Continuous-wave (CW) Doppler echocardiographic responses to passive tilting were measured in 39 men using the following protocol: standing; supine; +20° head-up; supine; â 20° head-down. Twenty of the subjects were normotensive (NTN) and the rest were borderline hypertensive (B-HTN) according to prior medical diagnosis. Doppler recordings of blood flow for aortic peak velocity (Pkv), peak acceleration (PkA), and stroke velocity integral (SVI) were taken after 15 minutes in each posture. A skilled technician, using the measurement procedures recommended by the instrument manufacturer, positioned the handâ he1d probe at the supra-sternal notch during recording. For both NTN and Bâ HTN groups, Pkv and PkA were unaffected by the imposed postural changes. The SVI was significantly altered (P<0.05) by postural stress, with the NTN group generally showing greater changes than the Bâ HTNs. The standing-to-supine postural change was associated with the largest change in SVI: NTN = 8.0 to 10.7 cm (+34%) and B-HTN = 7.6 to 8.8 cm (+15%). These results were interpreted as follows (1) SVI appears to be sensitive to changes in ventricular pre-load, while PkA and Pkv are not; (2) SVI changes with passive tilting follow the patterns expected for change in ventricular stroke volume and; (3) attenuated SVI responses to postural tilting may suggest impairment in cardiovascular regulation peculiar to individuals at risk for hypertension. / Master of Science

Ketone monoester (KME) supplements are one exogenous ketone intervention which has demonstrated benefits to multiple facets of brain health, including cerebral blood flow (CBF) and cognition. However, it is unknown how KME impact CBF and cognition acutely, and whether the size of KME dose differentially impacts these outcomes. Higher KME doses lower blood pH and arterial CO2 (PaCO2), which are important regulators of CBF. We hypothesized that high-dose KME ingestion would lower CBF via acidosis-induced compensatory reductions in PaCO2, whereas low-dose KME ingestion would enhance CBF, mirroring past findings from other exogenous ketone interventions. Changes in cognitive function were also hypothesized to parallel CBF responses. Twenty young adults (age=23±3 years; BMI=23.4±2.2 kg/m2) participated. In a double-blinded, counterbalanced, crossover design, participants completed 3 separate conditions: 1) high-dose KME (0.6 g/kg); 2) low-dose KME (0.3 g/kg); or 3) placebo. Outcome measures were assessed at fasting baseline, 45-, and 120-min post-ingestion. CBF was assessed using Duplex ultrasound of the internal carotid and vertebral arteries. End-tidal CO2 (PETCO2) was measured using a gas analyzer, to approximate PaCO2. Hippocampal-dependent function was assessed using the lure discrimination index (LDI) and recognition memory score (REC) from the mnemonic similarity task. Over a 2-hour period post-ingestion, low- and high-dose KME lowered CBF to a different extent relative to baseline (45-min (low-dose, high-dose): ∆10.4%, ∆14.0%; 120-min (low-dose, high-dose): ∆6.2%, ∆18.6%; P < 0.001). These reductions were mirrored by dose-dependent reductions in PETCO2 and changes in CBF were positively correlated with changes in PETCO2 (P < 0.001, R2 = 0.219). Despite reductions in CBF, both LDI (P = 0.619) and REC (P = 0.651) were unchanged in the KME conditions. These findings provide a foundational characterization of the acute effects of KME dose on CBF and cognition, which will inform potential therapeutic recommendations on KME for brain health. / Thesis / Master of Science (MSc) / In addition to being an alternative energy source used during fasting or when consuming low amounts of carbohydrates, ketone bodies may act as signals that impact various aspects of brain health. Recent studies suggest that supplementating with a drink that contains ketones is an alternative way to increase ketones in your blood, without dietary modifications. We investigated whether one-time ingestion of a ketone supplement (KME) affects brain blood flow and cognition, as well as whether the size of KME dose differentially impacts these outcomes. Our results show that KME ingestion lowers brain blood flow, to a different extent depending on the dose that was ingested. Despite this, there was no change in memory performance from taking this ketone supplement. These findings were important in demonstrating how KME ingestion impacts the brain, and will inform future guidelines on its potential use for protecting and/or improving brain health.

It was generally accepted that the rate of formation of cerebrospinal °uid (CSF) is independent of intraventricular pressure [26], until A. Sahar and a host of other scientists challenged this belief. A. Sahar substantiated his belief that the rate of (CSF) formation actually depends on intraventricular pressure, see A. Sahar, 1971 [26]. In this work we show that CSF formation depends on some other factors, including the intraventricular pressure. For the purpose of this study, we used the capillary blood °ow model proposed by K.Boryczko et. al., [5] in which blood °ow in the microvessels was modeled as a two-phase °ow; the solid and the liquid volume phase. CSF is formed from the blood plasma [23] which we assume to be in the liquid volume phase. CSF is a Newtonian °uid [2, 23]. The principles and methods of e®ective area" developed by N. Sauer and R. Maritz [21] for studying the penetration of °uid into permeable walls was used to investigate the ¯ltrate momentum °ux from the intracranial capillary wall through the pia mater and epithelial layer of the choroid plexus into the subarachnoid space. We coupled the dynamic boundary equation with the Navier-Stoke's constitutive equation for incompressible °uid, representing the °uid °ow in the liquid volume phase in the capillary to arrive at our model. / Mathematical sciences / M.Sc.

Submitted in partial compliance with the requirements for the Master’s Degree in Technology: Chiropractic, Durban University of Technology, Durban, South Africa, 2015. / Background: When a soft tissue injury occurs the blood vessels and surrounding tissue are damaged leading to haemorrhaging and inflammation. Cryotherapy (cold therapy) is generally acknowledged as the preferable treatment by manual therapists during this immediate post-traumatic period of an injury. Cryotherapy has been shown to result in vasoconstriction decreasing the rate of blood flow which has a favourable effect on inflammation and pain. The commercially available cooling cuff is a relatively new cryotherapy modality offering a mechanism of cooling that does not require freezing and is easy to use. The polymer granules within the cooling cuff are activated by emersion in water therefore freezing is not required making the cooling cuff readily available compared to more traditional forms of cryotherapy. Aim: The aim of this study was to determine the effect of a moist ice pack and a commercially available cooling cuff radial artery blood flow (cm.s-1) and radial artery lumen diameter (mm) after 15 minutes of application. Method: This study was a pre-test post-test design utilising 43 asymptomatic participants that were randomly allocated to one of two groups. Each group either received a standard moist ice pack or a commercially available cooling cuff, placed on the ventral surface of the participants forearm, over the radial artery, for a duration of 15 minutes. Measurements were taken with a Doppler ultrasound to determine radial artery blood flow and lumen diameter, prior to the intervention and 15 minutes after the cryotherapy application. Data analysis was performed using IBM SPSS VERSION 20 (IBM Corp. Released 2010.IBM SPSS Statistics for Windows, Version 19.0. Armonk, New York: IBM Corp.). Statistical significance was set at a p< 0.05 level. Intra-group and inter-group comparisons were measured using repeated measures ANOVA testing. Results: Both the moist ice pack and commercially available cooling cuff resulted in a significant decrease in radial artery blood flow (p< 0.001) after 15 minutes of application with no significant changes being observed in radial artery diameter Conclusions: The commercially available cooling cuff resulted in a similar effect on radial artery blood flow and lumen diameter as moist ice, indicating that the commercially available cooling cuff may be utilised in the acute phase of an injury to alter blood flow. / M

本研究採用結紮眼血管的方法誘發短暫性視網膜缺血，針對同缺血時間同存活時間化成年金黄地鼠中視網膜節細胞的存活和小型膠質細胞的激活。首先，我們的據顯示，和假缺血手術組相對應的存活時間比較，暫時性視網膜缺血10分鐘或30分鐘沒有導致視網膜節細胞的存活明顯下。暫時性視網膜缺血60分鐘再灌注後7天，視網膜節細胞的存活下至58%，14後為51%，28後為44%。暫時性視網膜缺血120分鐘之後再灌注7天，視網膜節細胞的存活急劇下，僅保22%，至14天，僅剩17%, 之後節細胞的死亡速減緩，至28天時，仍由18%存活。視網膜缺血10分鐘、30分鐘、60分鐘和120分鐘均引起大小型膠質細胞激活，激活在第七天達到頂峰，之後在14天和28天顯著並逐步下。相關性分析發現損傷後7天，視網膜節細胞的死亡和視網膜節細胞層中的小型膠質細胞存在緊密的相關性。 / 其次，我們首次證實缺血性預處僅有於提高視網膜節細胞對抗視網膜缺血/再灌注損傷，還對視神經斷後的視網膜節細胞同樣具有保護作用。結果顯示無是5分鐘還是10分鐘的缺血性預處，無是軸突橫斷術前1天還是前3天實施預處，都對視網膜節細胞有明顯的保護作用。在缺血性預處對抗神經橫斷損傷的實驗組, 的表達只表現在陽性細胞上的明顯優勢，但占全部存活細胞的百分比存在差；而缺血性預處對抗視網膜缺血再灌注損傷的實驗組，的陽性節細胞的無論還是存活百分比都存在差。在預處組和假處組的比較中， 的表達也只是陽性細胞上較多，占全部存活細胞的百分比存在差。在缺血性預處加視網膜缺血分鐘的實驗組中，我們測視網膜矢片中各層的厚。結果顯示，缺血性預處組中，視網膜的整體厚和節細胞層的厚都與正常組相當，而假處組中，這層的厚明顯減少。 / 進一步地，我們研究遠端缺血性後處對視網膜節細胞對抗視神經軸突橫斷術的保護作用。我們選用鉗夾右股動脈作為遠端缺血性後處的方法，鉗夾股動脈分鐘，之後放開，再鉗夾再放開，共個循環。結果顯示，軸突橫斷術后分鐘實施缺血性后處組，視網膜節細胞的存活較假處組明顯增加，包括術後天和天；軸突橫斷術后小時實施缺血性後處組，視網膜節細胞的存活只在術後天較假處組明顯較多，但在天的實驗組，者的差消失；軸突橫斷術小時實施缺血性後處組，視網膜節細胞的存活比假處組多。在缺血性後處的實驗中，視神經橫斷術后分鐘實施遠端缺血性後處的實驗組與假處組比較，的表達僅表現在陽性細胞上的明顯增加，而且占全部存活細胞的百分比也明顯增加。的表達與預處實驗組的結果相似，只存在上的優勢。 / 我们的實驗證明，缺血性預處在對抗視神經橫斷和視網膜缺血的損傷中，可以為節細胞提供有效的保護作用，遠端缺血性後處可以對抗視神經橫斷損傷提高節細胞的存活。陽性節細胞在三個同條件的實驗中，表現出同的結果，这可能暗示遠端缺血性後處對抗視神經橫斷術的損傷，節細胞的再生能較優，與遠端缺血性後處對抗視神經橫斷術的神經保護作用有一定關。的表達在三個實驗組中，處組與假處組比較，均只表現出陽性細胞上的優勢，占存活細胞的百分比就存在差，可能意味著與缺血性預處和後處的保護作用關係不大。 / Ligature of the ophthalmic vessels (LOV) was used as an animal model to study transient retinal ischemia/reperfusion in adult hamsters. Firstly, we quantified the loss of retinal ganglion cells (RGCs) and activation of microglia after10 min, 30 min, 60 min or 120 min retinal ischemia at 7, 14 and 28 days post-ischemia. The results showed that after 10-min or 30-min retinal ischemia, the number of RGCs had no significant decrease compared to sham LOV group at 7 days. In the retinal ischemia 60 min group, there were 58% of the RGCs population remained alive at 7 days, 51% at 14 days and 44% at 28 days post-ischemia, respectively. In the retinal ischemia 120 min group, the number of RGCs was reduced to 22% at 7 days and 17% at 14 days, but cell death slowed down from 14 to 28 days. Meanwhile, the number of microglia was increased sharply at 7 days and decreased gradually from 7 to 28 days. At the same time, it was found that the loss of RGCs and activation of microglia in the ganglion cell layer at 7 days post-insult existed strong positive correlation. / Secondly, the effects of ischemic preconditioning (IPC) were proved to promote RGCs survival after axotomy or retinal ischemia 120 min. It was presented firstly that a 5 or 10 min brief IPC which performed 1 or 3 days prior to axotomy enhanced the RGCs survival at 7 days and 14 days post-axotomy. The number of HSP27-positive RGCs was significantly higher in the IPC plus axotomy subgroup compared with the sham-operated subgroup, while the percentage of HSP27-positive RGCs did not show significant difference between subgroups. For the IPC plus retinal ischemia 60 min group, both the number and the percentage of HSP27-positive RGCs had no significant difference between IPC and sham-operated subgroups. The number of HSP70-positive RGCs exhibited significant difference but not the percentage in IPC plus axotomy or retinal ischemia 60 min experimental groups. The thicknesses of the whole retina and GCL were similar to the normal value in the IPC plus ischemia 60 min subgroup, while in the sham-operated subgroup, these two values decreased significantly. / Consequently, the effect of remote ischemic postconditioning (RIPostC) was also explored to promote RGCs survival after axotomy. Four cycles of 10 min occlusion and 10 min release of the right femoral artery were initiated on animals at 10 min, 6 h or 24 h after axotomy. In the10 min group, the effect of RIPostC on promoting RGCs survival was significant at both 7 and 14 days post-injury. In the 6 h group, the survival of RGCs was more in the RIPostC treatment subgroup at 7 days, while there was no significant difference at 14 days post-axotomy. In the 24 h group, RGC survival was not significantly different at 7 days post-axotomy. Both the number and the percentage of HSP27-positive RGCs were significantly higher in the RIPostC treatment subgroup. The results of the induction of HSP70 only showed a priority in absolute number of the HSP70-positive RGCs in the RIPostC treatment subgroup. / In summary, the effect of IPC has been proved that it could protect RGCs against axotomy and retinal ischemia/reperfusion injury, in addition, the application of RIPostC also protected RGCs from axotomy. The proportion of HSP27-positive RGCs increased significantly in the process of RIPostC against axotomy, which may clue that the ability of axonal regeneration is stronger which induced by the RIPostC intervention. The upregulation of HSP27 might play a role in the neuroprotection of the RIPostC against axotomy. The expression of HSP70 maybe plays a little role in the neuroprotection of the IPC and RIPostC. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liu, Xia. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 182-196). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / Abstract in Chinese --- p.iv / Acknowledgements --- p.vii / Table of Abbreviations --- p.viii / Table of Contents --- p.ix / Chapter Chapter 1 --- General Introduction --- p.1 / Chapter Chapter 2 --- Changes of retinal ganglion cells and microglia after different types of injuries / Introduction --- p.38 / Materials and Methods --- p.43 / Results --- p.49 / Discussion --- p.57 / Figures and tables --- p.71 / Chapter Chapter 3 --- Ischemic preconditioning protect retinal ganglion cells against axotomy and retinal ischemia/reperfusion injury and expression of heat shock protein 27 and 70 / Introduction --- p.93 / Materials and Methods --- p.98 / Results --- p.103 / Discussion --- p.109 / Figures and tables --- p.116 / Chapter Chapter 4 --- Remote ischemic postconditioning protect retinal ganglion cells against axotomy and expression of heat shock protein 27 and 70 / Introduction --- p.143 / Materials and Methods --- p.147 / Results --- p.150 / Discussion --- p.154 / Figures and tables --- p.161 / Chapter Chapter 5 --- General Discussion --- p.175 / References --- p.182

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Electrophysical agents (EPA) are a fundamental element of therapy practice and are vital for the treatment of a variety of conditions. Many of these agents employ some form of electromagnetic fields (EMF), in which radiofrequency (RF) is a major component. The therapeutic effects of RF are mainly linked to their effects on pain relief and potential effects on tissue repair. Although RF across various frequency ranges has been in use, reviews have shown that the frequency ranges currently used in therapy practice have narrowed to within 30 kHz-30,000 kHz (30 MHz). The most commonly used and hence the most commonly researched are shortwave therapies (SWT) that operate at 27.12 MHz, which is presently used predominantly in its pulsed form (PSWT). In addition to SWT, devices employing significantly lower RF ranges have also been used widely despite their lack of evidence. Capacitive Resistive Monopolar Radiofrequency (CRMRF) that operates at 448 kHz is one such RF. This programme of research was designed to investigate the physiological and clinical efficacy of CRMRF delivered using the 'Indiba Activ 902' device. The project also evaluated the scope and evidence for RF-based EPAs in therapy, through a comprehensive review of literature. A total of 120 relevant clinical studies on either acute (30 studies) or chronic (90 studies) conditions were reviewed. Notable evidence was identified for chronic OA knee and acute postoperative pain and wound healing. Some evidence also exists for chronic low back pain and healing of chronic wounds. Only eight studies reported devices that employed RF outside the shortwave frequency band. In a randomised crossover laboratory study on asymptomatic adults, the effects of contrasting doses of CRMRF on skin temperature (SKT), skin blood flow (SBF), nerve conduction velocity (NCV), deep blood flow and the extensibility of tissues were examined against a placebo dose and a control condition with no treatment. The study further compared CRMRF results with that of PSWT. The results showed that high (moderately thermal) and low (sub/minimally thermal) doses of CRMRF significantly enhanced and sustained SKT (p < 0.001), while only the high dose meaningfully increased SBF (p < 0.001). High dose PSWT increased SKT marginally (p < 0.001) but did not sustain it. Further, the high and low dose CRMRF significantly enhanced blood flow volume at depth (p=0.003), while PSWT failed to show any significant impact. None of the treatments significantly affected deep blood flow velocity, tissue extensibility or NCV. These results were reproduced on a cohort of patients affected by OA knee in a randomised controlled trial (RCT), and the effects appeared more pronounced in the patients than in the asymptomatic people. More importantly, the RCT showed that a four-week high dose CRMRF treatment (eight sessions) produced statistically and clinically significant gains in pain and function associated with OA knee in the short to medium term (p < 0.001), which was also significantly more pronounced than the gains produced by a placebo, or standard care (p=0.001for pain; p=0.031 for function). The findings of this study were considered promising. It is therefore suggested that CRMRF-based treatment can potentially be used as an adjunct to current therapeutic methods to enhance the clinical outcomes. However, further studies are needed to substantiate this, and the current results will provide credible baseline data for future research.

It was generally accepted that the rate of formation of cerebrospinal °uid (CSF) is independent of intraventricular pressure [26], until A. Sahar and a host of other scientists challenged this belief. A. Sahar substantiated his belief that the rate of (CSF) formation actually depends on intraventricular pressure, see A. Sahar, 1971 [26]. In this work we show that CSF formation depends on some other factors, including the intraventricular pressure. For the purpose of this study, we used the capillary blood °ow model proposed by K.Boryczko et. al., [5] in which blood °ow in the microvessels was modeled as a two-phase °ow; the solid and the liquid volume phase. CSF is formed from the blood plasma [23] which we assume to be in the liquid volume phase. CSF is a Newtonian °uid [2, 23]. The principles and methods of e®ective area" developed by N. Sauer and R. Maritz [21] for studying the penetration of °uid into permeable walls was used to investigate the ¯ltrate momentum °ux from the intracranial capillary wall through the pia mater and epithelial layer of the choroid plexus into the subarachnoid space. We coupled the dynamic boundary equation with the Navier-Stoke's constitutive equation for incompressible °uid, representing the °uid °ow in the liquid volume phase in the capillary to arrive at our model. / Mathematical sciences / M.Sc.

Dissertation (MD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Acute renal failure still is, with the exception of cardiac deaths, the most important pathological process associated with perioperative mortality in patients operated for abdominal aortic aneurysms. The intraoperative change in renal blood flow (RBF) and glomerular function have been investigated in human and animal models, particularly over the past 15 years. Despite large variation in study populations, measurement techniques and study designs in general, a significant body of evidence has developed which suggests infrarenal aortic clamp-induced renal ischemia to be the cause of postoperative acute renal failure when this complication does occur. It is rather surprizing then that, despite some recent studies which have reported on various pharmacological interventions to prevent intraoperative renal ischemia (with variable success), very little has apparently been done to unravel the pathogenesis and exact pathophysiology of this potentially lethal complication. Although a number of investigators suggest the possibility of hormonal involvement (particularly reninangiotensin, antidiuretic hormone (ADH) and catecholamines) in the process, the exact role of these mediators have not been explored (or reported) in a structured fashion. In an initial human study, renal hemodynamics and function were measured from the preoperative period, during the intraoperative phase and at least until 4 hours after aortic unclamping. To investigate the possibility of a temporal relationship between renal changes and fluctuations in hormonal concentrations, plasma concentrations of relevant hormones were determined at every sampling period where renal parameters were measured. The decrease in RBF and glomerular filtration rate (GFR) which we demonstrated to coincide with infrarenal aortic cross clamping, is consistent with results previously published. We demonstrated persistence of the impairment of these parameters as long as 4 hours into the postoperative phase; which has previously only been reported for the period until immediately after aortic unclamping with the abdomen still open. The persistence of a depressed GFR until the time of discharge of patients is cause for concern, particularly in patients with compromised renal function prior to surgery. Of the measured hormones with a potential influence on RBF and nephron function, renin was the only mediator where changes in plasma concentrations coincided with the depression of RBF and GFR after aortic cross clamping. The design of our study did not allow us to conclude whether the concomitant increase in angiotensin II was primarily responsible for the change in renal hemodynamics, or whether the raised renin (and angiotensin) levels were stimulated by the decrease in RBF induced by another mechanism. In another patient group, we demonstrated that the combination of mannitol and dopamine provided no protection against the deleterious effects of aortic cross clamping. In fact, the high urine volumes produced under the influence of these agents (which did not correlate with RBF at the corresponding periods), is likely to prompt a false sense of security. Given the lack of any objective benefit afforded by these agents, their use in these clinical circumstances should be discouraged. The animal studies were aimed at elucidation of the exact role of angiotensin in the pathogenesis and pathophysiology of the renal changes associated with infrarenal aortic clamping, as well as the interaction of angiotensin with other modulators for which an interactive relationship had been described previously under other experimental and/or clinical circumstances. The first study showed that, although renin (and thus angiotensin) concentrations were high after aortic unclamping, the hormone had no pathogenic or pathophysiological role of significance in the observed renal changes during this period (since blocking angiotensin II activation by the prevention of renin release, or by inhibiting the conversion enzyme, did not prevent a substantial decrease in RBF or GFR during that period). Preventing angiotensin II activation did, however, prevent renal changes during aortic clamping. This beneficial effect did not establish a primary role for angiotensin during that period, since the favourable influence could also (at least partially) be explained by prevention of the permissive influence of angiotensin on other vasoconstrictors and/or other vasodilatory influences of ACE inhibition and [1- blockade which are unrelated to angiotensin. This study did indicate that (at least partially) different mechanisms are responsible for the renal changes seen during aortic clamping, and after aortic unclamping. The second study explored the role of calcium in the renal pathophysiological changes during aortic clamping and after unclamping. The protective influence effected by the administration of a Ca2 + -blocker suggest the dependence of the renal vasoconstrictive and glomerular pathophysiological process( es) on the cellular influx of Ca2 + through voltage-gated channels. It unfortunately provides no definitive insight into the primary instigators of these processes. However, it does offer a clinically useful method of preventing these changes and protecting the kidney against ischemic injury during abdominal aortic surgery. The third component of the animal studies demonstrates the importance of the protective effect of renal prostaglandins during the specific experimental (and probably also the clinical) circumstances. Again, it does not provide definitive information on the mediators responsible for the renal changes, since the deleterious effects of numerous endogenous substances have previously been shown to be counterbalanced by intrarenal synthesis of prostaglandins under various experimental and clinical circumstances. The extent of the pathophysiological and ultrastructural changes which occurred under the influence of a NSAID does, however, suggest that these drugs should not be used under these clinical circumstances. The last component of the study provides evidence that angiotensin only plays a secondary/supplementary role in the renal pathophysiological process even during aortic clamping. This may explain the contradictory evidence regarding the potential beneficial effect of ACE inhibition (on renal hemodynamics and glomerular function) during abdominal aortic surgery (Licker et al. 1996, Colson et al. 1992a). Based on our studies, ACE inhibition can not be supported for this purpose. / AFRIKAANSE OPSOMMING: Akute nierversaking is met die uitsondering van kardiale sterftes, steeds die belangrikste patologiese proses wat geassosieer is met perioperatiewe mortaliteit in pasiënte wat opereer word vir abdominale aorta aneurismes. Die intraoperatiewe veranderinge in renale bloedvloei (NBV) en glomerulêre funksie is die afgelope 15 jaar ondersoek en gerapporteer in pasiënte- sowel as diere-modelle. Ten spyte van groot variasies in studie-populasies, meettegnieke en ontwerp van studies in die algemeen, dui 'n wesenlike hoeveelheid getuienis daarop dat infrarenale klemming van die aorta renale isgemie induseer, wat die oorsaak is van postoperatiewe akute nierversaking wanneer hierdie komplikasie voorkom. Dit is verbasend dat, ten spyte van sommige onlangse studies wat rapporteer oor 'n verskeidenheid farmakologiese ingrepe om intraoperatiewe renale isgemie te voorkom (met wisselende sukses), baie min oënskynlik gedoen is om die patogenese en die presiese patofisiologie van hierdie potensieel dodelike komplikasie te ontrafel. Hoewel verskeie outeurs die moontlikheid van hormonale betrokkenheid (veral renienangiotensien, antidiuretiese hormoon en katekolamiene) in hierdie proses suggereer, is die presiese rol van hierdie mediators nog nie op 'n gestruktureerde wyse ondersoek (of rapporteer) nie. In ons aanvanklike pasiënte-studie is renale hemodinamika en -funksie gemeet vanaf die preoperatiewe periode, gedurende die intra-operatiewe fase en tot minstens vier uur na ontklemming van die aorta. Serumkonsentrasies van relevante hormone is bepaal tydens elke metingsperiode waar renale parameters gemeet is, ten einde die moontlikheid van 'n temporale verwantskap tussen renale veranderinge en variasies in hormoonkonsentrasies te ondersoek. Die vermindering in NBV en glomerulêre filtrasiespoed (GFS) wat ons aangetoon het om saam te val met infrarenale aortaklemming, stem ooreen met resultate wat tevore deur ander navorsers publiseer is. Ons het aangetoon dat die inkorting van hierdie parameters voortduur tot minstens vier uur na aorta-ontklemming. Hierdie veranderinge is tevore slegs rapporteer vir periodes tot kort na aorta-ontklemming voor sluiting van die buikwond. Die feit dat die GFS steeds verlaag is met ontslag van hierdie pasiënte, skep rede tot kommer, veral in pasiënte wat alreeds ingekorte nierfunksie het voor die chirurgiese prosedure. Van die gemete hormone wat moontlik 'n invloed sou kon uitoefen op NBV eh nefronfunksie, was renien die enigste waarvan verandering in plasmakonsentrasies saamgeval het met die onderdrukking van NBV en GFS na aortaklemming. Die ontwerp van ons studie het ons nie toegelaat om 'n besliste uitspraak te maak of die geassosieerde verhoging in angiotensien II primêr verantwoordelik was vir die verandering in renale hemodinamika, of dat die verhoogde renien (en angiotensien) bloedvlakke moontlik sekondêr stimuleer is deur die verandering in NBV wat deur 'n ander meganisme induseer is. In 'n ander pasiëntegroep het ons aangetoon dat die kombinasie van mannitol en dopamien geen beskerming verleen het teen die nadelige effekte van aorta-klemming nie. Die groot volumes uriene wat uitgeskei is onder die invloed van hierdie middels (wat nie korreleer het met NBV tydens ooreenstemmende periodes nie), het inderwaarheid 'n ontoepaslike gerustheid uitgelok. Weens die ooglopende gebrek aan objektiewe voordeel wat verleen word deur hierdie middels, behoort hulle gebruik tydens hierdie kliniese omstandighede ontmoedig te word. Die doel van die diere studies was die identifisering van die presiese rol van angiotensien in die patogenese en patofisiologie van die renale veranderinge geassosieer met infrarenale aortaklemming, sowel as die interaksie van angiotensien met ander modulators waarvoor 'n interaktiewe verwantskap voorheen beskryf is onder eksperimentele en/of kliniese omstandighede. Die eerste studie het getoon dat alhoewel renien (en dus angiotensien) konsentrasies hoog was na aorta-ontklemming, die hormone geen betekenisvolle patogenetiese of patofisiologiese rol in die waargenome renale veranderinge gedurende hierdie periode het nie (aangesien blokkade van angiotensien aktivering deur voorkoming van renien vrystelling, of deur inhibisie van angiotensien omsettingsensiem (AOE), nie 'n daling in NBV of GFS kon voorkom nie). Voorkoming van angiotensien II aktivering het egter wel renale verandering voorkom gedurende aortaklemming. Dié voordelige effek het nie 'n primêre rol vir angiotensien gedurende die periode bevestig nie, aangesien die gunstige invloed ook (ten minste gedeeltelik) verduidelik kon word deur die voorkoming van die fassiliterende invloed van angiotensien op ander vasokonstriktore en/of ander vasodilator-invloede van die onderdrukking van AOE en ïs-blokkers (wat geen verband het met angiotensien of die blokkade daarvan nie). Die studie het aangetoon dat (ten minste gedeeltelik) verskillende meganismes verantwoordelik is vir renale veranderinge wat gesien is gedurende aortaklemming en na -ontklemming. Die tweede studie het die rol van kalsium in die renale patofisiologiese veranderinge gedurende aortaklemming en na ontklemming ondersoek. Die beskermende invloed wat deur die toediening van Ca2 + -blokkers bewerkstellig is, het bevestig dat die renale vasokonstriktoriese en glomerulêre patofisiologiese prosesse afhanklik is van sellulêre influks van kalsium deur spannings-afhanklike kannale. Dit het ongelukkig geen definitiewe insig verleen ten opsigte van die primêre inisieerders van die proses nie. Dit verskaf nogtans 'n bruikbare kliniese metode om daardie veranderinge te voorkom en die niere teen isgemiese besering gedurende abdominale aorta-chirurgie te beskerm. Die derde komponent van die diere-studies demonstreer die belangrikheid van die beskermende effek van renale prostaglandiene tydens die spesifieke eksperimentele (en waarskynlik ook die kliniese) omstandighede. Weereens gee dit nie definitiewe inligting oor die bemiddelaars wat verantwoordelik is vir die renale veranderinge nie, aangesien die skadelike effekte van verskeie endogene stowwe voorheen aangetoon is om beperk of voorkom te word deur die intrarenale vrystelling van prostaglandiene. Die omvang van die patofisiologiese en ultrastrukturele veranderinge wat ontstaan het onder die invloed van nie-steroïed anti-inflammatoriese middels (wat gebruik is om prostaglandien sintese te inhibeer), dui aan dat hierdie middels vermy moet word onder soortelyke kliniese omstandighede. Die laaste komponent van die studie verskaf 'n sterk aanduiding dat angiotensien slegs 'n sekondêre/aanvullende rol speel in die renale patofisiologiese proses, selfs gedurende aortaklemming. Dit mag die weersprekende getuienis oor die potensiële voordeel van AOE onderdrukking (op renale hemodinamika en glomerulêre funksie) gedurende abdominale aortachirurgie (Licker et al. 1996, Colson et al. 1992a) verklaar. Gebaseer op ons studies, kan AOE onderdrukking nie ondersteun word vir hierdie doel nie.