Browsing by Subject "hypertension"
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Item An Evaluation of Acanthosis Nigricans School Screening Results in Richardson Independent School District to Determine the Association of Acanthosis Nigricans and Other Factors for Type 2 Diabetes Mellitus(2005-05-01) Gardner, Janet E.; Urrutia-Rojas, Ximena; McConathy, Walter J.; Cipher, Daisha J.Gardner, Janet E., An Evaluation of Acanthosis Nigricans School Screening Results in Richardson Independent School District to Determine the Association of Acanthosis Nigricans and Other Risk Factors for Type 2 Diabetes Mellitus. Master of Public Health (Community Health), May 2005, 65 pp., 11 tables, reference list, 47 titles. Cases of Type 2 diabetes mellitus (T2DM) have been increasing at alarming rates in Texas. Identifying underlying factors, such as acanthosis nigricans (AN), elevated body mass index and hypertension, which might contribute to the development for type 2 diabetes, is critical. This study analyzed the relationship of AN with these risk factors of T2DM. Richardson Independent School District screening results for 2003-2004 were analyzed. This study concluded that calculated BMI values yielded the highest association with grades of AN. BMI-for-age percentiles greater than or equal to the 95th percentile and elevated diastolic and/or systolic blood pressures were strongly associated with AN grades.Item Cholinergic agonists reduce blood pressure in a mouse model of systemic lupus erythematosus(Wiley Periodicals, Inc., 2017-04-10) Fairley, Amber S.; Mathis, Keisa W.Increased inflammation arising from an abnormal immune response can damage healthy tissue and lead to disease progression. An important example of this is the accumulation of inflammatory mediators in the kidney, which can subsequently lead to hypertension and renal injury. The origin of this inflammation may involve neuro-immune interactions. For example, the novel vagus nerve-to-spleen mechanism known as the "cholinergic anti-inflammatory pathway" controls inflammation upon stimulation. However, if this pathway is dysfunctional, inflammation becomes less regulated and chronic inflammatory diseases such as hypertension may develop. Systemic lupus erythematosus (SLE) is an autoimmune disease with aberrant immune function, increased renal inflammation, and prevalent hypertension. We hypothesized that the cholinergic anti-inflammatory pathway is impaired in SLE and that stimulation of this pathway would protect from the progression of hypertension in SLE mice. Female SLE (NZBWF1) and control (NZW) mice were administered nicotine or vehicle for 7 days (2 mg/kg/day, subcutaneously) in order to stimulate the cholinergic anti-inflammatory pathway at the level of the splenic nicotinic acetylcholine receptor (alpha7-nAChR). Blood pressure was assessed posttreatment. Nicotine-treated SLE mice did not develop hypertension and this lower blood pressure (compared to saline-treated SLE mice) coincided with lower splenic and renal cortical expression of pro-inflammatory cytokines. These data provide evidence that the cholinergic anti-inflammatory pathway is impaired in SLE In addition, these data suggest that stimulation of the cholinergic anti-inflammatory pathway can protect the kidney by dampening inflammation and therefore prevent the progression of hypertension in the setting of SLE.Item Deltoid Opioid Receptor Phenotype Modulation of Hindlimb Vascular Conduction(2008-10-06) Barlow, Matthew A.; Raven, Peter B.; Gwirtz, Patricia A.; Dillon, Glenn H.Barlow, Matthew A. Deltoid Opioid Receptor Phenotype Modulation of Hindlimb Vascular Conduction. Doctor of Philosophy (Integrative Physiology), Oct 6th, 2008, 136 pp, 1 table 26 figures. Hypertension, diabetes mellitus and their presumed precursor the metabolic syndrome are part of a complex disease process associated with insulin resistance. Neurovascular complications in diabetics commonly involve the lower limbs resulting in a vicious cycle of autonomic neuropathy, painful occlusive claudication and resulting immobility that precipitates inactivity and progressive disability. The fixed neural and vascular diseases evolve slowly and the early events in this progressive decline in function are poorly understood. Sympathetic vasoconstriction is a major component of blood flow regulation in muscle. Active vasoconstriction in the lower limbs depends on continued transmission of efferent vasomotor signals through the lumbar sympathetic chain ganglia. Opioid receptors actively reduce normal ganglionic transmission presumably by lowering acetylcholine release. In the heart, the subtypes of delta-opioid receptors (DORs) facilitate (DOR-1, vagotonic) and inhibit (DOR-2, vagolytic) cholinergic transmission in the heart. The DOR-2 mediated inhibitory effects in heart are alterable and can change rapidly. Diabetes impairs vascular control. Ganglionic transmission is metabolically vulnerable during high fat feeding and insulin resistance. We hypothesized that the DOR-2 stimulation significantly facilitates vasodilation by reducing cholinergic transmission within the sympathetic chain ganglion. The ability to activate DOR-1 stimulation facilitates to cause further vasoconstriction in the anesthetized and surgically instrumented state of the dog did not show dose dependent activation. The DOR-1 activity in the insulin resistant dogs appears to be decreased as the DOR-1 blockade had no effect on the dose responses in the heart or the hindlimb. Enhanced sympathetic tone through BCO by increasing and reducing cholinergic transmission in the lumbar sympathetic ganglion shows an enhanced pro-constrictor phenotype under stresses of severe hypotension possibly through a DOR-1 mediated activation.Item Dysfunctional neuroimmune pathways promote the development and maintenance of lupus hypertension(2020-05) Pham, Grace S.; Mathis, Keisa W.; Rickards, Caroline A.; Goulopoulou, Styliani; Cunningham, J. Thomas; Ma, Rong; Mathew, Stephen O.Hypertension afflicts nearly half of the adults in the United States and the majority of cases have no known cause. Chronic inflammation has been implicated in the development and maintenance of hypertension, and autoimmunity may comprise one of its sources. Hypertension is highly prevalent in the autoimmune disease systemic lupus erythematosus (SLE), in which chronic aberrant inflammation may be a causative factor. Endogenous neuroimmune pathways, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cholinergic anti-inflammatory pathway, likely contribute to this phenomenon. The HPA axis is a classical neuroimmune mechanism that senses peripheral inflammation via afferent vagal fibers, culminating in the release of the anti-inflammatory hormone cortisol. Previous studies have characterized HPA axis dysfunction in SLE, but less is known about how this dysregulation specifically impacts the hypertension that occurs in the setting of SLE. A second neuroimmune interaction, the cholinergic anti-inflammatory pathway, is an efferent vagus nerve-to-spleen mechanism that relies on T cell-produced acetylcholine to quell inflammation in acute settings and may be hypoactive in chronic inflammatory diseases like SLE. Notably, both of these neuroimmune mechanisms depend on vagus nerve function, identifying the vagus as a potential target for neuromodulation. Furthermore, the relationship between chronic inflammation and hypertension validates the investigation of neuroimmune pathway dysfunction towards novel mechanisms of hypertension. Herewithin, the HPA axis and cholinergic anti-inflammatory pathway are investigated using the well-established NZBWF1 mouse model of lupus hypertension. Our findings are that (1) administration of an inflammatory stimulus that activates vagal afferents elicits comparable neuronal activation in the paraventricular nucleus of the hypothalamus, compared to control mice, despite heightened peripheral inflammation; (2) amplification of efferent vagus nerve activity reduces blood pressure and renal inflammation; and (3) chronic unilateral vagotomy paradoxically results in decreased blood pressure and renal inflammation. Taken together, these findings identify dysfunction in two neuroimmune pathways while demonstrating that interventions targeting these pathways may have therapeutic benefits in lupus hypertension. In terms of future impact, these results may promote continuing inquiry in a more recently discovered neuroimmune pathway (i.e., cholinergic anti-inflammatory pathway), as well as reinstate curiosity in an older, abandoned area of research (i.e., HPA).Item Establishing the Effects of Exercise Schema and Self-Schema on Emotional Distress(2003-08-01) Rodriguez, Leslie R.; Claudia Coggin; Joseph Doster; Daisha CipherRodriguez, Leslie R., BSN, RN, Establishing the Effects of Exercise Schema and Self-Schema on Emotional Distress. Masters of Public Health (Health Behavior), August 2003, 78 pp., 4 tables, references, 81 titles. Chronic diseases’ resulting from anger and depression represents a significant problem. Vast amounts of resources and dollars are expended and utilized. Their link to the development of cardiovascular disease, hypertension, and diabetes is recognized. Physical activity produces improvements in self-esteem, increased alertness, and decreased anxiety. The purpose of this study was determining the effect exercise and exercise schema has on mood states. College age students (N=198) of a large North Texas University were recruited. Data collection included States of change, the Exerciser self-schema questionnaire, Clinical Analysis Questionnaire, and the State Trait Anger Expression Inventory. Significance in some mood states of those who were exercising and exercise schematic were found.Item Genetic characterization of comorbidity patterns in aging associated diseases using integrative genomics(2019-08) Pathak, Gita A.; Phillips, Nicole R.; Planz, John V.; Barber, Robert C.; Zhou, Zhengyang; Gryczynski, IgnacyThe aging population in the US continues to grow at an exponential rate estimated to reach more than 90 million by 2060. The coexistence of two or more diseases (comorbidity) is prevalent in ages 65 years and above, and the number of comorbidities increases with age. The genetic factors underlying presence and absence of comorbidities is a severely understudied research domain. Alzheimer's disease (AD) is a type of dementia affecting 5.5 million people with an average age of diagnosis at 70 years. Hypertension is a coexisting condition in 60% AD individuals, also known as direct comorbidity. On the other hand, cancer is reported to be inversely comorbid with AD; individuals with cancer history have been reported to have lower risk of AD and vice versa. Furthermore, individuals with cancer history are diagnosed with long term side effects of radiation therapy — radiotoxicity. Twin-based studies have reported that certain gene variants are associated with radiotoxicity phenotypes with a heritability of 66%. This study proposes to investigate genetic factors associated with the direct and inverse comorbidity of AD with hypertension and cancer, and proctitis — a radiotoxicity phenotype observed in survivors of prostate cancer. The study aims to integrate gene variants, derived-gene expression and copy number variation (CNV), followed by functional and pathway-based prioritization of observed findings. We used genome-wide and cerebral spinal fluid profile to investigate presence of hypertension with AD to evaluate individual-level differences, followed by targeted investigation of neighboring gene expression profiles of identified variants. We found several novel genes associated with AD-hypertension comorbidity. The investigation between AD and cancer identified regions in chromosomes 4, 5 and 19 that are targeted by miRNA-17 family along with other miRNAs reported to be inversely expressed and play opposite role in pathogenicity of both diseases. The SNP-derived transcriptomic profile between AD and cancer highlighted involvement of sirtuin signaling. The findings together indicate involvement of mitochondrial and metabolic dysregulation which possibly contribute in differences of the epithelial-mesenchymal-transition. The SNP-derived expression and CNV association with proctitis highlighted genes involved in DNA-repair and mitochondrial ROS damage pathways.Item Interleukin-6 and its Relationship to Coronary Artery Calcium Burden-North Texas Healthy Heart Study(2008-05-01) AbdulRahim, Nashila; Roberto Cardarelli; Sejong Bae; Richard VirgilioAbdulRahim, Nashila, Interleukin-6 and its Relationship to Coronary Artery Calcium Burden- North Texas Healthy Heart Study. Master of Science (Primary Care Clinical Research), May, 2008, pp., 7 tables, 5 figures, bibliography, 73 titles. Atherosclerosis is highly associated with increased serum inflammatory markers. Coronary artery calcium (CAC) burden has allowed researchers to have a non-invasive proxy measure of atherosclerosis. We hypothesized that interleukin-6 (IL-6), after controlling for CV risk factors, would be associated with CAC scores, and this association will be modified by race/ethnicity. 344 subjects were recruited. IL-6 concentrations were measured, and computed tomography was used to calculate CAC scores. After accounting for age, gender, race, smoking, hypertension, diabetes, and cholesterol, a one-unit increase in IL-6 concentration is associated with 1.03 greater odds of an abnormal calcium score (OR: 1.03, 95% CI: 0.98, 1.07). Race/ethnicity did not modify this association. IL-6 did not prove to be a simple clinical marker of CAC.Item Maternal and fetal mitochondrial gene dysregulation in hypertensive disorders of pregnancy(American Physiological Society, 2023-05-15) Ricci, Contessa A.; Reid, Danielle M.; Sun, Jie; Santillan, Donna A.; Santillan, Mark K.; Phillips, Nicole R.; Goulopoulou, StylianiMitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.NEW & NOTEWORTHY This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.Item Promotores de Salud of North Texas: Impact of Health Education Intervention on the Change of Blood Pressure and Body Mass Index in Adult Participants in Dreams Project 1.(2008-05-01) Arslanagic, Enisa; Robert GracyArslanagic,Enisa, MD,CCRC., Promotores de Salud of North Texas: Impact of Health Education Intervention on the Change of Blood Pressure and Body Mass Index in Adult Participants in Dreams Project 1. Master of Public Health (Community Health), May 2008, 46 pp., 3 tables, references, 51 titles. The prevalence of obesity among Mexican Americans has been increasing over the past decade, and is associated with hypertension and diabetes. Secondary data from DREAMS study were used to evaluate whether behavioral intervention on diet and physical activity using promotores de salud model significantly reduced blood pressure and body mass index among adult participants. Results showed significant changes in systolic blood pressure after the trial within intervention and control group, without significant difference in changes of blood pressure and body mass index after the trial between groups. These findings suggest that more comprehensive programs are needed to better understand Hispanic population's health behavior.Item Renal Hypertension Impairs Coronary Hyperemia During Exercise(2003-08-01) Williams, Maurice A.; Patricia GwirtzWilliams, Maurice A., Renal Hypertension Impairs Coronary Hyperemia During Exercise. Doctor of Philosophy (Biomedical Sciences), August, 2003, 103 pp., 2 tables, 10 illustrations, bibliography, 180 titles. High blood pressure (hypotension) is a common disease that greatly impacts cardiovascular disease and quality of life making it a high priority for early detection and treatment. Hypertension is a major risk factor for coronary artery disease, heart failure, stroke and sudden death. The incidence of hypertension is increasing as the population ages. Exercise intolerance or exertional fatigue is a common complaint of patients with hypertension. We tested the hypothesis that the acute onset of renovascular hypertension results in a sustained, elevated sympathetic adrenergic stimulation of the heart which blunts the coronary hyperemic response and reduces the cardiac contractile response to exercise. Studies were conducted in chronically instrumented dogs before and after the acute onset of renosvascular hypertension of only 2 weeks. This degree of hypertension would normally go undetected or untreated by physicians. Short-term hypertension blunted coronary blood flow at rest and during each level of submaximal exercise. Hypertensive dogs showed a significant reduction in cardiac pump function during submaximal exercise compared to the responses in the normotensive dogs. These changes were very dramatic for such a short term of a mild hypertension. These studies were designed to examine mechanisms mediating the blunted coronary hyperemic response during exercise which imposes a limit on cardiac function. The results of these experiments addressed fundamental questions regarding alterations in neurohumoral control of cardiac contractile function and the mechanisms by which neurohumoral control of the heart is altered by hypertension. These studies should also clarify the mechanistic rationale for medical therapies to treat patients with hypertension.Item Role of ΔFosB in nucleus of the solitary tract (NTS) in cardiovascular adaptations to chronic intermittent hypoxia (CIH) in rats(2015-08-01) Wu, Qiong; Mifflin, Steve W.; Cunningham, J. Thomas; Schreihofer, Ann M.Chronic intermittent hypoxia (CIH) rodent model is widely utilized to study obstructive sleep apnea (OSA) associated disease such as hypertension. Arterial chemoreceptor is activated by CIH, and leads to increased sympathetic nerve discharge, resulting in elevated arterial pressure. The central neuronal mechanisms of CIH induced hypertension are barely understood. The nucleus of the solitary tract (NTS) receives the first synaptic inputs from arterial chemoreceptor afferents. Transcription factor ΔFosB is increased in the NTS after a 7 day-CIH exposure. We hypothesize that NTS ΔFosB could mediate neuronal plasticity, contribute to CIH induced hypertension. Three specific aims were addressed. Aim 1: To determine the relationship between NTS ΔFosB and CIH hypertension. Viral constructs were delivered into NTS to functionally block ΔFosB (ΔJunD group). Mean arterial pressure (MAP) was measured in day time when rats were exposed to intermittent hypoxia and night time when they were in normoxia. The increase in MAP observed in ΔJunD and sham groups during day time was dampened in ΔJunD group during night time, indicating the contribution of ΔFosB to the sustained component of CIH associated hypertension. Aim 2: To determine the time-course of induction of ΔFosB immunoreactive NTS neurons during CIH exposure. Rats were separated into normoxia, 1 day, 3, 5, 7 days CIH, and 1 day, 3, 7 days recovery after 7 days CIH groups. ΔFosB immunoreactivity increased within 1 day CIH, and maintained this elevation throughout 7 days of CIH. 1 day recovery was sufficient to reduce ΔFosB immunoreactivity to normoxia level. Therefore, ΔFosB under CIH develops rapidly. Aim 3: To determine the function of ΔFosB in glutamatergic transmission after CIH. Miniature excitatory post-synaptic current (mEPSC) properties of NTS neurons of rats exposed to either different days of CIH or room air were compared. CIH increased mEPSC amplitude but not frequency, suggesting a post-synaptic site of effect. Additionally, functional blockade of NTS ΔFosB with ΔJunD decreased mEPSC amplitude back to normoxia level. Finally, overexpression of NTS ΔFosB increased mEPSC amplitude to similar levels as CIH. These results suggest that ΔFosB in NTS neurons mediates molecular adaptations which might play an important role in CIH associated hypertension.Item Sex differences in toll like receptor 7-mediated renal injury in a murine model of autoimmune-induced hypertension(2020-05) D'Souza, Bradley M.; Mathis, Keisa W.; Hodge, Lisa M.; Phillips, Nicole R.Systemic lupus erythematosus (SLE) is a female-dominant autoimmune disease associated with hypertension. We confirmed that SLE develops later in life in male vs. female SLE mice (35 vs. [less than] 30 weeks), yet both sexes develop hypertension by 35 weeks. Renal injury is a factor in hypertensive female SLE mice only, so we aimed to investigate this latent sex difference. We hypothesized that increased toll-like receptor 7 (TLR7), an immune mediator that instigates tissue damage, promotes renal injury in female SLE mice. We found that renal cortical expression of TLR7 was indeed higher in female SLE mice. In a follow-up study we found that renal hemodynamics were impaired in female SLE mice, but not males. Our data suggest that while the hypertension in female SLE mice may be due to renal mechanisms, hypertension in males is not. Future studies will dissect sex-specific factors that should be considered when treating hypertensive patients with underlying autoimmunity.Item The Acute and Chronic Effects of Beta Blockade on Dynamic Exercise Performance and Cardiac Adaptation to Dynamic Exercise Training(1998-06-01) Robbins, H. Bart; Peter B. Raven; Patricia A. Gwirtz; Robert MalletWidespread use of beta-adrenergic blocking agents as treatments for hypertension, ischemic heart disease and postmyocardial infarction has raised many questions concerning the effect of these drugs during exercise. Since exercise is often prescribed as an adjunct treatment in combination with beta blockade, the effect of these drugs on cardiac function during exercise is important to know. It is also important to ascertain if patients taking beta blockers will benefit from chronic dynamic exercise training the same way as normal subjects or if they should be viewed differently. This review of the current biomedical literature is meant to elucidate the cardiac effects, both acute and chronic, of beta-adrenoceptor blockade during dynamic exercise. The acute effects during dynamic exercise and the compensatory mechanisms in the cardiovascular system will be outlined. I will further explore if and how beta blockade significantly affects cardiac adaptation to chronic exercise training. Be reviewing the current literature I will show what is already known and will demonstrate where current knowledge is lacking and where further research is needed. There are two questions which will be addressed by this research. The first question is: “What happens to the cardiovascular system during dynamic exercise when a beta blocker is present in the system?” This question deals with the acute effects of such agents on exercise performance and cardiac function. The second question is: “What effect does beta blockade have on the cardiac adaptations to chronic dynamic exercise training?” This question examines areas of cardiac adaptation that have been postulated to be mediated by beta-adrenergic receptor stimulation (e.g. myocardial hypertrophy). I hypothesize that the acute effects of beta blockade on exercise performance are minimal, while the chronic effects on cardiac adaptation to dynamic exercise training may be significant.Item The Role of Angiotensin Converting Enzyme 1 within the Median Preoptic Nucleus Following Chronic Intermittent Hypoxia(2016-08) Faulk, Katelynn E.; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.; Ma, Rong; Jung, Marianna E.These experiments focused on the importance of the brain renin-angiotensin system (RAS) in hypertension caused by a chronic intermittent hypoxia (CIH) model of the hypoxemia associated with sleep apnea. In the CIH model, the sustained diurnal blood pressure increase has been shown to be dependent on the transcription factor FosB and its downstream target genes such as angiotensin converting enzyme 1 (ACE1) in the median preoptic nucleus (MnPO) in the anterior hypothalamus. These studies focused on the transcriptional regulation of MnPO ACE1 and the development of the sustained CIH hypertension. The first project focused on ACE1 within the MnPO and its regulation by FosB during CIH. Using immunohistochemistry, ACE1 staining within the MnPO did not overlap with glial fibrillary acidic protein (GFAP), a glial cell marker. ACE1 and FosB colocalization increased within the MnPO following 7 days of CIH. A retrograde tract tracer, fluorogold, was used to determine if ACE1 positive MnPO neurons project to the paraventricular nucleus of the hypothalamus (PVN). MnPO cells containing ACE1 and FosB immunoreactivity after CIH did project to the PVN, an area known to regulate sympathetic nerve activity. Chromatin Immunoprecipitation Assay was used to authenticate an association of FosB with ACE1 within the MnPO following CIH. In the MnPO, the association of FosB with the ACE1 gene was significantly increased by CIH. The second aim tested the functional role of MnPO ACE1 in sustained diurnal CIH hypertension. We used virally mediated expression of short hairpin RNA (shRNA) against ACE1 to significantly knockdown MnPO ACE1. Rats injected in the MnPO with shRNA against ACE1 demonstrated normal blood pressure responses to hypoxic events but the sustained blood pressure increase to CIH was significantly attenuated. ACE1 knockdown within the MnPO also decreased FosB/ΔFosB staining within the MnPO, the PVN and the rostral ventrolateral medulla (RVLM) but not in the nucleus of the solitary tract. Together, these studies suggest that MnPO ACE1 contributes to the development of sustained CIH hypertension.Item The role of Angiotensin II in central autonomic and endocrine regulation(2014-08-01) Saxena, Ashwini; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.Renin-Angiotensin system (RAS) is a peptidergic hormonal system that is known to regulate hemodynamic and fluid balance. Clinical success of RAS inhibitors in several cardiovascular and renal diseases such as hypertension (HTN), chronic heart failure, and diabetic nephropathy underscore its involvement in their pathophysiology. Recent research efforts are not only helping us understand the mechanisms through which RAS orchestrate the pathophysiology of cardiovascular diseases but are also identifying its involvement in other pathological conditions such as mood disorders and cancer. Although, initially identified as an endocrine system in peripheral circulation, the discovery of renin in the brain ushered in the concept of ‘local’ or ‘tissue’ RAS. Now, local RAS components are increasingly identified to be present in nearly all organ systems. The In the first project we investigated the role played by the communication between circulating Ang II and subfornical organ (SFO), a circumventricular organ lacking blood brain barrier, in chronic intermittent hypoxia (CIH) associated sustained increase in MAP even during period of normoxic breathing. Using viral mediated delivery of shRNA against Ang II type 1a receptors (AT1aR), it was found that the rats that received AT1aRshRNA in their SFO, exhibited increased MAP responses during CIH but their MAP recovered to levels of normoxic control during room air breathing. Also, disruption of this communication led to decreased FosB/ΔFosB staining in the autonomic regions of forebrain. FosB/ΔFosB staining identifies the expression of transcription factor FosB and its splice variant ΔFosB. These transcription factors are known to orchestrate transcriptional adaptations that lead to lasting neuroplastic adaptations. These data suggest that Ang II-SFO communication is essential in neuroplastic adaptations of forebrain autonomic nuclei, which may sustain the CIH associated increase in MAP even during periods of room air breathing. Second project was initiated to study the mechanisms through which synaptically released Ang II could affect post-synaptic neuronal sensitivity and function. It is known that bile duct ligated rats, an experimental model of cirrhosis, exhibit impaired osmoregulation. We previously reported that bile duct ligated rats show increased presence of a non-specific cation channel (TRPV4) in the hypothalamic membrane extracts. In addition, an activated RAS is also associated with fluid-electrolyte imbalance, a hallmark feature of cirrhosis. In this project it was investigated if Ang II could translocate TRPV4 to neuronal surface in vitro, in a hypothalamic neuronal cell line, 4B. In 4B cells, Ang II incubation was associated with increased TRPV4 localization to the cell membrane and was also associated with increased calcium influx in response to specific TRPV4 agonist, GSK 1016790A. In addition, these effects were completely blocked in the presence of AT1R receptor antagonist (Losartan) and Src kinase inhibitor, PP2. Taken together, these data suggest that Ang II could translocate TRPV4 to neuronal membrane via Src kinase pathway. These observations could explain one of the mechanisms through which Ang II could contribute to the pathophysiological adaptations that lead to increased water retention and dilutional hyponatremia associated with chronic liver failure.Item The Role of the MnPO in Body Fluid Balance and Blood Pressure Regulation(2019-05) Marciante, Alexandria B.; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.; Goulopoulou, Styliani; Ma, Rong; Bugnariu, Nicoleta L.The median preoptic nucleus (MnPO) is situated on the anteroventral wall of the third ventricle (AV3V) between two circumventricular organs (CVOs) that lack a functional blood-brain barrier, the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT). The SFO and OVLT project to the MnPO and together these regions regulate neuroendocrine and autonomic function, arousal, and fluid balance. Early studies demonstrated that the MnPO and other regions in the AV3V contribute to regulating thirst associated with body fluid homeostasis, as well as several forms of neurogenic hypertension. The MnPO is key in relaying signals from the SFO and OVLT to downstream regions that control fluid intake and autonomic function; however, pathway-specific and stimulus-dependent mechanisms are not fully understood. These studies investigate how the MnPO differentially responds to models of physiological challenges that induce thirst, as well as pathway-specific mechanisms of blood pressure in a known model of hypertension. To study the role of the MnPO in thirst, rats were tested with models of cellular (hyperosmolality) and extracellular (angiotensin II, ANG II) dehydration associated with hypovolemia. Previous studies have shown that different populations of MnPO neurons are osmo- or ANG II-sensitive; however, both stimuli lead to a converging behavioral outcome: water consumption. This led to the hypothesis that osmotic challenges and ANG II activate MnPO neurons that project to different regions in a stimulus-dependent manner. Results show that the MnPO signals to specific thirst-driving regions of the brain and the activation of these regions is dependent on the stimulus. To study the role of the MnPO in regulating blood pressure, an experimental model of chronic intermittent hypoxia (CIH) associated with obstructive sleep apnea (OSA) is used to successfully mimic the oxygen deprivation associated with apneic breathing patterns patients with mild to moderate forms of OSA experience. Both patients with OSA and rodents in the CIH model develop diurnal hypertension, which is a sustained increase in blood pressure that persists into the waking hours. Hypertension involves multiple organ systems, including the central nervous system, and can be a heterogenous disease state that manifests from a number of factors, including CIH, ANG II from renin-angiotensin system (RAS), and changes in body fluid osmolality. This led to the hypothesis that pathway-specific inhibition of MnPO neurons that project to pre-autonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus would block persistent hypertension. Results indicate that lesioning PVN-projecting MnPO neurons can block CIH-induced hypertension, resulting in decreases in oxidative stress and improved cardiovascular health. These findings provide new information about how the MnPO differentially regulates behavioral and physiological outcomes in a stimulus-dependent manner. These outcomes also have broad clinical implications relating to the role of the central nervous system in disease states affecting body fluid balance and blood pressure regulation.