Robert L Hester

• University of Mississippi Medical Center

Primary aldosteronism (PA) is associated with hypertension (HTN), and these patients have significant lowering of blood pressure (BP) and improved hypokalemia when moving to a DASH dietary intervention (≤65 mEq/day Na ⁺ and ≥120 mEq/day K ⁺ ). However, current guidelines for PA treatment briefly recommend lowering Na ⁺ intake and make no specific m...

For the last 20 years, we have observed that patients with drug resistant hypertension due to primary aldosteronism (PA) have significant lowering of blood pressure (BP) and improved hypokalemia when moving to a DASH dietary intervention (≤65 mEq/day Na ⁺ / ≥120 mEq/day K ⁺ ). However, current guidelines for PA treatment briefly recommend lowering...

Recently, SGLT2 inhibitors have been approved for chronic kidney disease (CKD) based on their ability to slow renal disease progression and reduce cardiovascular mortality independent of diabetes status. However, the exact mechanisms of their cardiovascular and renal protection in these patients remain unclear. While some believe hyperglycemia driv...

Clinical trials demonstrate baroreflex activation therapy (BAT) reduces LV mass and blood pressure (BP) in hypertensive patients and in patients with hypertensive heart failure with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in the disease progression seen in these patient...

Clinical trials evaluating the efficacy of chronic electrical stimulation of the carotid baroreflex for the treatment of hypertension (HTN) are ongoing. However, the mechanisms by which this device lowers blood pressure (BP) are unclear, and it is uncertain which patients are most likely to receive clinical benefit. Mathematical modeling provides t...

In this review, we discuss the science of model validation as it applies to physiological modeling. There is widespread disagreement and ambiguity about what constitutes model validity. In areas in which models affect real-world decision-making, including within the clinic, in regulatory science, or in the design and engineering of novel therapeuti...

Background African Americans (AA) develop hypertension (HTN) at an earlier age, have a greater frequency and severity of HTN, and greater prevalence of uncontrolled HTN as compared to the white population. Mineralocorticoid antagonists have been shown to be very effective in treating uncontrolled HTN in both AA and white patients, but sex-specific...

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be du...

Early post-trauma hyperglycemia (EPTH) is correlated with later adverse outcomes including acute kidney injury (AKI). We have shown that following orthopedic trauma, obese Zucker rats (OZ) exhibit EPTH and a later development of AKI (within 24 hours). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in OZ...

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation are often attributed to renal sympathoinhibition. However, baroreflex activation also decreases heart rate, and...

African Americans (AA) develop hypertension (HTN) at an earlier age, have a greater frequency and severity of HTN, and have poorer control of blood pressure (BP) as compared to the white population. The mechanisms responsible for these disparities are unknown. The multifactorial nature of HTN and the similar presentation of its etiologies complicat...

Disturbances in water and electrolyte homeostasis are common following transsphenoidal surgery. These disturbances are variable and unpredictable, increasing patient risk and complicating postsurgical treatment decisions. Clinically, it is generally accepted that damage to the pituitary stalk is the source of these disturbances, but the mechanisms...

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt-sensitive hypertension for many individuals. Factors that are important in the condition of decreased renal mass and how they affect blood pressure (BP) or salt sensitivity are unc...

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure (AP) and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation (BA) are often attributed to renal sympathoinhibition. However, BA also decreases heart rate (HR) and, sur...

Background: Disturbances in water and electrolyte homeostasis are common following transsphenoidal surgery. These disorders are variable and unpredictable, increasing patient risk and complicating postsurgical treatment. Clinically, it is generally accepted that damage to the pituitary is the etiology, but the mechanisms behind the response variab...

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. Reduced functional renal mass plays an important role in causing salt sensitive hypertension for many individuals but the mechanisms are unclear. Moreover, different derangements in human physiology can result in the same phenotype. Methodologies tha...

Mathematical modeling is an important tool for understanding quantitative relationships among components of complex physiological systems and for testing competing hypotheses. We used HumMod, a large physiological model, to test hypotheses of blood pressure (BP) salt sensitivity. Systemic hemodynamics, renal, and neurohormonal responses to chronic...

Exercise is the act of increasing metabolic rate for the purpose of enhancing physical fitness. Exercise can be one of the most stressful physiological responses that the body undertakes. With exercise, there are increases in metabolic rate, heart rate, blood flow (hyperemia), respiration, and heat production. The increased metabolic requirement du...

Water homeostasis is one of the body's most critical tasks. Physical challenges to the body, including exercise and surgery, almost always coordinate with some change in water handling reflecting the changing needs of the body. Vasopressin is the most important hormone that contributes to short-term water homeostasis. By manipulating vascular tone...

A surrogate model is a black box model that reproduces the output of another more complex model at a single time point. This is to be distinguished from the method of surrogate data, used in time series. The purpose of a surrogate is to reduce the time necessary for a computation at the cost of rigor and generality. We describe a method of construc...

Salt sensitivity, with or without concomitant hypertension, is associated with increased mortality. In the clinical setting, determining salt‐sensitivity in patients is laborious and an expensive challenge with low patient compliance. A large subset of salt‐sensitive patients with hypertension are known to be resistant to diuretic therapy. Personal...

Objective: Hyperglycemia in diabetes mellitus is associated with endothelial dysfunction as evidenced by increased oxidative stress and vascular permeability. Whether impaired glucose control in metabolic syndrome impacts pulmonary vascular permeability is unknown. We hypothesized that in metabolic syndrome, hyperglycemia increases lung vascular p...

Technological advancements have paved the way for new approaches to modeling, simulation, and visualization. This chapter introduces the fundamentals of physics-based modeling (PBM) and simulation in the medical and health sciences from the academic, industrial, and regulatory aspects. It summarizes the efforts of multiple consortia dedicated to im...

Insufficient pre-oxygenation before emergency intubation, and hyperventilation after intubation are mistakes that are frequently observed in and outside the operating room, in clinical practice and in simulation exercises. Physiological parameters, as appearing on standard patient monitors, do not alert to the deleterious effects of low oxygen satu...

Sato et al. (1) showed that β2-adrenoreceptor–mediated phosphorylation of mammalian target of rapamycin complex 2 (mTORC2) in skeletal muscles increased GLUT4 translocation to the plasma membrane and thus increased cellular glucose uptake. In diabetes and obesity, an upregulated G-protein–coupled receptor kinase, which inhibits G-protein–coupled re...

Stress hyperglycemia following trauma has been shown to potentiate morbidity and mortality. Glucose control in obese patients can be challenging due to insulin resistance. Thus, understanding the mechanisms for glucose generation following hemorrhage may provide important insights into alternative options for glycemic control in obesity. Obesity is...

Following trauma, obese patients have an increased risk of developing acute kidney injury (AKI). We have demonstrated that obese Zucker (OZ), but not lean Zucker (LZ) rats, develop AKI 24 hours following orthopedic trauma. Reactive oxygen species (ROS) have been implicated in the pathophysiology of AKI in models of critical illness. However, the co...

Objective In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases the capillary filtration coefficient (Kf). We hypothesized that pulmonary capillary Kf is increased in a model of type I diabetes due to elevated vascular superoxide and resultant TRPM2 channel activation.Methods Type I diabetes was induced in Zucker rats usi...

Early hyperglycemia following trauma increases morbidity and mortality. Insulin is widely used to control post-trauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early post-trauma hyperglycemia control by suppressing hepatic glycogenolysis via β2-adrenoreceptor blockade (ICI 118551, ICI). We have sho...

Understanding variation between humans is a critical step in maximizing the efficiency of clinical trials. We studied the chronic blood pressure response to salt loading in a population of virtual patients created in HumMod, an integrative mathematical model of human physiology. Patients differed in the parameterization of their cardiovascular and...

The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca2+]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion const...

Lung capillary filtration coefficient (Kf) and impacts of oxidative stress have not been determined in the setting of severe trauma, especially in obese patients who exhibit increased lung injury. We hypothesized that severe trauma leads to a greater increase in lung Kf in obesity due to exacerbated production of and/or vulnerability to oxidative s...

It is well known that renal nerves directly affect renal vascular resistance, tubular sodium reabsorption and renin secretion. Inhibition of renal sympathetic nerve activity (RSNA) decreases renal vascular resistance, tubular sodium reabsorption and renin secretion, leading to an increase in sodium excretion. Although there are several studies show...

Obesity is associated with an increased risk of acute kidney injury (AKI) after blunt traumatic injury in humans. Because limitations exist in studying trauma in human patients, animal models are necessary to elucidate mechanisms of remote organ injury after trauma. We developed a model of severe orthopedic trauma in lean (LZ) and obese (OZ) Zucker...

Objective Obese subjects exhibit decreased exercise capacity (VO2max). We have shown that vascular KATP channel mediates arteriolar dilation to muscle contraction. We hypothesize that exercise capacity is decreased in obesity due to impaired vascular KATP function. Methods The VO2max was measured in LZR and OZR by treadmill running before and follo...

We present a small integrative model of human cardiovascular physiology. The model is population-based; rather than using best fit parameter values, we used a variant of the Metropolis algorithm to produce distributions for the parameters most associated with model sensitivity. The population is built by sampling from these distributions to create...

Complex physiological events such as hemorrhage are met with a continuum of responses in individual test subjects that range from complete compensation to circulatory failure. Predicting the circulatory outcome of an individual potentially affects treatment modalities, for example, by indicating that aggressive intervention is justified based on th...

We present HumMod Browser, a multi-scale exploratory visualization tool that lets physiologists validate human physiology simulation results. Showing correlations, exploring causality relationships, analyzing important attributes, and comparing numerous set of ensemble runs are common tasks in model validation. The lack of interactive exploration o...

The dynamics of parathyroid hormone (PTH) secretion in response to calcium perturbation are complex, requiring a solution that passes beyond the four‐parameter steady state solution proposed by Brown. It has been previously noted that dispersed parathyroid cells have disparate responses to hypocalcemia. This suggests that dynamic heterogeneity in t...

Obese patients with orthopedic trauma exhibit increased inflammation and complications correlated with high glucose levels. We hypothesize that in obesity there is increase risk of trauma‐induced hyperglycemia due to insulin resistance and inflammation. Fasted lean (LZ) and obese Zucker (OZ) rats were treated with vehicle or etanercept, a TNF‐α inh...

Computational fluid dynamics (CFD) simulations were performed for unsteady periodic breathing conditions, using large-scale models of the human lung airway. The computational domain included fully coupled representations of the orotracheal region and large conducting zone up to generation four (G4) obtained from patient-specific CT data, and the sm...

Computational fluid dynamics (CFD) simulations were performed to predict the air flow in the human lung during cyclic breathing. The study employed a morphologically complex computational geometry generated using a combination of patient-specific CT-scan data for the extrathoracic and upper airway regions and a representative branching geometry for...

A complex network of hormones, buffers, and signaling mechanisms must work together to maintain proper calcium and phosphate levels in the human body. Quantification of this network is necessary to gain understanding about how various pathophysiologies develop, and how they can be treated. In particular, calcium and phosphate homeostasis are intert...

Obesity is characterized by impaired autonomic activity which may adversely affect cardiovascular responses under pathological conditions such as acute hypovolemia. We hypothesize that obesity can impair acute blood pressure regulation during hemorrhage via lack of sympathetic effectiveness and impaired neural reflexes. Severe hemorrhage (a loss of...

An impaired exercise performance and functional vasodilation has been observed in obesity. There is an increase in reactive oxygen species (ROS), which impairs functional vasodilation in obese Zucker rats (OZ), but the mechanism by which ROS impairs vascular function remains unclear. Since our laboratory has demonstrated that K ATP channel activati...

Diabetes is an independent risk factor for the development of acute renal dysfunction following orthopedic trauma (OT). Whether OT affects renal hemodynamics has yet to be investigated. The hypothesis tested in this study was that OT reduces renal hemodynamics in type 1 diabetes. Male lean Zucker rats (12 wks) were divided into 4 treatment groups (...

We have shown that obese Zucker rats with orthopedic trauma (OZT) exhibit a loss of arteriolar tone in skeletal muscle. We hypothesize that the loss of arteriolar tone in OZT blunts vasoconstrictor responses to hemorrhage, resulting in an impaired blood pressure recovery. Orthopedic trauma was induced with soft tissue injury and local injection of...

HumMod [Hester et al. 2011] models interactions between the cardiovascular, respiratory, renal, neural, endocrine, skeletal muscle, and metabolic physiologies. One of the difficulties which must be overcome with HumMod is the fact that the number of parameters is prohibitive in developing a clear and comprehensive view of the interactions between p...

It has been noted in multiple studies that the calcium-PTH axis, among others, is subject to an apparent hysteresis. We sought to explain a major component of the observed phenomenon by constructing a simple mathematical model of a hormone and secretagogue system with concentration dependent secretion and containing two delays. We constructed profi...

Exercise is the act of increasing metabolic rate for the purpose of enhancing physical fitness. Exercise can be one of the most stressful physiological responses that the body undertakes. With exercise, there are increases in metabolic rate, heart rate, blood flow (hyperemia), respiration, and heat production. The increased metabolic requirement du...

One of the key challenges for computational fluid dynamics (CFD) simulations of human lung airflow is the sheer size and complexity of the complete, multiscale geometry of the bronchopulmonary tree. Since 3-D CFD simulations of the full airway tree are currently intractable, researchers have proposed reduced geometry models in which multiple airway...

Obese individuals exhibit impaired functional vasodilation and exercise performance. We have demonstrated in obese Zucker rats (OZ), a model of morbid obesity, that insulin resistance impairs functional vasodilation via an increased thromboxane receptor (TP)-mediated vasoconstriction. Chronic treadmill exercise training improves functional vasodila...

Mathematical models and simulations are important tools in discovering key causal relationships governing physiological processes. Simulations guide and improve outcomes of medical interventions involving complex physiology. We developed HumMod, a Windows-based model of integrative human physiology. HumMod consists of 5000 variables describing card...

Over the last 10 years, 'Systems Biology' has focused on the integration of biology and medicine with information technology and computation. The current challenge is to use the discoveries of the last 20 years, such as genomics and proteomics, to develop targeted therapeutical strategies. These strategies are the result of understanding the aetiol...

Obese subjects with orthopedic trauma exhibit increased inflammation and an increased risk of pulmonary edema. Prostaglandin E(2) (PGE(2) ) production is elevated during inflammation and associated with increased vascular permeability. We hypothesize that pulmonary edema in obesity following orthopedic trauma is due to elevated PGE(2) and resultant...

The DigitalLung project represents an attempt to develop a multi-scale capability for simulating human respiration with application to predicting the effects of inhaled particulate matter. To accomplish this objective, DigitalLung integrates macroscale models of integrative human physiology, meso-to-microscale computational fluid dynamics simulatio...

Computational models of integrative physiology may serve as a framework for understanding the complex adaptive responses essential for homeostasis in critical illness and resuscitation and may provide insights for design of diagnostics and therapeutics. In this study a computer model of human physiology was compared to results obtained from experim...

Obesity has been shown to impair muscle blood flow in humans. Vasodilatory control mechanisms such as metabolic control, myogenic mechanisms, conducted vasodilation, and release of endothelium-derived factors may be impaired in obesity due to insulin resistance, hyperglycemia, dyslipidemia, inflammation, oxidative stress, and endothelial dysfunctio...

Obesity is associated with impaired functional hyperemic response. We have shown that ATP-sensitive potassium (K(ATP)) channels are important in mediating functional vasodilation. Adipocyte-derived factors (ADFs) can alter vascular tone via opening K(ATP) channels. We hypothesize that, in an animal model of obesity, ADFs will decrease basal arterio...

Quantitative Human Physiology (QHP) is an open‐source XML model of human physiology based on Quantitative Circulatory Physiology (QCP), a previous model created to incorporate over 4000 simultaneous equations. The QHP model has been expanded to include a female (F) subject, allowing investigation of gender differences on human physiology. For this...

Adipocyte derived factors (ADFs) are suggested to contribute to endothelial dysfunction and cardiovascular diseases. We have shown that in ob/ob mice (ob), a model of obesity, both subcutaneous (SF) and visceral fats (VF) produce ADFs and induce vasodilation by activating KATP channels. There is evidence that MC4R‐/‐ mice, another model of obesity,...

Women are more predisposed to orthostatic intolerance than men. The mechanisms for this difference to orthostatic challenges may involve reduced neural sympathetic activation and/or lower blood volume in women. We used the Female and Male models developed under the Quantitative Human Physiology model to investigate these mechanisms. The female mode...

Quantitative Human Physiology (QHP) is an open‐source XML model of human physiology based on Quantitative Circulatory Physiology (QCP), a previous model from our department that incorporates over 4000 simultaneous equations. With QHP, the model has been expanded to include a female (F) subject, which will allow investigation of gender differences o...

In obesity, skeletal muscle blood flow during exercise (functional hyperemia) is impaired. We have indirectly demonstrated that an altered arachidonic acid metabolism is responsible for the impaired functional vasodilation in the obese Zucker rat (OZR), a model of obesity. In this study, we tested the hypothesis that there is an impaired release of...

Skeletal muscle blood flow during exercise is impaired in obesity. We tested the hypothesis that the attenuated vasodilation in skeletal muscle arterioles of obese Zucker rats (OZR) is due to altered K(ATP) channel-mediated vasodilation. K(ATP) channel function was determined in isolated skeletal muscle arterioles in response to the K(ATP) opener c...

1. The present study was designed to determine the mechanisms responsible for functional vasodilation of arterioles paired and unpaired with venules in the rat spinotrapezius muscle. 2. The spinotrapezius muscle (from Sprague-Dawley rats) was treated with combinations of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME...

1. Obesity/metabolic syndrome is associated with augmented a-adrenoceptor sensitivity and impaired hyperaemic responses to exercise. Thus, it is possible that this elevated a-adrenoceptor constriction contributes to the blunted hyperaemic response. 2. Male lean and obese Zucker rats were instrumented for acute measurements of blood pressure (BP) an...

Individuals with metabolic syndrome exhibit insulin resistance and an attenuated functional vasodilatory response to exercise. We have shown that impaired functional vasodilation in obese Zucker rats (OZRs) is associated with enhanced thromboxane receptor (TP)-mediated vasoconstriction. We hypothesized that insulin resistance, hyperglycemia/hyperli...

We have developed Quantitative Human Physiology (QHP), an open source Windows‐based mathematical model of integrative human physiology containing over 3000 variables. QHP describes human physiology using whole‐body properties, organs, and multi‐organ systems. Users can view time‐dependent solutions and interactively alter parameters to investigate...

During exercise, endothelial cell synthesis of prostacyclin (PGI 2 ) increases while thromboxane (TXA 2 ) levels decrease. One hypothesis for the altered functional hyperemia in obesity is a shift in the normal balance of these arachidonic acid (AA) metabolites, resulting in an attenuation of normal vasodilation. Thus, we hypothesize that in the ob...

Preeclampsia (PE) is associated with increased total peripheral resistance (TPR), reduced cardiac output (CO), and diminished uterine and placental blood flow. We have developed an animal model that employs chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats to generate a "preeclamptic-like" state during late gestation that is...

An arteriovenous fistula (AVF) creates high blood flow through the artery and fistula. With this high flow, there is flow-induced remodeling and an increase in diameter, but no intimal hyperplasia. Estrogen has been shown to modify vascular remodeling, decreasing intimal hyperplasia after endothelial injury. These experiments tested the hypothesis...

We have developed Quantitative Circulatory Physiology (QCP), a mathematical model of integrative human physiology containing over 4,000 variables of biological interactions. This model provides a teaching environment that mimics clinical problems encountered in the practice of medicine. The model structure is based on documented physiological respo...

Individuals with hyperglycemia exhibit impaired exercise performance and functional vasodilatory response. Based on the importance of arachidonic acid (AA) metabolites in functional vasodilation and the increased thromboxane-to-prostacyclin ratio in diabetes, we hypothesized that chronic hyperglycemia in diabetes increases thromboxane-receptor (TP)...

Aberrant vascular smooth muscle cell (VSMC) proliferation is one of the etiological factors for hypertension and stroke. Angiotensin II (Ang II) and ethanol (EtOH) have been shown to modulate the proliferation of vascular smooth muscle cells (VSMCs) individually, but the combined effects of Ang II and EtOH on VSMC proliferative activities are unkno...

These studies tested the hypothesis that in obese Zucker rats (OZRs), a model of metabolic syndrome, the impaired functional vasodilation is due to increased thromboxane receptor (TP)-mediated vasoconstriction and/or decreased prostacyclin-induced vasodilation. Spinotrapezius arcade arterioles from 12-wk-old lean (LZR) and OZR were chosen for micro...

Obesity, insulin resistance, dyslipidemia, and hypertension are components of the pathophysiological state known as metabolic syndrome. Adrenergic vasoconstriction is mediated through increases in cytosolic Ca2+ and the myofilaments' sensitivity to Ca2+. In many pathophysiological states, there is an enhanced role for Rho kinase (ROK)-mediated incr...

The purpose of this study was to test the hypothesis that exercise training improves microvascular function in obese Zucker rats, a model of obesity and type II diabetes. Animals were divided into four age-matched groups: lean sedentary (LS), lean exercise (LE), obese sedentary (OS), and obese exercise (OE). The exercise groups were treadmill-exerc...

ATP-stimulated prostacyclin release from veins was investigated using epigastric veins isolated from hamsters. Veins were perfused with MOPS-buffered physiological salt solution (PSS). ATP was administered into the perfusate, and the bath solution (MOPS-PSS) was collected and assayed for the presence of the stable prostacyclin metabolite 6-keto-PGF...

During an increasing metabolic demand, as in exercise, the close venular-arteriolar pairing allows for diffusion of vasoactive substances from the venular blood to the arterioles. Adenosine triphosphate release from red blood cells may stimulate the venular endothelium to release vasoactive metabolites of arachidonic acid. The venous circulation is...

Muscle blood flow is regulated to meet the metabolic needs of the tissue. With the vasculature arranged as a successive branching of arterioles and the larger, >50 microm, arterioles providing the major site of resistance, an increasing metabolic demand requires the vasodilation of the small arterioles first then the vasodilation of the more proxim...

Prostacyclin is a powerful vasodilator that is released from vascular endothelial cells. Previous studies in our laboratory have indicated that arachidonic acid metabolites from venous endothelium play an important role in the dilation of adjacent arterioles during muscle stimulation. Furthermore, recent studies have suggested that ATP released fro...

This study was designed to test the hypothesis that venular administration of ATP resulted in endothelium-dependent dilation of adjacent arterioles through a mechanism involving cyclooxygenase products. Forty-three male golden hamsters were anesthetized with pentobarbital sodium (60 mg/kg ip), and the cremaster muscle was prepared for in vivo micro...

Indomethacin or glibenclamide treatments attenuate functional dilation of larger-diameter "feed" arterioles paired with venules in hamster cremaster muscle. We tested the hypothesis that release of cyclooxygenase products from venules is important for functional dilation of third- and fourth-order arterioles. We also tested whether ATP-sensitive po...

P32 Previous studies from our laboratory suggest that functional arteriolar dilation of larger diameter “feed” arterioles paired with venules is mediated by arachidonic acid metabolites released from the venular endothelium. The aim of the present study was to test the hypothesis that the release of prostanoids from venules is important in the func...