Physiological Modeling and Simulation-Validation, Credibility, and Application.

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 therapeutics, this question is of critical importance. Without an answer, it impairs the usefulness of models and casts a shadow over model credibility in all domains. To address this question, we examine the use of nonmathematical models in physiological research, in medical practice, and in engineering to see how models in other domains are used and accepted. We reflect on historic physiological models and how they have been presented to the scientific community. Finally, we look at various validation frameworks that have been proposed as potential solutions during the past decade.

Preeminent role of the cardiorenal axis in the antihypertensive response to an arteriovenous fistula: an in silico analysis.

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated 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 due to 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and/or 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After a small fistula was stimulated, there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 wk, BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Furthermore, when chronic resetting of atrial mechanoreceptors was prevented during the fistula, RSNA decreased 7%, and along with the same threefold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared with the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after the creation of an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.NEW & NOTEWORTHY The mechanisms that contribute to the antihypertensive effects of a small arteriovenous (AV) fistula comparable to the size used by the ROX coupler currently in clinical trials are unclear and not readily testable in clinical or experimental studies. The integrative mathematical model of human physiology used in the current study provides a tool for understanding key causal relationships that account for blood pressure (BP) lowering and for testing competing hypotheses. The findings from the simulations suggest that after creation of a small AV fistula increased ANP secretion plays a critical role in mediating long-term reductions in BP. Measurement of natriuretic peptide levels in hypertensive patients implanted with the ROX coupler would provide one critical test of this hypothesis.

Early treatment with GLP-1 after severe trauma preserves renal function in obese Zucker rats.

Early posttrauma hyperglycemia (EPTH) is correlated with later adverse outcomes, including acute kidney injury (AKI). Controlling EPTH in the prehospital setting is difficult because of the variability in the ideal insulin dosage and the potential risk of hypoglycemia, especially in those with confounding medical comorbidities of obesity and insulin resistance. Glucagon-like peptide-1 (GLP-1) controls glucose levels in a glucose-dependent manner and is a current target in antidiabetic therapy. We have shown that after orthopedic trauma, obese Zucker rats exhibit EPTH and a later development of AKI (within 24 h). We hypothesized that GLP-1 treatment after trauma decreases EPTH and protects renal function in obese Zucker rats. Obese Zucker rats (~12 wk old) were fasted for 4 h before trauma. Soft tissue injury, fibula fracture, and homogenized bone component injection were then performed in both hind limbs to induce severe extremity trauma. Plasma glucose levels were measured before and 15, 30, 60, 120, 180, 240, and 300 min after trauma. GLP-1 (3 µg·kg-1·h-1, 1.5 ml/kg total) or saline was continuously infused from 30 min to 5 h after trauma. Afterwards, rats were placed in metabolic cages overnight for urine collection. The following day, plasma interleukin (IL)-6 levels, renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygen delivery (Do2) and consumption (V̇o2) were measured. EPTH was evident within 15 min after trauma but was significantly ameliorated during the 5 h of GLP-1 infusion. One day after trauma, plasma IL-6 was markedly increased in the trauma group and decreased in GLP-1-treated animals. RBF, GFR, and Do2 all significantly decreased with trauma, but renal V̇o2 was unchanged. GLP-1 treatment normalized RBF, GFR, and Do2 without affecting V̇o2. These results suggest that GLP-1 decreases EPTH and protects against a later development of AKI. Early treatment with GLP-1 (or its analogs) to rapidly, effectively, and safely control EPTH may be beneficial in the prehospital care of obese patients after trauma.

Role of the heart in blood pressure lowering during chronic baroreflex activation: insight from an in silico analysis.

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 robust blood pressure lowering occurs even after renal denervation. Because controlling renal sympathetic nerve activity (RSNA) and cardiac autonomic activity cannot be achieved experimentally, we used an established mathematical model of human physiology (HumMod) to provide mechanistic insights into their relative and combined contributions to the cardiovascular responses during baroreflex activation. Three-week responses to baroreflex activation closely mimicked experimental observations in dogs including decreases in blood pressure, heart rate, and plasma norepinephrine and increases in plasma atrial natriuretic peptide (ANP), providing validation of the model. Simulations showed that baroreflex-induced alterations in cardiac sympathetic and parasympathetic activity lead to a sustained depression of cardiac function and increased secretion of ANP. Increased ANP and suppression of RSNA both enhanced renal excretory function and accounted for most of the chronic blood pressure lowering during baroreflex activation. However, when suppression of RSNA was blocked, the blood pressure response to baroreflex activation was not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that baroreflex activation effectively lowers blood pressure in subjects with previous renal denervation. NEW & NOTEWORTHY Both experimental and clinical studies have shown that the presence of renal nerves is not an obligate requirement for sustained reductions in blood pressure during chronic electrical stimulation of the carotid baroreflex. Simulations using HumMod, a mathematical model of integrative human physiology, indicated that both increased secretion of atrial natriuretic peptide and suppressed renal sympathetic nerve activity play key roles in mediating long-term reductions in blood pressure during chronic baroreflex activation.

Mechanisms of blood pressure salt sensitivity: new insights from mathematical modeling.

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 changes in salt intake were examined during normal renal function, fixed low or high plasma angiotensin II (ANG II) levels, bilateral renal artery stenosis, increased renal sympathetic nerve activity (RSNA), and decreased nephron numbers. Simulations were run for 4 wk at salt intakes ranging from 30 to 1,000 mmol/day. Reducing functional kidney mass or fixing ANG II increased salt sensitivity. Salt sensitivity, associated with inability of ANG II to respond to changes in salt intake, occurred with smaller changes in renal blood flow but greater changes in glomerular filtration rate, renal sodium reabsorption, and total peripheral resistance (TPR). However, clamping TPR at normal or high levels had no major effect on salt sensitivity. There were no clear relationships between BP salt sensitivity and renal vascular resistance or extracellular fluid volume. Our robust mathematical model of cardiovascular, renal, endocrine, and sympathetic nervous system physiology supports the hypothesis that specific types of kidney dysfunction, associated with impaired regulation of ANG II or increased tubular sodium reabsorption, contribute to BP salt sensitivity. However, increased preglomerular resistance, increased RSNA, or inability to decrease TPR does not appear to influence salt sensitivity. This model provides a platform for testing competing concepts of long-term BP control during changes in salt intake.

Microcirculatory Effects of Botulinum Toxin A in the Rat: Acute and Chronic Vasodilation.

BACKGROUND: Botulinum toxin-A (BTX) has numerous cosmetic and therapeutic applications. Our previous studies have found that BTX augments pedicled flap survival through both vasodilatory effects and attenuation of the inflammatory response to ischemia in the rat. This study examines the effect of chronic BTX on microcirculatory vascular tone and its response to acute topical vasodilators in muscle flaps. METHODS: The spinotrapezius muscle of Sprague-Dawley rats underwent a single 2-week pretreatment of 0.2 mL saline either with (n = 5) or without (n = 5) 2u BTX. After surgical elevation, an arcade arteriole was observed using a video caliper device. Vessel diameter was measured at 30-second intervals after sequential superfusion of nitroglycerin (100 and 200 µg/mL), multiple concentrations of lidocaine, and a combination of adenosine (10 µM) and nitroprusside (10 µM) to induce maximum dilation. RESULTS: Baseline and dilation diameters were expressed as ratios of pharmacologically induced maximum dilation, whereas percent dilation was defined as the change in diameter over baseline diameter. We found a significant increase in resting diameter with BTX pretreatment (P = 0.0028). Compared with the control group, mean baseline diameter was 15% greater, and percent dilation was 25% less in BTX-pretreated flaps. There was no significant relationship between BTX pretreatment and dilation diameter (P = 0.2895) after adjusting for the effect of acute vasodilators. CONCLUSIONS: Pretreatment with BTX may induce the arteriolar resting diameter to be closer to their maximum potential diameter. Additionally, BTX does not display a synergistic effect with topical vasodilators on vasodilation.

Hyperglycemia-Mediated Oxidative Stress Increases Pulmonary Vascular Permeability.

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 permeability through superoxide. METHODS: Lung capillary Kf and vascular superoxide were measured in the isolated lungs of LZ and OZ rats. OZ were subjected to 4 weeks of metformin treatment (300 mg/kg/day orally) to improve insulin sensitivity. In a separate experiment, lung vascular permeability and vascular superoxide were measured in LZ exposed to acute hyperglycemia (30 mM). RESULTS: As compared to LZ, OZ had impaired glucose and insulin tolerance and elevated vascular superoxide which was associated with an elevated lung Kf. Chronic metformin treatment in OZ improved glucose control and insulin sensitivity which was associated with decreased vascular oxidative stress and lung Kf. Acute hyperglycemia in isolated lungs from LZ increased lung Kf, which was blocked with the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (3 mM). Apocynin also decreased baseline Kf in OZ. CONCLUSIONS: These data suggest that hyperglycemia in metabolic syndrome exacerbates lung vascular permeability through increases in vascular superoxide, possibly through NADPH oxidase.

Oxidative stress contributes to orthopedic trauma-induced acute kidney injury in obese rats.

After trauma, obese patients have an increased risk of developing acute kidney injury (AKI). We have demonstrated that obese Zucker (OZ) rats, but not lean Zucker (LZ) rats, develop AKI 24 h after orthopedic trauma. ROS have been implicated in the pathophysiology of AKI in models of critical illness. However, the contribution of ROS to trauma-induced AKI in the setting of obesity has not been determined. We hypothesized that AKI in OZ rats after trauma is mediated by increased oxidative stress. Male LZ and OZ rats were divided into control and trauma groups, with a subset receiving treatment after trauma with the antioxidant apocynin (50 mg/kg ip, 2 mM in drinking water). The day after trauma, glomerular filtration rate, plasma creatinine, urine kidney injury molecule-1, and albumin excretion as well as renal oxidant and antioxidant activity were measured. After trauma, compared with LZ rats, OZ rats exhibited a significant decrease in glomerular filtration rate along with significant increases in plasma creatinine and urine kidney injury molecule-1 and albumin excretion. Additionally, oxidative stress was significantly increased in OZ rats, as evidenced by increased renal NADPH oxidase activity and urine lipid peroxidation products (thiobarbituric acid-reactive substances), and OZ rats also had suppressed renal superoxide dismutase activity. Apocynin treatment significantly decreased oxidative stress and AKI in OZ rats but had minimal effects in LZ rats. These results suggest that ROS play an important role in AKI in OZ rats after traumatic injury and that ROS may be a potential future therapeutic target in the obese after trauma.

Preventing and Treating Hypoxia: Using a Physiology Simulator to Demonstrate the Value of Pre-Oxygenation and the Futility of Hyperventilation.

INTRODUCTION: 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 saturation on coronary perfusion, or that of low carbon dioxide concentrations on cerebral perfusion. We suggest the use of HumMod, a computer-based human physiology simulator, to demonstrate beneficial physiological responses to pre-oxygenation and the futility of excessive minute ventilation after intubation. METHODS: We programmed HumMod, to A.) compare varying times (0-7 minutes) of pre-oxygenation on oxygen saturation (SpO2) during subsequent apnoea; B.) simulate hyperventilation after apnoea. We compared the effect of different minute ventilation rates on SpO2, acid-base status, cerebral perfusion and other haemodynamic parameters. RESULTS: A.) With no pre-oxygenation, starting SpO2 dropped from 98% to 90% in 52 seconds with apnoea. At the other extreme, following full pre-oxygenation with 100% O2 for 3 minutes or more, the SpO2 remained 100% for 7.75 minutes during apnoea, and dropped to 90% after another 75 seconds. B.) Hyperventilation, did not result in more rapid normalization of SpO2, irrespective of the level of minute ventilation. However, hyperventilation did cause significant decreases in cerebral blood flow (CBF). CONCLUSIONS: HumMod accurately simulates the physiological responses compared to published human studies of pre-oxygenation and varying post intubation minute ventilations, and it can be used over wider ranges of parameters than available in human studies and therefore available in the literature.

Inhibition of NADPH oxidase prevents acute lung injury in obese rats following severe trauma.

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 stress. Severe trauma was induced in lean and obese Zucker rats by muscle injury, fibula fracture, and bone component injection to both hindlimbs, with or without 24-h treatments of apocynin, a NADPH oxidase (NOX) inhibitor. Lung wet/dry weight ratios, lung vascular Kf, lung neutrophil counts, lung NOX and myeloperoxidase (MPO) activity, and plasma IL-6 levels were measured 24 h after trauma. In an additional study, lungs were isolated from nontrauma lean and obese rats to determine the acute effect of phenazime methosulfate, a superoxide donor, on pulmonary vascular Kf. After trauma, compared with lean rats, obese rats exhibited greater increases in lung capillary Kf, neutrophil accumulation, NOX and MPO activity, and plasma IL-6. The lung wet/dry weight ratio was increased in obese rats but not in lean rats. Apocynin treatment decreased lung Kf, neutrophil counts, NOX and MPO activities, wet/dry weight ratio, and plasma IL-6 in obese rats. Phenazime methosulfate treatment resulted in a greater increase in lung Kf in nontrauma obese rats compared with nontrauma lean rats. These results suggest that obese rats are susceptible to lung injury following severe trauma due to increased production of and responsiveness to pulmonary oxidative stress.

ß(2)-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats.

Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via ß2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg(-1)·h(-1) iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that ß2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

Oxidative stress increases pulmonary vascular permeability in diabetic rats through activation of transient receptor potential melastatin 2 channels.

OBJECTIVE: In vitro superoxide activates pulmonary endothelial TRPM2 channels and increases 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 using STZ. Half of the STZ animals were treated with apocynin, a NOX inhibitor. After four weeks, lung Kf was measured in the isolated lung in the presence or absence of TRPM2 inhibitors (2-APB and FA). In an additional set of experiments, Kf was measured in nondiabetic Zucker rats after applying the superoxide donor (PMS). RESULTS: As compared to control rats, hyperglycemic rats exhibited increased vascular superoxide and Kf , along with decreased lung vascular TRPM2-L expression. Apocynin treatment reduced superoxide and Kf in hyperglycemic rats with no effect in control rats. TRPM2 channel inhibition decreased Kf in hyperglycemic rats with no effect in control rats. PMS increased the lung Kf in control rats, with TRPM2 inhibition attenuating this response. CONCLUSION: Diabetic rats exhibit a TRPM2-mediated increase in lung Kf , which is associated with increased TRPM2 activation and increased vascular superoxide levels.

Impaired vascular KATP function attenuates exercise capacity in obese zucker rats.

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 following treatment with the KATP blocker glibenclamide i.p. One week later, the spinotrapezius muscle was prepared for in vivo microscopy. Arcade arteriolar diameters were measured following muscle contraction or application of the KATP opener cromakalim before and after glibenclamide application. In additional animals, LZR and OZR were treated with apocynin for five weeks. VO2max and arteriolar dilation experiments were repeated. RESULTS: The OZR exhibited decreased VO2max , functional and cromakalim-induced vasodilation as compared with LZR. Glibenclamide had no effect on VO2max and functional vasodilation in OZR, but significantly inhibited responses in LZR. Vascular superoxide levels and NADPH oxidase activity were increased in OZR, but reduced in apocynin-treated OZR. Apocynin increased the VO2max , functional and cromakalim-induced vasodilation in OZR with no effect in LZR. CONCLUSIONS: Exercise capacity is dependent on vascular KATP channel function. The reduced exercise capacity in OZR appears to be due in part to superoxide-mediated impairment in vascular KATP function.

The apparent hysteresis in hormone-agonist relationships.

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 profiles of the hormone-agonist axis in this model via four types of protocols, three of which emulating experiments from the literature, and observed a delay- and load-dependent hysteresis that is an expected mathematical artifact of the system described. In particular, the delay associated with correction allows for over-secretion of the hormone influencing the corrective mechanism; thus rate dependence is an artifact of the corrective mechanism, not a sensitivity of the gland to the magnitude of change. From these observations, the detected hysteresis is due to delays inherent in the systems being studied, not in the secretory mechanism.

Systems biology and integrative physiological modelling.

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 aetiologies of complex diseases. Scientists predict the data will make personalized medicine rapidly available. However, the data need to be considered as a highly complex system comprising multiple inputs and feedback mechanisms. Translational medicine requires the functional and conceptual linkage of genetics to proteins, proteins to cells, cells to organs, organs to systems and systems to the organism. To help understand the complex integration of these systems, a mathematical model of the entire human body, which accurately links the functioning of all organs and systems together, could provide a framework for the development and testing of new hypotheses that will be important in clinical outcomes. There are several efforts to develop a 'Human Physiome', with the strengths and weaknesses of each being presented here. The development of a 'Human Model', with verification, documentation and validation of the underlying and integrative responses, is essential to provide a usable environment. Future development of a 'Human Model' requires integrative physiologists working in collaboration with other scientists, who have expertise in all areas of human biology, to develop the most accurate and usable human model.

Improved functional vasodilation in obese Zucker rats following exercise training.

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 vasodilation in the spinotrapezius muscle of the OZ, but the mechanisms responsible for the improvement in functional vasodilation are not clear. Based on evidence that exercise training improves insulin resistance, we hypothesized that, in the OZ, exercise training increases functional vasodilation and exercise capability due to decreases TP-mediated vasoconstriction associated with improved insulin sensitivity. Six-week-old lean Zucker rats (LZ) and OZ were exercised on a treadmill (24 m/min, 30 min/day, 5 days/wk) for 6 wk. An oral glucose tolerance test was performed at the end of the training period. We measured functional vasodilation in both exercise trained (spinotrapezius) and nonexercise trained (cremaster) muscles to determine whether the improved functional vasodilation following exercise training in OZ is due to a systemic improved insulin resistance. Compared with LZ, the sedentary OZ exhibited impairments in glucose tolerance and functional vasodilation in both muscles. The TP antagonist SQ-29548 improved the vasodilator responses in the sedentary OZ with no effect in the LZ. Exercising training of the LZ increased the functional vasodilation in spinotrapezius muscle, with no effect in the cremaster muscle. Exercising training of the OZ improved glucose tolerance, along with increased functional vasodilation, in both the spinotrapezius and cremaster muscles. SQ-29548 treatment had no effect on the vasodilator responses in either cremaster or spinotrapezius muscles of the exercise-trained OZ. These results suggest that, in the OZ, there is a global effect of exercising training to improve insulin resistance and increase functional vasodilation via a decreased TP-mediated vasoconstriction.

In silico trial of baroreflex activation therapy for the treatment of obesity-induced hypertension.

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 the ability to analyze complicated interrelated effects across multiple physiological systems. Our current model HumMod is a large physiological simulator that has been used previously to investigate mechanisms responsible for BP lowering during baroreflex activation therapy (BAT). First, we used HumMod to create a virtual population in which model parameters (n = 335) were randomly varied, resulting in unique models (n = 6092) that we define as a virtual population. This population was calibrated using data from hypertensive obese dogs (n = 6) subjected to BAT. The resultant calibrated virtual population (n = 60) was based on tuning model parameters to match the experimental population in 3 key variables: BP, glomerular filtration rate, and plasma renin activity, both before and after BAT. In the calibrated population, responses of these 3 key variables to chronic BAT were statistically similar to experimental findings. Moreover, blocking suppression of renal sympathetic nerve activity (RSNA) and/or increased secretion of atrial natriuretic peptide (ANP) during BAT markedly blunted the antihypertensive response in the virtual population. These data suggest that in obesity-mediated HTN, RSNA and ANP responses are key factors that contribute to BP lowering during BAT. This modeling approach may be of value in predicting BAT responses in future clinical studies.

Orthopedic trauma-induced pulmonary injury in the obese Zucker rat.

OBJECTIVE: 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 increases in pulmonary permeability. METHODS: Orthopedic trauma was induced in both hindlimbs in lean (LZ) and obese Zucker rats (OZ). On the following day, plasma interleukin-6 (IL-6) and PGE(2) levels, pulmonary edema, and pulmonary gas exchange capability were compared between groups: LZ, OZ, LZ with trauma (LZT), and OZ with trauma (OZT). Vascular permeability in isolated lungs was measured in LZ and OZ before and after application of PGE(2) . RESULTS: As compared with the other groups, the OZT exhibited elevated plasma IL-6 and PGE(2) levels, increased lung wet/dry weight ratio and bronchoalveolar protein concentration, and an impaired pulmonary gas exchange. Indomethacin treatment normalized plasma PGE(2) levels and pulmonary edema. Basal pulmonary permeability in isolated lungs was higher in OZ than LZ, with a further increase in permeability following treatment with PGE(2) . CONCLUSIONS: These results suggest that pulmonary edema in OZ following orthopedic trauma is due to an elevated PGE(2) and resultant increases in pulmonary permeability.