Demonstramos na fase crônica da hipertensão por coarctação, depressão acentuada do controle reflexo da freqüência cardíaca (Michelini et al, Hypertension, 1992; 19:II159-II163) e que o tratamento crônico com losartan, embora não reverta os elevados níveis de pressão, normaliza o controle reflexo da freqüência cardíaca (Santos et al, Am. J. Physiol, 1995; 269:H812-H818). No presente estudo investigamos em ratos hipertensos e seus controles normotensos os efeitos do bloqueio crônico dos receptores AT1 sobre a atividade aferente do nervo depressor aórtico (NDA, protocolo I) e sobre a atividade simpática esplâncnica (ASE, protocolo II) na situação basal e após estimulação por hipotensões e hipertensões transitórias. Ratos Wistar adultos machos (180-300g) foram tratados cronicamente com veículo (VEH=água destilada, 0,1ml/100g/dia, po.) ou losartan (LOS= 10mg/kg/dia, po.) por 8 dias. No 4º dia após a determinação da pressão de cauda, foram submetidos à coarctação subdiafragmática da aorta (CH) ou à cirurgia fictícia (SHAM) e ao final do 7º dia, instrumentados com cânula arterial para registro direto da pressão arterial, realizada no 8º dia, com os animais acordados. Foram a seguir anestesiados para isolamento do nervo depressor aórtico ou do simpático esplâncnico, que foram registrados simultaneamente à pressão arterial em duas situações distintas: a) durante a situação basal (registro da atividade espontânea por 10-15 minutos), b) durante estimulação dos pressorreceptores por variações transitórias da pressão arterial (infusões/retiradas de sangue e injeções/infusões de fenilefrina e nitroprussiato de sódio iv.). Os registros da atividade neural foram retificados, integrados e aquisitados simultaneamente aos registros de pressão arterial em computador (programa de aquisição de dados Codas - Windaq DI-200, Ohio, USA). Tratamento com LOS determinou queda significante da pressão de cauda (104+-3 vs. 117+-3 mmHg nos grupos VEH). Em ambos os grupos VEH e LOS, CH determinou aumento significativo e similar da pressão arterial (em média 29%) que foi acompanhada, nos grupos tratados com VEH, por significativo aumento da variabilidade associada à depressão no ganho da correlação da atividade do NDA com a pressão arterial (CHVEH=1,04+-0,11 vs. SHAMVEH=1,63+-0,14 %/ciclo/mmHg, p<0,05, protocolo I) e por facilitação da resposta da ASE (CHVEH=-10,36+-1,05 vs. SHAMVEH=-5,81+-0,60 %/ciclo/mmHg, p<0,05, protocolo II). Nos grupos tratados com LOS, o estabelecimento da hipertensão foi acompanhado por redução da variabilidade e significativa melhora no ganho do NDA, uma vez que na faixa fisiológica de variações da pressão a depressão da atividade do NDA foi significativamente menor (CHLOS=3,30+-0,33 vs. CHVEH=2,18+-0,37 %/ciclo/mmHg, p<0,05, uma recuperação de 40% quando comparado aos respectivos controles ~5,01+-0,33 %/ciclo/mmHg). Houve ainda nos CHLOS normalização do ganho de resposta de ASE (CHLOS=-6,58+-0,62 %/ciclo/mmHg que não diferia dos SHAMLOS e SHAMVEH). O tratamento crônico com LOS determinou ainda correção parcial da atividade basal do NDA, mas não alterou a descarga espontânea da ASE. As alterações de atividade do NDA e ASE observadas nos CHLOS ocorreram simultaneamente, mas foram independentes da redução da pressão arterial pelo LOS. Nossos dados sugerem que a Ang II, ativada durante o desenvolvimento da CH, deprime a sinalização aferente pelo NDA, sendo responsável pela facilitação da resposta simpática durante alterações transitórias da pressão arterial. Nossos dados permitem ainda discriminar entre o efeito pressor e o efeito modulatório da Ang II, indicando restauração parcial do ganho da NDA e normalização da resposta simpática após o bloqueio crônico dos receptores AT1, mesmo na presença da hipertensão. / In the chronic phase of coarctation hypertension (CH) we have shown both marked depression of baroreceptor reflex control of heart rate (Michelini et al, Hypertension, 1992, 19: II159-II163) and normalization of the depressed reflex control even with the persistence of hypertension in losartan-treated animals (Santos et al, Am. J. Physiol, 1995, 269: H812-H818). In the present study we analyzed the effects of chronic AT1tors blockade on the both the afferent aortic nerve activity (AON, protocol I) and splanchnic sympathetic nerve activity (SSNA, protocol II) of CH and sham operated controls in two conditions: spontaneous activity (basal condition) and stimulated discharge during transient increases/decreases in arterial pressure. Male Wistar rats (180-300g aged 2-3 months) were chronically treated with vehicle (VEH=distilled water, 1ml/kg/day, po.) or losartan (LOS=10mg/kg/day, po.) during 8 days. Tail pressure was measured at the beginning and on the 4th day, before subdiaphragmatic aortic coarctation (CH) or sham surgery (SHAM). On day 7 the rats were instrumented with a catheter to record arterial pressure in conscious freely moving rats on day 8. Rats were then anesthetized to record AON or SSNA simultaneously with pressure during 10-15 min (basal or spontaneous activity) and during baroreceptor loading/unloading (infusion/withdrawal of blood or injections/infusions of phenylephrine and sodium nitroprusside iv.). Nerve activity was rectified and integrated and acquired simultaneously with pressure in a computer (Windaq DI-200, Ohio, USA). Losartan-treatment caused a significant decrease in tail pressure (104+-3 vs. 117+-3 mmHg in VEH groups). In both LOS- and VEH-treated groups, CH caused significant and similar increases in arterial pressure (mean of 29%) that was accompanied in the VEH groups by both significant increase in variability and depression of the AON/activity/pressure relationship (CHVEH=1,04+-0,11 vs. SHAMVEH=1,63+-0,14 %/cycle/mmHg, p<0,05, protocol I) and by potentiation of SSNA responses (CHVEH=-10,36+-1,05 vs. SHAMVEH=-5,81+-0,60 %/cycle/mmHg, p<0,05, protocol II). In the LOS-treated groups, establishment of CH was accompanied by smaller variability and marked improvement in AON gain: in the physiological range of pressure changes, depression of AON activity was significantly smaller (CHLOS=3,30+-0,33 vs. CHVEH=2,18+-0,37 %/cycle/mmHg, p<0,05, a recovery of 40% when compared to respective controls of ~5,01+-0,33 %/cycle/mmHg). CHLOS showed also normalization of SSNA responses: gain in the CHLOS=-6,58+-0,62 %/cycle/mmHg, that was not different from SHAMLOS and SHAMVEH groups. In addition chronic treatment with LOS caused partial correction of spontaneous AON activity but did not change spontaneous SSNA discharge. Both AON and SSNA responses observed in CHLOS occurred simultaneously but were independent from pressure reductions observed in these groups. The date suggested that Ang II, activated during development of hypertension, depresses the afferent signaling by aortic receptors and is factor responsible for the facilitation of SSNA during pressure changes. The date permits to discriminate between pressor and a modulatory effects of Ang II and indicates that after chronic AT1 receptors blockade hypertension persists, but there is a partial restoration of AON gain accompanied by normalization of the sympathetic response.

The investment and financing instrument AT1, or Contingent Convertible bond, has become popular in the post-crisis capital markets, prompting interest and research in the academic world. The instrument's debt definition but equity boosting properties makes it rather extraordinary, and its stochastic features makes multiple mathematical valuation methodologies relevant, especially with regard to the risk of extending the call date of the instrument. With investors still relying on screening tools for valuation, there is an absence of applications using existing mathematical approaches. This report therefore aims to narrow the gap between academia and industry by evaluating the use of such mathematical approaches in a practical investment setting, in particular the Improved Credit Derivative approach and the Extension Premium Relative Value approach shall be examined. Both models strive to account for the extension risk, a commonly disregarded yet critical risk, adding computational challenges to the implementation. Besides from discovering necessary practical adjustments, and their effects, the two pricing approaches are compared in an attempt to confirm their joint purpose of accounting for extension risk. Ending up with varying results consisting of evident offsets for the improved credit derivative model but significant correlations in the case of the extension premium model, their individual performance was diverse while the hypothesis of joint behaviour could be dismissed. / Investerings- och finansieringsinstrumentet AT1, eller Contingent Convertible bond, har blivit populärt i kapitalmarknaderna efter finanskrisen, vilket lett till intresse och forskning i den akademiska världen. Instrumentets grund som skuld men egenskaper för att tillskjuta eget kapital gör det extraordinärt, och dess stokastiska funktioner öppar upp för flertalet värderingsmetoder, speciellt gällande förlängningsrisken hos datumet för kallning. Eftersom att investerare fortfarande använder sig utav screening-verktyg för värdering finns det endast begränsad forskning rörande användande av matematiska metoder. Denna rapport har därför som mål att minska avståndet mellan den akademiska världen och industrin genom att utvärdera användandet av sådana matematiska metoder för praktiska investeringar, särskillt skall Improved Credit Derivative och Extension Premium Relative Value metoderna användas. Båda modellerna strävar efter att ta hänsyn till förlängningsrisken, en risk vanligtvis bortsedd ifrån men trots det kritisk, vilket tillägger ytterligare beräkningsutmaningar vid implementationen. Bortsätt ifrån att upptäcka praktiska justeringar och dess effekter jämförs de två värderingsmetoderna i ett försök att bekräfta deras gemensamma syfte, att ta hänsyn till förlängningsrisken. Att i slutändan nå blandade resultat besående av uppenbara avvikelser för improved credit derivative modellen men starka korrelationer i fallet av extension premium modellen gjorde att man kunde dra slutsatsen att deras individuella prestanda skilde sig medan hypotesen om gemensamt beteende kunde avfärdas.

Contingent convertible bonds (often referred to as CoCo bonds, or simply CoCos) are a relatively new financial instrument designed to absorb unexpected losses. This instrument became increasingly more common after the financial crisis of 2008, as a way to decrease the risk of insolvency among banks and other financial institutions. In this thesis, we will investigate two mathematical models for valuation of CoCo bonds, known as the credit derivative approach and the equity derivative approach, previously developed by De Spiegeleer and Schoutens [1]. We will investigate how these models can be modified in order to be applied to a large set of bonds available on the market. The effect of parameter alterations will also be studied, in order to determine which parameters that influence the pricing accuracy the most. We reach the conclusion that by estimating market triggers, conversion prices and by computing a continuous interest rate from a discrete rates table, the models are indeed executable on a large set of bonds available on the market. However, these parameter estimations come at the cost of reduced accuracy. In general, both investigated models produces prices which follows the overall movements of the market prices quite well, but at the same time with a relatively large absolute distance from the market prices. In other words, the correlation with the market is often high, but the absolute error (measure by root mean square error) is often large. The sensitivity analysis of the parameters shows that the market trigger is the most influential parameter in both investigated models. The fact that we had to estimate the market trigger in order to be able to price a large number of bonds is believed to be the main cause of reduced accuracy. By utilizing a more bond-specific parameter estimation, the accuracy of the investigated models could most likely be improved. We can conclude that there is a trade-off between being able to price a large set of bonds with a mediocre accuracy, or being able to price a few bonds with high accuracy. / Det finansiella instrumentet contingent convertible bond (ofta benämnt CoCo bond, eller endast CoCo) är en relativt ny obligationstyp som används av banker och andra finansiella institutioner för att absorbera oväntade förluster. Instrumentet blev mer vanligt förekommande efter finanskrisen 2008, som ett sätt att minska risken för insolvens. I detta examensarbete undersöker vi två matematiska modeller för värdering av CoCo bonds, nämligen den så kallade credit derivative approach och equity derivative approach, som tidigare har utvecklats av De Spiegeleer och Schoutens [1]. Vi kommer att undersöka hur dessa modeller kan modifieras för att bli applicerbara på ett stort antal obligationer tillgängliga på marknaden. En omfattande parameterstudie kommer att genomföras, för att dra slutsatser kring de mest betydelsefulla parametrarna för prissättningen. Genom att skatta så kallade market triggers, conversion prices och en kontinuerlig ränta är det möjligt att exekvera de undersökta modellerna på ett stort antal obligationer. Dessa skattningar medför dock en viss försämrad noggrannhet. Generellt sett följer priserna från modellerna marknadens rörelser ganska väl, men är samtidigt ganska långt ifrån marknadspriset. Med andra ord är korrelationen hög, men absolutfelet är relativt stort. Parameterstudien visar att parametern som kallas market trigger är mest betydelsefull för prissättningen. Faktumet att vi måste skatta market triggers för att kunna prissätta ett stort antal obligationer tros vara den största anledningen till försämrad noggrannhet. Genom att använda en mer ”obligationsspecifik” skattning av parametrar bör noggrannheten kunna förbättras. I dessa modeller är det en tydlig avvägning mellan att kunna prissätta många obligationer med relativt låg noggrannhet, och att kunna prissätta få obligationer med hög noggrannhet.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

The Angiotensin II Type 1 (AT1) receptor is the main receptor responsible for the effects of the renin-angiotensin system, and its expression pattern is altered in several diseases. [11C]Methyl-Losartan has been developed based on the clinically used AT1 receptor antagonist Losartan. The aim of this work is to characterize the pharmacokinetics, repeatability and reliability of measurements, binding specificity and selectivity of [11C]Methyl-Losartan in rats using in vivo small animal positron emission tomography (PET) imaging, ex vivo biodistribution and in vitro autoradiography methods. Also, we aim to measure the presence of metabolites in the kidney and plasma using high-performance liquid chromatography. We have demonstrated in vivo that [11C]Methyl-Losartan is taken up in the AT1 receptor-rich kidneys and that it is displaceable by selective AT1 receptor antagonists. Using ex vivo biodistribution, we have confirmed these results and demonstrated that [11C]Methyl-Losartan binds selectively to the AT1 receptor over the AT2, Mas and β-adrenergic receptors. In vitro autoradiography results confirmed these renal binding selectivity studies. [11C]Methyl-Losartan was also shown to have one and two C-11 labeled metabolites in the plasma and kidneys, respectively. In conclusion, [11C]Methyl-Losartan is a promising agent for studying the AT1 receptor in rat models with normal and altered AT1 receptor expression using small animal PET imaging.

The Angiotensin II Type 1 (AT1) receptor is the main receptor responsible for the effects of the renin-angiotensin system, and its expression pattern is altered in several diseases. [11C]Methyl-Losartan has been developed based on the clinically used AT1 receptor antagonist Losartan. The aim of this work is to characterize the pharmacokinetics, repeatability and reliability of measurements, binding specificity and selectivity of [11C]Methyl-Losartan in rats using in vivo small animal positron emission tomography (PET) imaging, ex vivo biodistribution and in vitro autoradiography methods. Also, we aim to measure the presence of metabolites in the kidney and plasma using high-performance liquid chromatography. We have demonstrated in vivo that [11C]Methyl-Losartan is taken up in the AT1 receptor-rich kidneys and that it is displaceable by selective AT1 receptor antagonists. Using ex vivo biodistribution, we have confirmed these results and demonstrated that [11C]Methyl-Losartan binds selectively to the AT1 receptor over the AT2, Mas and β-adrenergic receptors. In vitro autoradiography results confirmed these renal binding selectivity studies. [11C]Methyl-Losartan was also shown to have one and two C-11 labeled metabolites in the plasma and kidneys, respectively. In conclusion, [11C]Methyl-Losartan is a promising agent for studying the AT1 receptor in rat models with normal and altered AT1 receptor expression using small animal PET imaging.