Browsing by Subject "Hypertension"
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Item ANGIOTENSIN CONVERTING ENZYME 1 (ACE1) KNOCKDOWN IN THE MEDIAN PREOPTIC NUCLEUS (MNPO) ATTENUATES SUSTAINED DIURNAL HYPERTENSION FOLLOWING CHRONIC INTERMITTENT HYPOXIA(2014-03) Faulk, Katelynn; Cunningham, J. Thomas; Nedungadi, Thekkethil P.In order to study hypertension associated with Sleep Apnea, our lab uses a hypoxia model on rats. Rats are routinely used to model cardiovascular diseases of humans. We try to discover how the brain controls blood pressure in certain cardiovascular risk groups such as sleep apnea patients. This will help the scientific community better understand how sustained hypertension develops and progresses in sleep apnea patients and may lead to other discoveries about cardiovascular diseases. Purpose (a): Chronic Intermittent Hypoxia (CIH) is a model for the arterial hypoxemia seen in sleep apnea and is associated with a sustained increase in blood pressure throughout the diurnal cycle. Studies indicate that the MnPO contributes to this sustained component of CIH hypertension that persists during normoxia. MnPO neurons from rats show increased expression of the transcription factor FosB following CIH. Dominant-negative inhibition of a FosB splice variant in MnPO attenuates the sustained hypertension in CIH. We identified the pro-hypertensive ACE1 as a possible FosB target gene that may contribute to the sustained hypertension seen in CIH. Methods (b): We tested this hypothesis using a viral vector to knockdown ACE1 in the MnPO. Isoflurane anesthetized adult male rats were microinjected in the MnPO with 500nl of an adeno-associated virus containing GFP and either shRNA against ACE1 (shACE1) or a scrambled shRNA (shSCM). Changes in Mean arterial blood pressure (MAP) were recorded using radio telemetry. Rats were then exposed to CIH for 7 days through 3 minute periods of hypoxia (10% oxygen) and 3 minute periods of normoxia (21% oxygen) for 8 hours per day (0800-1600 h). Normoxic controls were exposed to room air. Laser capture microdissection followed by qRT-PCR showed that shACE1 significantly decreased ACE1 message in MnPO. Results (c): During CIH exposure, MAP significantly increased in both shACE1 and shSCM treated rats. During the normoxic dark phase, knockdown of ACE1 in the MnPO statistically decreased the sustained MAP component of CIH as compared to shSCM controls (P<0.001). Conclusions (d): These results show that ACE1 in the MnPO contributes to the sustained hypertension seen in our CIH model.Item Angiotensin II type 1 receptor agonistic autoantibody blockade improves postpartum hypertension and cardiac mitochondrial function in rat model of preeclampsia(BioMed Central Ltd., 2021-11-02) Booz, George W.; Kennedy, Daniel; Bowling, Michael; Robinson, Taprieka; Azubuike, Daniel; Fisher, Brandon; Brooks, Karen; Chinthakuntla, Pooja; Hoang, Ngoc H.; Hosler, Jonathan P.; Cunningham, Mark W., Jr.Women with preeclampsia (PE) have a greater risk of developing hypertension, cardiovascular disease (CVD), and renal disease later in life. Angiotensin II type I receptor agonistic autoantibodies (AT1-AAs) are elevated in women with PE during pregnancy and up to 2-year postpartum (PP), and in the reduced uterine perfusion pressure (RUPP) rat model of PE. Blockade of AT1-AA with a specific 7 amino acid peptide binding sequence ('n7AAc') improves pathophysiology observed in RUPP rats; however, the long-term effects of AT1-AA inhibition in PP is unknown. Pregnant Sprague Dawley rats were divided into three groups: normal pregnant (NP) (n = 16), RUPP (n = 15), and RUPP + 'n7AAc' (n = 16). Gestational day 14, RUPP surgery was performed and 'n7AAc' (144 mug/day) administered via osmotic minipump. At 10-week PP, mean arterial pressure (MAP), renal glomerular filtration rate (GFR) and cardiac functions, and cardiac mitochondria function were assessed. MAP was elevated PP in RUPP vs. NP (126 +/- 4 vs. 116 +/- 3 mmHg, p < 0.05), but was normalized in in RUPP + 'n7AAc' (109 +/- 3 mmHg) vs. RUPP (p < 0.05). PP heart size was reduced by RUPP + 'n7AAc' vs. RUPP rats (p < 0.05). Complex IV protein abundance and enzymatic activity, along with glutamate/malate-driven respiration (complexes I, III, and IV), were reduced in the heart of RUPP vs. NP rats which was prevented with 'n7AAc'. AT1-AA inhibition during pregnancy not only improves blood pressure and pathophysiology of PE in rats during pregnancy, but also long-term changes in blood pressure, cardiac hypertrophy, and cardiac mitochondrial function PP.Item AT1A RECEPTOR KNOCKDOWN IN THE MEDIAN PREOPTIC NUCLEUS ATTENUATES THE SUSTAINED COMPONENT OF HYPERTENSION RESULTING FROM CHRONIC INTERMITTENT HYPOXIA(2013-04-12) Shell, BrentPurpose: Obstructive sleep apnea produces hypertension and increases sympathetic nerve activity during the hypoxic sleeping events as well as during the waking hours. This study examined a possible receptor contribution to the sustained component of hypertension. Methods: To model the hypoxemia experienced during sleep apnea, rodents are exposed to chronic intermittent hypoxia (CIH). The median preoptic nucleus (MnPO) is a forebrain region that contributes to this sustained increase in mean arterial pressure (MAP) from CIH. This region integrates information from forebrain circumventricular organs and projects to the paraventricular nucleus to influence sympathetic nerve activity. Our lab has previously shown that in response to CIH there is increased ΔFosB expression in the MnPO and that after a 7 day hypoxia protocol MnPO AT1a receptor mRNA is increased 7 fold whereas AT1b shows no change. In this study, we tested the hypothesis that MnPO AT1a receptors contribute to CIH hypertension using adult male Sprague Dawley rats injected with a neuron specific adenoviral vectors with either shRNA to knock down expression of AT1a receptors in the MnPO or a scrambled RNA sequence. Results: All rats showed an increase in MAP during the hypoxic light period, but rats receiving the AT1a knock down did not exhibit the sustained increase in MAP during the normoxic dark phase (P<.05). Conclusions: This data indicates that the AT1a receptors in the MnPO is necessary for the sustained component of hypertension resulting from CIH.Item CONTRIBUTION OF THE MNPO ANGIOTENSIN RECEPTORS TO BRAIN STEM ACTIVITY AND HYPERTENSION(2014-03) Shell, Brent; Cunningham, TomSleep apnea can increase blood pressure. It is not understood what changes in the brain occur while experiences lack of oxygen during sleep apnea that results in high blood pressure both during the day and during the sleeping hours. Our lab uses a model of sleep apnea that exposes rodents to periods of reduced oxygen. We have found that removing a receptor for a specific chemical in the front of the brain prevents the increase of blood pressure during the normal oxygen waking hours. This current study shows that the knockdown of this receptor decreases activity in the rear portions of the brain that directly control blood pressure. Understanding the mechanisms how sleep apnea leads to hypertension is essential for effective treatment of the disease. Purpose (a): The repeated bouts of hypoxia experienced by sufferers of sleep apnea results in persistent blood pressure elevation. This pathophysiological increase in pressure exists in both the hypoxic night phase and the normoxic period. Neurological mechanisms that drive this maladaptive blood pressure increase are not well understood. Our lab has shown that knockdown of the Angiotensin type 1a (At1a) receptor in a forebrain nucleus, the median preoptic nucleus (MnPO), prevents the normoxic blood pressure increase. How the MnPO At1a receptors affect downstream nuclei to maintain normal pressure is not known. In the current study, rats were exposed to chronic intermittent hypoxia (CIH) to simulate the hypoxic effects of sleep apnea. We then examined the activity of downstream nuclei by performing immunohistochemistry for ∆FosB, a marker for neuronal activity. We hypothesize that knockdown of AT1a in the MnPO results in decreased ∆FosB expression in downstream hypertensive nuclei such as the caudal ventrolateral medulla (CVLM), the rostral ventrolateral medulla (RVLM), and the nucleus tractus solitaries (NTS). Methods (b): After exposure to chronic intermittent hypoxia (CIH), rats are sacrificed, perfused with 4% paraformaldehyde, dehydrated with sucrose, and serial sectioned at 40 microns on a cryostat. Sections are split into three groups; one group is used for immunohistochemistry. Sections are processed with primary goat antibody for ∆FosB, a secondary biotinilated anti-goat, and finally visualized using diaminobenzidine. Localization of the NTS, CLVM, and RVLM was performed by double labeling for dopamine-β-hydroxylase (DβH), an enzyme used in the production of catecholamines. DβH was visualized using a CY3 fluorophore. Cell counts utilized at least 3 brain sections per nucleus. Results (c): A significant difference was found between the AT1a knockdown rats and the scramble rats in the subpostremal region of the NTS. This region has neurons that are responsible for processing both baroreceptor and chemoreceptor information. Conclusions (d): The MnPO is connected to this region through the paraventricular nucleus. Decreased MnPO activity could cause a decrease in the quantity of inputs to the hindbrain. These results, coupled with the prevention of the normoxic blood pressure increase, indicate that angiotensin acting through the MnPO is affecting the activity of neurons in the brainstem that are directly controlling blood pressure regulation.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 Mechanisms of Glucocorticoid-induced ocular hypertension(2003-08-01) Zhang, Xinyu; Thomas YorioZhang, Xinyu, Mechanisms of glucocorticoid-induced ocular hypertension. Doctor of Philosophy (Pharmacology & Neuroscience). August 2003; 163p; 4 tables; 24 figures; 102 titles. Glucocorticoids, frequently used anti-inflammatory and immunosuppressive agents, are associated with ocular hypertension and glaucoma. Endothelin-1 (ET-1) is also implicated in glaucoma pathology and optic neuropathy as its concentration is elevated in glaucoma patients and in animal models of glaucoma and chronic administration of ET-1 produces damage to the optic nerve head in rats. Glucocorticoids have been reported to regulate the expression of ET-1 gene and ET receptors in the cardiovascular system. However in the eye, the interactions between glucocorticoids and ET-1 have been implicated in the regulation of intraocular pressure and contribute to glaucoma pathology. Therefore, the purpose of the investigations described herein was to determine the novel mechanisms that may be involved in the regulation of intraocular pressure by glucocorticoids with interactions with ET-1 and ET receptors in NPE cells, a source of ET-1, and in TM cells where both glucocorticoids and ET-1 effect aqueous humor outflow. The hypothesis was that ET-1 exacerbates the actions of glucocorticoids on TM cells and contributes to increased outflow resistance. Furthermore, individual sensitivities to glucocorticoids differ considerably. About one in every three people in the general population is considered potential steroid responders while almost all primary open angle glaucoma (POAG) patients are steroid responders and develop ocular hypertension after ocular administration of glucocorticoids. The molecular mechanisms underlying the higher glucocorticoid responsiveness among POAG patients remain unknown. The glucocorticoid receptor beta isoform (hGRβ) has become a candidate for glucocorticoid resistance in some diseases, especially in asthma, based on the reports of its negative activity. The purpose of this segment of the investigations was to test the hypothesis that glucocorticoid responsiveness was regulated by the expression of hGRβ in TM cells. We demonstrated that dexamethaosone (Dex), a synthetic glucocorticoid, increased ET-1 synthesis and release from human non-pigmented ciliary epithelial (HNPE) cells. Dex also suppressed ETB receptor protein expression and attenuated ET-1 mediated increase in nitric oxide (NO) while Dex had no effect on ETA receptor expression and ETA receptor mediated intracellular Ca2+ mobilization in TM cells. The increase in the release of ET-1 from HNPE cells with a concomitant decrease of ETB receptor protein expression and ETB receptor mediated NO release by Dex in TM could result in an increase in the contraction and decrease in relaxation of trabecular meshwork thus reducing the intratrabecular space. Such actions by ET-1 may exacerbate Dex effects on the outflow pathway leading to increased outflow resistance and consequently elevated intraocular pressure that typically is associated with glucocorticoids. We have also found a significant difference in hGRβ levels among normal versus glaucomatous TM cell lines, with the POAG TM cell lines having lower hGRβ receptor expression. This is coincidence with the fact that in the normal population, there is a low rate of glucocorticoid responders as compared to almost all POAG patients considered as glucocorticoid responders. Overexpression of hGRβ in TM cells, produced by transfecting a hGRβ expression construct, inhibited Dex-induced expression of myocilin, a glaucomatous gene, supporting the contention that hGRβ acts as a negative regulator of glucocorticoid activity. In addition, we studied the machinery of cytoplasm to nuclear transport of hGRβ. We identified that a chaperon protein, hsp90, is a requirement for the nuclear translocation of hGRβ. In conclusion, we have described a novel-signaling pathway for glucocorticoids through the regulation of ET-1 and ET receptors in the anterior segment which have consequences on aqueous humor outflow. We have also demonstrated a possible molecular mechanism by which glucocorticoid responsiveness in POAG patients is achieved as a result of the low level of nuclear hGRβ receptor isoform expression. Furthermore, we have, for the first time, identified hap90 as a chaperon protein for the translocation of hGRβ from the cytoplasm to the nucleus.Item MEDIAN PREOPTIC NUCLEUS NEURONS ACTIVATED FOLLOWING CHRONIC INTERMITTENT HYPOXIA PROJECT TO THE PARAVENTRICULAR NUCLEUS(2013-04-12) Faulk, KatelynnPurpose: Chronic Intermittent Hypoxia (CIH) is a model for the arterial hypoxemia seen in sleep apnea and is associated with hypertension and increased sympathetic tone. In rats, the MnPO demonstrates increased FosB expression following CIH. A major projection from the MnPO is to the paraventricular nucleus (PVN). This projection may serve as one possible pathway for increased sympathetic tone and sustained hypertension in CIH. The purpose of this study is to further characterize MnPO neurons transcriptionally activated by CIH and determine if they project to the PVN. Methods: Isoflurane anesthetized adult male rats were microinjected with 200nl of a retrograde tracer, flourogold, unilaterally into PVN. Rats were then exposed to CIH for 7 days through 3 minute periods of hypoxia (10% oxygen) and 3 minute periods of normoxia (21% oxygen) for 8 hours per day (0800-1600 h). Controls were not exposed to to room air. Forebrains were fixed through paraformaldehyde perfusion and later processed for immunohistochemistry. Antibodies used were goat polyclonal FosB (1:2000). The sections were imaged using an Olympus DSU confocal microscope. Results: In the MnPO, CIH exposure increased FosB positive cells (Control 7.75± l.l; CIH 25.7±4.4; P<0.05) and colocalization of FosB with flourogold positive cells (Control 0.67±0.4; CIH 7.25±1.2; P<0.05). Conclusions: These results show that MnPO neurons transcriptionally activated by CIH project to the PVN. P01 HL88052Item Potential Predictors of Hypertension Among Children in Fort Worth, Texas: A Cross-Sectional Epidemiologic Study(2002-05-01) Egbuchunam, Christie U.; Bayona, Manuel; Urrutia-Rojas, Ximena; Wilkinson, GreggEgbuchunam, Christie U., Potential Predictors of Hypertension Among Children in Fort Worth, Texas; A Cross-Sectional Epidemiologic Study. Master of Public Health (Epidemiology), May, 2002, 110 pp., 15 tables, 2 illustrations, bibliography, 84 titles. Most studies have identified obesity, gender and age as major factors that influence blood pressure increase in children. The objective of this study was to assess factors that may either directly influence hypertension in children, or interact with obesity, age and gender. A cross-sectional study was carried out to identify and assess the crude and multiple logistic regression adjusted associations between selected variables and hypertension. Obesity and Acanthosis Nigricans (AN) were importantly associated with hypertension. Reduced playing time, and excessive television watching or playing of video games were also associated with hypertension; especially among those who were obese or had AN. Hispanic and African American children had higher likelihood of hypertension than Caucasian children.Item The Phenotype of Cells Expressing Estrogen Receptor Alpha in the Nucleus of the Solitary Tract(2018-05) Horn, Christopher L.; Mifflin, Steve W.; Schreihofer, Ann M.; Cunningham, J. Thomas; Phillips, Nicole R.Estrogen protects females from hypertension. The nucleus tractus solitarius (NTS) is a hindbrain site involved in the regulation of blood pressure, however little is known about estrogen receptors within the NTS. The purpose of these studies was to determine the phenotype of the cells expressing estrogen alpha receptors in the nucleus tractus solitarius. Four female Sprague-Dawley rats were transcardially perfused with 4% paraformaldehyde and hindbrains harvested. In coronal sections containing the NTS (40μm thick), immunohistochemistry was performed to determine which type of cells were expressed with estrogen receptor alpha (ERα) expressing cells. We used the anti-ERα antibody with an antibody for each protein of interest: anti-tyrosine hydroxylase (TH), anti-glial fibrillary acidic protein (GFAP), anti-NeuN, and anti-Iba-1. Sections were captured using an Olympus BX41 Fluorescence Microscope and analyzed using ImageJ. The NTS was divided into 2 regions: sections caudal to the area postrema (caudal) and sections lying below the area postrema (sub-postrema, SP) and the number of immunoreactive neurons in each region counted and expressed as an average number of labeled neurons per section±SEM. The number of sections analyzed ranged from 5-10 per individual in caudal and 2-4 per individual in SP. At sacrifice, females were in estrus (1), diestrus (2) or proestrus (3). NeuN in SP NTS (n=4) was observed in 151±53 and ERα in 50±21 neurons per section. Colocalization of ERα and NeuN in SP NTS was observed in 11±6 neurons per section (about 7%). NeuN in caudal NTS was observed in 59±7 and ERα 27±3 neurons per section. Colocalization of ERα and NeuN in caudal NTS was observed in 4±1 neurons per section (about 7%). TH in SP NTS (n=6) was observed in 49±8 and ERα in 51±12 neurons per section. Colocalization of ERα and TH in SP NTS was observed in 26±4 neurons per section (about 53%). TH in caudal NTS was observed in 26±6 and ERα 29±7 neurons per section. Colocalization of ERα and TH in caudal NTS was observed in 17±4 neurons per section (about 51%). Due to the quantity and shape of GFAP immunoreactive cells in the NTS (n=4), we were not able to count the number cells. Colocalization of ERα and GFAP expressing cells were not observed in our study. Cells expressing Iba1 were not observed in the later trials of our study (n=4). ERα is expressed on a subset of catecholaminergic NTS neurons, as well as non-catecholaminergic neurons. Since the NTS catecholaminergic neurons contribute to responses to stress (e.g., hypoxia), this finding could provide a substrate for estrogen-mediated cardiovascular protection in females.Item TRENDS IN THE DIAGNOSIS AND TREATMENT OF ANTIHYPERTENSIVEAMBULATORY PATIENTS BY US OFFICE-BASED PHYSICIANS(2004-05-01) Barnett, David W.; Karan SinghThis descriptive study assessed trends in ambulatory.patients' antihypertensive therapy by US office-based physicians for visits in 2001 in which hypertension was a diagnosis. These trends were compared with the Sixth Report by the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-6) guidelines; the therapeutic antihypertensive standard in 2001. Data from the National Center for Health Statistics' 2001 National Ambulatory Medical Care Survey were used. Blood pressure measurements were documented in 8SO!c. of the patient office visits. No significant trends were observed in diagnostic screening services or in lifestyle modification services. Diuretics and beta-blockers, the antihypertensive drug classes preferred by the JNC-6 guidelines, were mentioned in 9.SO!c. and 16.']0/o of antihypertensive patient office visits. Antihypertensive drug visits mentioning ACE inhibitors and calcium channel blockers were 24.3 and 21.7 percent respectively. Antihypertensive drug therapy was mentioned in 77.4 percent of patient office visits. Physician antihypertensive drug prescribing was generally consistent with the basic antihypertensive drug guidelines of JNC-6.