Bifurcation study of blood flow control in the kidney.

Renal blood flow is maintained within a narrow window by a set of intrinsic autoregulatory mechanisms. Here, a mathematical model of renal hemodynamics control in the rat kidney is used to understand the interactions between two major renal autoregulatory mechanisms: the myogenic response and tubuloglomerular feedback. A bifurcation analysis of the model equations is performed to assess the effects of the delay and sensitivity of the feedback system and the time constants governing the response of vessel diameter and smooth muscle tone. The results of the bifurcation analysis are verified using numerical simulations of the full nonlinear model. Both the analytical and numerical results predict the generation of limit cycle oscillations under certain physiologically relevant conditions, as observed in vivo

Assessment and Mechanisms of Autonomic Function in Health and Disease

The autonomic nervous system is a master regulator of homeostasis, and the conviction that autonomic outflow is important on a patient-by-patient, minute-to-minute basis in both health and disease is the motivation for this thesis. The dissertation explores three aims that advance our understanding of the autonomic nervous system by elucidating the molecular mechanisms of autonomic regulation, validating widely used techniques for autonomic assessment, and developing and applying a new method to assess sympathetic vascular control. The first aim of the dissertation was to investigate the role of the Rho kinase pathway as a mediator of the autonomic effects of central angiotensin-II. This study was performed in conscious, chronically instrumented rabbits that received intracerebroventricular infusions of angiotensin-II, angiotensin-II with the specific Rho kinase inhibitor Fasudil, Fasudil alone, or a vehicle control over two weeks. Baseline hemodynamics were assessed daily, and cardiac and global vasomotor sympathetic tone was assessed by the hemodynamic response to autonomic blockers. Angiotensin-II raised blood pressure and cardiac and global vasomotor sympathetic outflow in a Rho-kinase dependent manner. In a separate cohort, renal sympathetic nerve activity was directly recorded and sympathetic baroreflex sensitivity was assessed, providing clear evidence that angiotensin-II increases renal sympathetic nerve activity and impairs baroreflex control thereof via a Rho kinase-dependent mechanism. In summary, the pressor, sympatho-excitatory, and baroreflex dysfunction caused by central angiotensin-II depend on Rho kinase activation. The second aim was to investigate the relationship between measures of pulse rate variability obtained by a chronically implanted arterial pressure telemeter with measures of heart rate variability derived by the standard electrocardiogram and the ability of pulse rate variability to reflect the autonomic contributions of heart rate variability. This study was conducted in conscious rabbits chronically instrumented with epicardial leads and arterial pressure telemeters. The autonomic contribution to pulse rate variability was assessed by pharmacological blockade, and the intrinsic variability of pulse rate was assessed by ventricular pacing. This study showed that pulse rate variability is a generally acceptable surrogate for heart rate variability for time- and frequency-domain measures, but the additional contribution of respiration to and the differing nonlinear properties of pulse rate variability should be considered by investigators. The third aim was to critically test the idea that the renal sympathetic nerves do not participate in the physiological control of renal blood flow. This study was conducted in conscious rabbits that underwent unilateral renal denervation and chronic instrumentation with arterial pressure telemeters and bilateral renal blood flow probes. Using time-varying transfer function analysis, this study showed active, rhythmic vasoconstriction of the renal vasculature with baroreflex properties in normally innervated kidneys, consistent with sympathetic vasomotion, which was absent in denervated kidneys. This refutes the long-held idea that sympathetic control of the renal vasculature is not physiological and has important applications to the burgeoning field of therapeutic renal denervation for cardiovascular disease

Sodium channel regulatory mechanisms : current fluctuation analysis on frog skin epithelium

This project examined the role of the cytoskeleton in regulatory mechanisms of the amiloride-sensitive Na⁺ channels in isolated frog skin epithelium. The epithelium from ventral frog skin is a model tissue which has proved significant in our understanding of the basic principles involved in water and Na⁺ homeostasis. In particular, this project examines ways in which local (non-hormonal) and hormonal regulatory mechanisms adjust the Na⁺ permeability of apical membranes of frog skin epithelium. Both mechanisms contain factors that are known to increase the apical membrane Na⁺ permeability mainly by increases in the number of open channels. The origin of these new open channels is unknown but, it is postulated that they could arise either by activation of quiescent channels already present in the apical membrane, or by recruitment of channels from cytoplasmic stores. Regarding the latter hypothesis, we also examined the idea that the cytoskeleton might somehow be involved in the insertion of Na⁺ channels within vesicles, into the apical membrane. This is based on the fact that the cytoskeleton is involved in a similar mechanism whereby, in the toad urinary bladder, anti-diuretic hormone (ADH) causes the insertion of aggregates with water channels. Much current interest focuses on the role of the cytoskeleton in the regulation of epithelial Na⁺ channels. To test this hypothesis, we used noise analysis to examine the effects of disrupting the cytoskeleton, on two different mechanisms which bring about changes in open channel densities. The mechanisms are: (1) lowering mucosal Na⁺ concentration (non-hormonal), and (2) addition of arginine-vasopressin (A VP) (hormonal). Non-hormonal, autoregulatory changes in apical membrane Na⁺ conductance were examined by investigating the effects of reducing the mucosal Na⁺ concentration. Our results showed that lowering the mucosal Na⁺ concentration induced large increases in the open channel density in order to stabilise the transport rate. In addition, we observed an average 55-60% increase in the open channel probability, which implies that in epithelium from Rana fuscigula, changes of channel open probability are also an important mechanism in the autoregulation of channel densities in response to a reduction in mucosal Na⁺. The hormonal control of Na⁺ channels by A VP has been intensively studied by noise analysis and the patch clamp. Our results confirmed previous reports that A VP increases the Na⁺ transport rate by increasing the number of open Na⁺ channels, primarily through large changes in the total number of channels, without a significant change in open probability. Regarding the role of the cytoskeleton in regulation of Na⁺ channels and/or its possible role in control of inserting putative vesicles with Na⁺ channels, we studied the effects of disrupting the cytoskeleton on the two regulatory mechanisms. Disrupting microtubules with colchicine had no, or very little effect on either of the regulatory mechanisms. On the other hand, the integrity of the microfilaments was very important for the autoregulatory changes in the number of open channels. After cytochalasin B treatment, lowering the mucosal Na⁺ concentration did not result in the usual compensatory changes in channel densities. There was no prior evidence that cytochalasin B had any actual effect on the F-actin network in the frog skin epithelium. Accordingly, modified cytochemical techniques were designed to demonstrate and localise F-actin in the epithelial granular cells. The direct immunofluorescent method proved useful, but did not allow sufficient resolution to examine the changes to different populations of actin in the cells. We then modified an immunogold method to suit our conditions, and the results demonstrated the localisation of different pools of F-actin and showed the effects of the cytochalasin B and vasopressin

Regulation of the renal circulation

It is a great pleasure for me to participate in honoring my mentor, Dr. Donald W. Seldin. When I began my fellowship in Dailas in 1967, the field of renal physiology was booming. Laboratories all over the world were beginning to unravel the puzzle of sodium handling by the nephron and Seldin was one of the main catalysts. From this intellectual experience in Dallas, I spent the next decade or so studying the renal circulation, its effect on sodium transport, and various humoral factors that play a role in the regulation of renal resistance. It's incredible how much our knowledge has changed in these 23 years. I first heard of prostaglandins in 1968 at one of the weekly sessions in Dallas from a visiting professor. Renal autoregulation was poorly understood and few incisive experimental studies had been done. The kinin system was just beginning to emerge and obviously no one had heard of atrial natriuretic peptide or endothelin.In this brief article, I'd like to review two facets of the renal circulation: autoregulation and various humoral agents which regulate renal vasomotor tone. Because of space constraints, this will be quite brief and I would refer interested readers to a more extensive review of the subject by Dr. Claudia Hura and myself [1]

High salt diet impairs cerebral blood flow regulation via salt‐induced angiotensin II suppression

ObjectivesThis study sought to determine whether salt‐induced ANG II suppression contributes to impaired CBF autoregulation.MethodsCerebral autoregulation was evaluated with LDF during graded reductions of blood pressure. Autoregulatory responses in rats fed HS (4% NaCl) diet vs LS (0.4% NaCl) diet were analyzed using linear regression analysis, model‐free analysis, and a mechanistic theoretical model of blood flow through cerebral arterioles.ResultsAutoregulation was intact in LS‐fed animals as MAP was reduced via graded hemorrhage to approximately 50 mm Hg. Short‐term (3 days) and chronic (4 weeks) HS diet impaired CBF autoregulation, as evidenced by progressive reductions of laser Doppler flux with arterial pressure reduction. Chronic low dose ANG II infusion (5 mg/kg/min, i.v.) restored CBF autoregulation between the pre‐hemorrhage MAP and 50 mm Hg in rats fed short‐term HS diet. Mechanistic‐based model analysis showed a reduced myogenic response and reduced baseline VSM tone with short‐term HS diet, which was restored by ANG II infusion.ConclusionsShort‐term and chronic HS diet lead to impaired autoregulation in the cerebral circulation, with salt‐induced ANG II suppression as a major factor in the initiation of impaired CBF regulation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/1/micc12518_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149286/2/micc12518.pd

Detection of Spatial and Temporal Interactions in Renal Autoregulation Dynamics

Renal autoregulation stabilizes renal blood flow to protect the glomerular capillaries and maintain glomerular filtration rates through two mechanisms: tubuloglomerular feedback (TGF) and the myogenic response (MR). It is considered that the feedback mechanisms operate independently in each nephron (the functional unit of the kidney) within a kidney, but renal autoregulation dynamics can be coupled between vascular connected nephrons. It has also been shown that the mechanisms are time-varying and interact with each other. Understanding of the significance of such complex behavior has been limited by absence of techniques capable of monitoring renal flow signals among more than 2 or 3 nephrons simultaneously. The purpose of this thesis was to develop approaches to allow the identification and characterization of spatial and temporal properties of renal autoregulation dynamics. We present evidence that laser speckle perfusion imaging (LSPI) effectively captures renal autoregulation dynamics in perfusion signals across the renal cortex of anaesthetized rats and that spatial heterogeneity of the dynamics is present and can be investigated using LSPI. Next, we present a novel approach to segment LSPI of the renal surface into phase synchronized clusters representing areas with coupled renal autoregulation dynamics. Results are shown for the MR and demonstrate that when a signal is present phase synchronized regions can be identified. We then describe an approach to identify quadratic phase coupling between the TGF and MR mechanisms in time and space. Using this approach we can identify locations across the renal surface where both mechanisms are operating cooperatively. Finally, we show how synchronization between nephrons can be investigated in relation to renal autoregulation effectiveness by comparing phase synchronization estimates from LSPI with renal autoregulation system properties estimated from renal blood flow and blood pressure measurements. Overall, we have developed approaches to 1) capture renal autoregulation dynamics across the renal surface, 2) identify regions with phase synchronized renal autoregulation dynamics, 3) quantify the presence of the TGF-MR interaction across the renal surface, and 4) determine how the above vary over time. The described tools allow for investigations of the significance and mechanisms behind the complex spatial interactions and time-varying properties of renal autoregulation dynamics

The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature.

Funder: CIHRFunder: NINDS NIH HHSIntravenous norepinephrine (NE) is utilized commonly in critical care for cardiovascular support. NE's impact on cerebrovasculature is unclear and may carry important implications during states of critical neurological illness. The aim of the study was to perform a scoping review of the literature on the cerebrovascular/cerebral blood flow (CBF) effects of NE. A search of MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to December 2019 was performed. All manuscripts pertaining to the administration of NE, in which the impact on CBF/cerebral vasculature was recorded, were included. We identified 62 animal studies and 26 human studies. Overall, there was a trend to a direct vasoconstriction effect of NE on the cerebral vasculature, with conflicting studies having demonstrated both increases and decreases in regional CBF (rCBF) or global CBF. Healthy animals and those undergoing cardiopulmonary resuscitation demonstrated a dose-dependent increase in CBF with NE administration. However, animal models and human patients with acquired brain injury had varied responses in CBF to NE administration. The animal models indicate an increase in cerebral vasoconstriction with NE administration through the alpha receptors in vessels. Global and rCBF during the injection of NE displays a wide variation depending on treatment and model/patient

Magnetic resonance imaging and cerebrovascular hemodynamics in (pre)-eclampsia

Hoge bloeddruk tijdens de zwangerschap is gevaarlijk. De mogelijke gevolgen, zoals hersenoedeem, stuipen en hersenbloedingen, eisen jaarlijks wereldwijd 50 tot 65 duizend vrouwenlevens. Ook in Nederland is deze zogeheten 'preëclampsie' de hoofdoorzaak van moedersterfte. Toch grijpen artsen vaak te laat in volgens Gerda Zeeman. Dit omdat er te weinig bekend is in de medische wetenschap over veranderingen in de hersendoorbloeding. Ook leren de handboeken dat vrouwen in principe geheel herstellen. Zeeman bracht als eerste de veranderingen in de hersenen in beeld en constateert onder meer dat er wel degelijk blijvende schade kan zijn. Hoge bloeddruk komt ongeveer bij vijf tot tien procent van de zwangerschappen voor. Bij een patiënt met preëclampsie (ook wel zwangerschapsvergiftiging of toxicose genoemd) kunnen stuipen ontstaan, soms gevolgd door een hersenbloeding. Dit komt omdat de bloeddruk dan acuut stijgt. Zeeman heeft tijdens haar opleiding veel ervaring opgedaan met de behandeling van deze patiënten: ‘Een stuipende vrouw zorgt voor een angstaanjagend moment voor artsen en verpleegkundigen en het is een drama wanneer je een moeder daarna ziet overlijden.’ Medische handboeken onderwijzen dat een vrouw geheel herstelt na stuipen en dat hersenbloedingen zeldzaam zijn. Daarom wordt er momenteel vaak veel te laat gestart met bloeddrukverlagende medicatie. Maar een groot deel van de vrouwen lijkt jarenlang verschijnselen over te houden aan de stuipen, zoals geheugenverlies en gebrek aan concentratievermogen. Blijvende schade Het is bekend dat zwangerschap voor grote veranderingen zorgt in de belasting van hart en bloedvaten, maar de veranderingen in de doorbloeding van de hersenen zijn tot nu toe nagenoeg niet onderzocht. Daarom zijn artsen onzeker welke preventie of behandeling toe te passen. Met moderne MRI-technieken bracht Zeeman in beeld dat bij gezonde zwangere vrouwen de bloeddoorstroming in de hersenen afneemt, terwijl er juist een toename is bij vrouwen met zwangerschapshypertensie. Waarschijnlijk leidt dit mechanisme uiteindelijk tot stuipen. Verder ontdekte de promovendus dat een kwart van de patiënten in meer of mindere mate blijvende hersenschade overhoudt aan stuipen. Stuipen en hersenbloedingen zijn in veel gevallen te voorkomen door tijdig de bloeddruk te verlagen en magnesiumsulfaat toe te dienen. Dat gebeurt helaas nog veel te weinig in Nederland. Hoe het magnesiumsulfaat werkt is niet bekend. Men denkt dat het samentrekking van de hersenvaten tegengaat, maar Zeeman ontdekte dat het gunstige effect van magnesiumsulfaat daar niet aan toe te schrijven is.