces the heart rate and blood pressure in the inactin anaesthetized rat. The reduction in heart rate involves reducing sympathetic cradiac drive. The fall in blood pressure includes a reduction in peripheral resistance.Using a newly developed "delayed" hindlimb perfusion the reduction in peripheral resistance was seen to be neurally mediated. A peripheral vasodilator action was not seen with clonidine.Clonidine was administered by four different routes which were expected to provide access to selected areas in the brain. Intravenous, intracarotid artery, intraventricular and intravertebral artery. Administration into the ventricular system of the brain was slighty more potent in reducing arterial pressure than intravenous injection. Intracarotid and intravenous were equipotent. Intravertbral was by far the most effective, requiring 5% of the intravenous dose to cause an equivalent cardiovascular response.Autoradiography with H-clonidine was used to locate the injected clonidine. The new CEA Verken tritium sensitive film was used and proved able to detect very low levels of tritium. Each route of administration resulted in a different pattern of distribution.Clonidine administered intravenously distributed evenly throughout the CN3.Intacarotid administration selectively reached rostral areas. Intraventricular administration had the spread limited to periventicular areas.Intravertebral clonidine reached the medulla, pons, areas of the cerebellum and upper areas of the spinal cord.Comparison with the different hypotensive affects led to the conclusion that the site of action was within the medulla but not in the periventricular areas

117th Annual Meeting of the Iowa Academy of Science [Program, 2005]

https://scholarworks.uni.edu/ias_docs/1009/thumbnail.jp

Characteristics, causes and functional consequences of brain inflammation in diabetes and hypertension

Diabetes and its complications, such as hypertension and diabetic cardiomyopathy, increase the risk of morbidity and mortality in human populations. Despite decades of research, the full aetiology of these complications still remains unclear. Strong evidence suggests there is dysfunction in the autonomic neurons system, including abnormal activity in the sympathetic nervous system and baroreflex impairment, which may contribute to the development of cardiovascular complications in diabetes; however, the mechanisms behind these abnormalities in diabetes are not well understood. Autonomic nuclei within the central nervous system (CNS) that are involved in the control of sympathetic nerve activity, the sensitivity of the baroreflex and the cardiovascular system are the paraventricular nucleus of the hypothalamus (PVN), the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS). Inflammation and oxidative stress in these centres have been identified to contribute to the hyperactivity of the sympathetic nerves and baroreflex dysfunction in other diseases, but whether this true in diabetes is not clear. Microglia and astrocytes are the resident immune inflammatory cells within the CNS. Once they become activated in response to various stimuli, they can release pro-inflammatory molecules and reactive oxygen species; however, the role of these cells in the development of diabetic cardiovascular complications remains unclear. Drinking 1% NaCl has been shown to have biphasic effects on the development of diabetic complications in animals, but whether these effects are mediated via influencing brain inflammation has not been investigated. In addition, little is known about the influence of antioxidants and high fat feeding on microglial activation in central autonomic centres in diabetic animals. Thus, the aim of this thesis was to identify whether inflammation occurs in central autonomic centres in different species and models of diabetes and to explore the consequences of neuroinflammation in these animals. In chapter 3, the effect of the inhibition of microglia in the PVN on blood pressure and heart rate in long-term (8 weeks) STZ-diabetic rats was investigated. Microglia and astrocytes were activated in the PVN in STZ diabetic rats. Pro-inflammatory cytokines released from both activated microglia and astrocytes have been implicated in spinal neuronal hyperexcitability. This suggested that the activation of microglia and astrocytes may be important for mediating inflammation in the PVN in diabetic rats, which may cause neuronal hyperactivity and then lead to increased sympathetic activity. Minocycline treatment inhibited PVN microglial activation but not the activation of astrocytes, suggesting that microglial activation was not responsible for astrocyte activation; however, in this study, the consequence of the inhibition of microglial activation could not be tested for several reasons, including morbidity and the lack of hypertension in STZ diabetic animals. Therefore, an alternative approach to this study was justified. In most studies on long-term (6-8 weeks) STZ diabetic rats, unchanged or lowered blood pressure has been observed, which is consistent with the data presented in chapter 3. Drinking 1% NaCl, which may prevent dehydration, causes hypertension in diabetic rats within 2 weeks after STZ treatment, but how this occurs and whether brain inflammation contributes to this hypertension has not been investigated. Therefore, in chapter 4, we investigated the effects of 1% NaCl intake on blood pressure, baroreflex sensitivity and inflammation in the PVN, NTS and RVLM in 2-week STZ diabetic rats. In addition, we investigated whether the inhibition of microglia in the PVN can prevent hypertension in STZ diabetic rats given 1% NaCl. Diabetic rats given saline exhibited hypertension, dysfunction of the bradycardic baroreflex and signs of normalised blood volume in comparison with the control rats and the diabetic rats that drank water. Diabetic rats that drank 1% NaCl also showed increased microglial activation in the PVN, NTS and RVLM. The inhibition of activated microglia in the PVN via administering ICV minocycline prevented the hypertension seen in diabetic rats given 1% NaCl, strongly suggesting that microglial activation plays an important role in the generation of hypertension in these animals. Despite this, the possibility that increased blood volume and/or baroreflex dysfunction are mechanisms by which 1% NaCl intake induces hypertension in STZ diabetic rats cannot be ruled out. While it is clear from these studies that 1% NaCl intake can reduce baroreflex sensitivity in 2-week STZ diabetic rats, another study reported that the prolonged drinking of 1% NaCl causes improvement in ex vivo cardiac function in 6-week STZ diabetic rats. Whether treatment with 1% NaCl for longer periods produces similar beneficial effects on the baroreflex sensitivity is not known. Therefore, in chapter 5, we aimed to investigate the effects of 1% NaCl on the baroreflex sensitivity and to determine whether 1% NaCl intake influences inflammation cardiovascular centres in longer term (6 weeks) STZ diabetic rats. The diabetic rats showed dysfunction in the barorflex sensitivity. This dysfunction was associated with increased microglial activation in the NTS and PVN. Drinking 1% NaCl for 6 weeks restored the function of bradycardic baroreflex and also reduced the activation of microglia and neurons in the NTS in these animals. The data suggest that microglial activation in the NTS may be responsible for the baroreflex dysfunction seen in 6-week STZ diabetic animals. The data also suggest that drinking 1% NaCl can prevent cardiovascular complications through a reduction in microglial activation in longer term STZ diabetic rats. In addition to hypertension and the baroreflex dysfunction, cardiomyopathy is a common form of diabetic complication and can occur independently of hypertension in diabetes. There is evidence that inflammation in the PVN is a potential contributing factor to the development of cardiomyopathy in other diseases. In chapters 3 and 5, evidence is provided that microglial cells are activated in the PVN in 6-8 STZ diabetic rats, but the role of these cells in diabetic cardiomyopathy has not been investigated. Therefore, in chapter 6, we aimed to investigate the structural and functional parameters of the left ventricle in diabetic rats at 6 weeks following STZ injection and to determine whether the inhibition of microglial activation in the PVN could reverse any of the changes observed. Six-week STZ diabetic rats showed clear left ventricular dysfunction, including elevated end diastolic pressure, an increased internal diameter in the systole and diastole and a decreased E/A ratio when compared with the control rats. These animals also displayed marked activation of microglia and neurons in the PVN. Inhibition of microglial activation via administering ICV minocycline reduced the PVN neuronal activity and significantly normalised the left ventricular function. This study suggests that microglial activation in the PVN leads to PVN neuronal excitation in STZ diabetic rats. The data also confirm our proposal that microglial activation in the PVN plays a critical role in the pathogenesis of diabetic complications. Drinking 1% NaCl for 6 weeks in STZ diabetic rats reduces cardiovascular complications, but the exact mechanism is still unclear. The data from chapter 6 indicated that microglial activation in the PVN contributes to cardiac dysfunction in STZ diabetic rats; however, whether the beneficial effects of the prolonged drinking of 1% NaCl on the cardiac function are mediated by reducing the inflammatory response is not known. Therefore, in chapter 7, we investigated the effects of 1% NaCl on the cardiac function in vivo and whether 1% NaCl intake influences microglial activation in 6-week STZ diabetic rats. Drinking 1% NaCl restored elevated end diastolic pressure but not the other parameters of the left ventricle in these animals. The 1% NaCl intake also reduced the activation of microglia and neurons in the NTS and PVN when compared to the STZ diabetic rats given tap water. When the drug minocycline was accompanied by prolonged 1% NaCl intake, the STZ diabetic rats showed a further improvement in cardiac performance and a reduction in microglial and neuronal activation in PVN compared with STZ diabetic rats given saline alone. These results indicated that changes in cardiac function are paralleled by the level of microglial activation in the PVN observed in diabetic animals. Because the mouse is the most suitable animal model for genetic manipulations, it was important to examine whether microglia and neurons are also activated in the PVN in STZ diabetic mice as well as the time period of any activation. Hydrogen sulphide (H2S) has been shown to inhibit microglial activation in vitro experiments, but the effect of the systemic infusion of H2S on PVN function in STZ mice has not been investigated. Therefore, in chapter 8, we examined the dose and time dependence of microglial and neuronal activation and the effects of H2S in STZ treated mice at 7 weeks. The microglia were activated in the PVN in STZ diabetic mice at 16 weeks after STZ injection but not at the 7-week time period compared to the control. In diabetic mice treated with a low dose of STZ, the microglia in the PVN were not activated at the 10-week time period; however, the PVN neuron activation was observed in STZ diabetic mice at all time periods as well as in diabetic mice treated with a low dose of STZ, suggesting neuronal activation precedes microglial activity. H2S treatment attenuated the increase in neuronal activation in the PVN and prevented dehydration at 7 weeks following STZ injections. These findings suggest that H2S treatment may play an important role in regulating kidney and PVN neuron function in diabetes. A high fat diet is a major contributing factor in the pathogenesis of type 2 diabetes, which is the most common form of diabetes in humans. Whether PVN inflammation occurs in models of type II diabetes requires investigation. Thus, in chapter 8, we also examined the PVN inflammation in mice treated with a low dose of STZ and high fat feeding. No significant difference was observed in the percentage of microglia activated in the PVN in mice treated with STZ and high fat feeding when compared to the control; however, the neuronal activation was significantly increased in the PVN in these mice. The addition of a high fat diet to the STZ treatment attenuated the increase in neuronal activation in the PVN. These findings suggest that the activation of microglia in the PVN does not occur in all animal models of diabetes. In conclusion, microglial activation occurs in the PVN in long-term STZ-induced diabetic rats and mice but not in a mouse model of type II diabetes. Although the cause is not fully known, microglial activation in the PVN plays an important role in the pathogenesis of diabetic complications. While 1% NaCl prevents dehydration in short and long-term STZ diabetic rats, it has a biphasic effect on diabetic complications. This effect was mediated, at least in part, by changes in neuroinflammation. The beneficial effects of hydrogen sulphide on PVN function may be mediated via reducing neuroinflammation and/or oxidative stress in diabetes. Thus, new therapeutic approaches aimed to target neuroinflammation may be of clinical importance in preventing diabetic cardiovascular complications in humans

Influence of Dietary-Induced Obesity on Opiatergic Regulation of Appetite and Blood Pressure in Sheep

Physiological Science