Current Perspective on the Location and Function of Gamma- Aminobutyric Acid (GABA) and its Metabolic Partners in the Kidney.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter located in the mammalian central nervous system, which binds to GABAA and GABAB receptors to mediate its neurological effects. In addition to its role in the CNS, an increasing number of publications have suggested that GABA might also play a role in the regulation of renal function. All three enzymes associated with GABA metabolism; glutamic acid decarboxylase, GABA ?-oxoglutarate transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH) have been localised to the kidney providing the necessary machinery for localised GABA synthesis and metabolism. Moreover GABA receptors have been localised to both tubular and vascular structures in the kidney, and GABA is excreted in urine (~3 ?M) in humans. Despite the collective evidence describing the presence of a GABA system in the kidney, the precise function of such a system requires further clarification. Here we provide an overview of the current renal GABA literature and provide novel data that indicates GABA can act at contractile pericyte cells located along vasa recta capillaries in the renal medulla to potentially regulate medullary blood flow

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 125

This special bibliography lists 323 reports, articles, and other documents introduced into the NASA scientific and technical information system in January 1974

A quantitative estimation of regulation and transport limitations in the human cardiopulmonary system

The object of this dissertation is to quantitatively describe the regulation of some of the exchange processes within the human body. Conceptually this dissertation is divided into two sections. In the first section a macroscopic view was adopted to describe the overall regulation of the cardiovascular and respiratory systems. These overall system models were used as heuristic tools to gain an understanding of physiological behavior in micro-gravity. In the second section, a microscopic view was used to estimate the role played by the surfactant system of the lung in regulating the transfer of fluid across the pulmonary-capillary wall;The basis of the cardiovascular system model is the maintenance of arterial blood pressure homeostasis. Sub-models constituting the overall model are: the pressure-flow model, the heart action model, the controller model which describes short term-control, and the renal model which describes long term control and the regulation of total body water content. Model predictions show that incorporating the fluid shift from the lower to the upper part of the body in micro-gravity is sufficient to account for the cardiovascular changes occurring in micro-gravity;The respiratory model is concerned with the maintenance of a constant carbon dioxide level in the tissue and body fluids. The sub-models constituting the overall respiratory model are: the gas-exchange model, the mechanics model, and the controller model which determines the ventilation and cardiac output on the basis of arterial blood gas tensions. Simulation results show that pleural pressure homogeneity, increased lung diffusing capacity and decreased lung volume are sufficient to describe respiratory changes in micro-gravity;In the penultimate section the lung mechanics model is coupled with a model of fluid exchange across the pulmonary-capillary wall. The lung mechanics model estimates the influence of the surfactant system of the lung in controlling the interstitial space hydrostatic pressure while the fluid exchange model determines the influence of the interstitial space hydrostatic pressure in regulating fluid movement across the pulmonary-capillary wall. This model quantitatively estimates the influence of the surfactant alone in regulating fluid movement across the pulmonary-capillary wall

A Translational Study of the Correlation Between Low Birth Weight, Hypertension, and Kidney Function Using a Rat Model

We studied the correlation between low birth weight, hypertension, and kidney function using a rat model. There is a strong correlation between these three phenomena especially in the Southeastern United States and in non-White populations. We hypothesized that the anti-hypertensive drugs Reserpine and Hydralazine would prevent hypertension and improve renal function in low birth weight rats. We used a rat model created by Dr. Barbara Alexander in this study. Pregnant rats were subjected to Reduced Uterine Perfusion Pressure surgery. Silver clips were placed on the abdominal aorta and uterine arteries approximately two weeks after fertilization in order to restrict blood flow to the developing fetus. The reduced nutrient availability results in slower fetal development and low birth weight offspring. Two drugs with effects on cardiovascular function were used to lower blood pressure. Hydralazine was administered via drinking water at a dose of 80mg/L initiated at 6 weeks of age until the end experiment at 12 weeks of age. Reserpine was administered via drinking water at a dose of 5mg/L initiated at 6 weeks of age until the end of experiments at 12 weeks of age. Administration of this medication constituted the “treated” rats. At 12 weeks of age, catheters were inserted to measure blood pressure and glomerular filtration rate was calculated. Mild schemia reperfusion was performed to see how the kidneys reacted to mild stress. We found that the uterine restricted rats had normal gestations, but weighted significantly less than the controls at birth. The rats gained weight at the same rate and weighed the same at the end of the study. As expected, low birth weight untreated offspring had higher blood pressure than any other group. Surprisingly, GFR/g in the uterine-restricted, unstressed, untreated animals was not significantly higher, as predicted from both the higher MAP and presumably lower nephron number in these rats. Thus, there was no evidence of significant hyperfiltration occurring, and so this seemingly cannot explain the hypertension which developed. Based on this study, I would advocate using low birth weight as a biomarker for elevated risk of hypertension and kidney disease

The modeling and simulation of feedback control systems

A brief description of the principles of mathematical models and their development is given. It should serve as an introduction to those unfamiliar with the topic

Physiologic adaptations of the tubuloglomerular feedback system

The maintenance of volume homeostasis is sufficiently important to mammalian terrestrial life that a large amount of evolutionary energy has been expended in the development of multiple control systems, each involved in regulating the volume and composition of internal body fluids. The kidney, which participates in most of these systems, has evolved physiologic attributes which enhance the efficiency of volume regulation. Perhaps the most fundamental of these attributes is a close coordination between the processes of glomerular filtration and tubular reabsorption. Such coordination is required to prevent the amplification of small fluctuations in glomerular filtration rate into large fluctuations in total body salt and water content.It was first suggested by Homer Smith that reabsorption of fluid from the nephron should increase as the delivery of tubular fluid into that segment increases [1]. When applied to the proximal tubule, this principle of flow-dependent transport has come to be referred to as “glomerulotubular balance” [2, 3]. Glomerulotubular balance depends upon intrinsic properties of the proximal nephron including the affinities and densities of various solute transporters and the differential permeabilities of the nephron to various solutes and water, and upon the trans-epithelial concentration gradients of these solutes [4–6]. By definition, glomerulotubular balance describes the functional dependence of tubular reabsorption on glomerular filtration rate independently of other neuro-humoral effectors of tubular transport. However, since glomerulotubular balance is a substrate-driven process, it cannot accomplish an increment in proximal tubular reabsorption which exceeds an increment in delivered load. Therefore, in the absence of effectors other than glomerulotubular balance the volume of fluid entering the distal nephron must be a monotonically increasing function of GFR [7].How then, may the kidney avert an unintentional diuresis should the hemodynamic forces favoring glomerular filtration combine to overwhelm the reabsorptive capacity of the nephron? In 1937 Goormaghtigh suggested that the juxtaglomerular apparatus might participate in the maintenance of volume homeostasis by generating some sort of signal in response to changes in the composition of distal tubular fluid [8]. The peculiar anatomic arrangement of the nephron would facilitate transmission of this signal to the upstream glomerulus and lead to alterations in the physiologic determinants of glomerular filtration. This hypothesis has been refined over the past three decades as substantial experimental data have accrued to support the existence of an operational system of tubuloglomerular feedback (TGF) [9]. Contemporary models of the TGF system, by analogy to negative feedback-driven control systems in engineering control theory, divide the system into three component processes [10]. The first of these components is a parameter which the system is designed to regulate, in this case, the rate at which tubular fluid transits the late proximal nephron or VLP. The second component includes the macula densa and surrounding interstitium which serve to detect differences between the current value of VLP and some internal set-point, and translate this information into an output command. The third component, or effector limb, of the TGF system is constituted by the contractile glomerular mesangium and glomerular arterioles which respond to the aforementioned output command by altering nephron filtration rate (SNGFR) to keep VLP in line with the system's internal set-point. When TGF is allowed to function as a closed-loop system [7], as is the case in vivo, its presence is, by nature, undetectable. However, when late proximal flow is uncoupled from nephron filtration by artificial microperfusion of the late proximal tubule, a dependence of SNGFR on VLP can be defined [11]. This relationship is referred to as the “TGF function”, or “gain” of the TGF system [7, 10]. This TGF function specifies a continuum of points in the VLP-SNGFR plane at which the nephron may operate. The actual operating point of the system exists at the point in this plane where the TGF and glomerulotubular balance functions intersect (Fig. 1).The TGF function may vary in response to the changing needs of the organism, both with regard to volume homeostasis and renal function. The altering of TGF under conditions of pregnancy, loss of renal mass, and a variety of other pathophysiologic conditions suggests that the juxtaglomerular apparatus is involved in events pertinent not merely to volume regulation but to overall renal growth and function

Heart-Lung Interactions in Aerospace Medicine

Few of the heart-lung interactions that are discussed have been studied in any detail in the aerospace environment, but is seems that many such interactions must occur in the setting of altered accelerative loadings and pressure breathing. That few investigations are in progress suggests that clinical and academic laboratory investigators and aerospace organizations are further apart than during the pioneering work on pressure breathing and acceleration tolerance in the 1940s. The purpose is to reintroduce some of the perennial problems of aviation physiology as well as some newer aerospace concerns that may be of interest. Many possible heart-lung interactions are pondered, by necessity often drawing on data from within the aviation field, collected before the modern understanding of these interactions developed, or on recent laboratory data that may not be strictly applicable. In the field of zero-gravity effects, speculation inevitably outruns the sparse available data