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Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Physiology. Title from title-page of electronic thesis. Bibliography: leaves 94-110.

Thesis (doctoral)--Katholieke Universiteit te Nijmegen.

Discoveries made with KCl-induced contractions have elucidated the more complex reactions involved in GPCRs signaling; once the mechanisms of smooth muscle Ca2+ sensitization and desensitization are fully understood, then the development of advanced treatments for vascular disorders such as hypertension, cerebral and coronary vasospasm, and vascular hyporeactivity following hemorrhagic shock may be possible. Studies have shown that KCl-induced contractions induce Ca2+-sensitization. Therefore, we tested the hypothesis that KCl induced Ca2+-sensitization is due to ROK activation by the increase in [Ca2+]i. To test this hypothesis, rabbit femoral arteries were permeabilized with 20µg/ml α-toxin and 1% Triton X-100 and subjected to different calcium concentrations in the presence or absence of various ROK inhibitors. For a comparison we also used various PKC and MLCK inhibitors and repeated these experiments in intact tissues. We found that either [Ca2+]i alone does not directly activate ROK or the permeabilization technique itself disrupts the normal ROK signaling system. Secondary findings revealed that α-toxin activates PKC pathways; in both chemically permeabilized preparations proteases also appear to be activated and MLCK is the primary kinase responsible for contraction.

It is well known that the overlap between the thick and thin filaments in striated muscle is responsible for the single active length-tension (L-T) curve. With the lack of visible striations, a sarcomeric unit has not been identified in smooth muscle. Though once thought to function like striated muscle via a sliding filament mechanism of contraction, recent studies on length-adaptation (L-adaptation) in airway smooth muscle (ASM), in which increased tension is generated with repeated contraction, have led to the hypothesis of a dynamic L-T curve in smooth muscle. Although more established in ASM, two studies have shown L-adaptation in vascular smooth muscle (VSM). In this project, the L-T curve over a 3-fold length range in rabbit femoral artery was investigated and the presence of more than one active and passive L-T curve was identified. The third of three repeated KCL-induced contractions at a single, shortened length resulted in L-adaptation in which the phasic and tonic phases of contraction demonstrated a 10-15% increase in active tension (Ta) relative to the first contraction. Experiments investigating possible mechanism(s) responsible for this phenomenon demonstrated that neither an increase in [Ca2+]i nor an increase in MLC20 phosphorylation was responsible for the increased tension. However, actin polymerization did appear to play a role in the L-adaptation of both phases of contraction. Thus directions for future research could include further study of actin polymerization in VSM that contributes to L-adaptation and may ultimately result in artery remodeling.

Hung Hoi Yan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 138-160). / Abstracts in English and Chinese. / ABSTRACT --- p.i / ACKNOWLEDGEMENTS --- p.v / PUBLICATIONS BASED ON THE WORK IN THIS THESIS --- p.vi / TABLE OF CONTENTS --- p.vii / ABBREVIATIONS --- p.ix / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Prostanoids and vasoconstriction --- p.1 / Chapter 1.1.1 --- EP3 receptors --- p.2 / Chapter 1.1.2 --- EP1 receptors --- p.16 / Chapter 1.1.3 --- FP receptors --- p.23 / Chapter 1.1.4 --- TP receptors --- p.30 / Chapter 1.2 --- Role of Ca2+ in vascular smooth muscle contraction --- p.36 / Chapter 1.2.1 --- Ca2+ as second messenger --- p.36 / Chapter 1.2.2 --- Ca2+ sensitization --- p.41 / Chapter 1.3 --- Aim of study --- p.48 / Chapter CHAPTER 2 --- METHODS AND MATERIALS --- p.49 / Chapter 2.1 --- Experiments with rat femoral artery --- p.49 / Chapter 2.2 --- Experiments with guinea-pig trachea --- p.56 / Chapter 2.3 --- Materials --- p.59 / Chapter 2.4 --- Data analysis --- p.61 / Chapter 2.5 --- Measurement of rat knee joint blood flow --- p.62 / Chapter CHAPTER 3 --- RESULTS --- p.68 / Chapter 3.1 --- Effects of EP3 agonists and other vasoactive agents on the rat femoral artery preparation --- p.68 / Chapter 3.2 --- Interactions between EP3 agonists and other vasoactive agents --- p.69 / Chapter 3.2.1 --- Interactions with phenylephrine --- p.69 / Chapter 3.2.2 --- Interactions with KCl --- p.71 / Chapter 3.3 --- Effect of nifedipine --- p.72 / Chapter 3.4 --- Effects of Rho-kinase inhibitors --- p.73 / Chapter 3.5 --- Effect of EP1 receptor antagonist --- p.76 / Chapter 3.6 --- Other properties of the rat femoral artery --- p.77 / Chapter 3.8 --- Effect of sulprostone on blood flow of rat knee joint --- p.79 / Chapter CHAPTER 4 --- DISCUSSION --- p.118 / Chapter 4.1 --- Effect of PGE analogues on rat femoral artery --- p.118 / Chapter 4.1.1 --- Prostanoid receptor (s) responsible for the contractile effects --- p.118 / Chapter 4.1.2 --- Prostanoid Receptors involved in the synergism --- p.122 / Chapter 4.1.3 --- Synergism models --- p.124 / Chapter 4.2 --- Mechanisms of synergistic contractions --- p.126 / Chapter 4.2.1 --- Role of Ca2+ influx --- p.126 / Chapter 4.2.2 --- Role of Ca2+ sensitization --- p.127 / Chapter 4.3 --- Effect of sulprostone in vivo --- p.132 / Chapter 4.4 --- Conclusion --- p.136 / REFERENCES --- p.138

Σκοπός της πρόδρομης αυτής τυχαιοποιημένης μελέτης ήταν να εκτιμήσουμε την αποτελεσματικότητα της εξωτερικής ακτινοβόλησης και την προφυλακτική της δράση στην μείωση της επαναστένωσης του αυλού της επιπολής μηριαίας αρτηρίας μετά από αγγειοπλαστική και τοποθέτηση μεταλλικής ενδοπρόθεσης (stent). Στην μελέτη συμπεριελήφθησαν ασθενείς με σοβαρού βαθμού στένωση ή απόφραξη της επιπολής μηριαίας αρτηρίας, οι οποίοι υποβλήθηκαν σε διαδερμική αγγειοπλαστική με μπαλόνι και τοποθέτηση stent για την αποκατάσταση του προβλήματός τους, και τυχαιοποιήθηκαν σε δυο ομάδες. Οι ασθενείς της πρώτης ομάδας υποβλήθηκαν σε αγγειοπλαστική με μπαλόνι και τοποθέτηση stent στην περιοχή της στένωσης ή της απόφραξης χωρίς να υποβληθούν σε εξωτερική ακτινοβόληση της περιοχής. Οι ασθενείς της δεύτερης ομάδας, 24 ώρες μετά την αγγειοπλαστική με μπαλόνι και τοποθέτηση stent στην περιοχή της στένωσης ή της απόφραξης, υποβλήθηκαν σε εξωτερική ακτινοβόληση στην περιοχή, με συνολικά χορηγούμενη δόση 24Gy που δόθηκαν σε 6 συνεδρίες ανά 48 ώρες. Μετά το τέλος της ακτινοβόλησης οι ασθενείς παρακολουθούνταν ανά τακτά χρονικά διαστήματα. Η συνολική διάρκεια παρακολούθησης ήταν 1 έτος, με τελικό σημείο αξιολόγησης το 1 έτος. / Purpose: To evaluate the long-term results of external beam irradiation (EBI), for the prevention of neointimal hyperplasia, after percutaneous transluminal angioplasty (PTA) and stenting of the superficial femoral artery. Materials and methods: A prospective randomised study was conducted from November 2000 to February 2002. A total of 60 patients who suffered from superficial femoral artery stenoses or short occlusions included in this study. Following successful post-angioplasty stenting, patients were randomly assigned in two groups and thirty of them received external beam irradiation (6 MV photons, total dose of 24 Gy in 6 fractions,during a 2 week period) at the stented area (EBI group) while the rest thirty received no radiation therapy (Control group).All patients were advised to receive anti-platelet therapy. Results and conclusions: Radiation therapy was technically feasible in all patients, without radiation related side effects. Statistically significant differences (p<0,05) observed at the 1- year follow-up concerning the primary patency (66% for the irradiated patients vs 33% for the control patients) and re-intervention rates (40% for the irradiated patients vs 70% for the control patients) between the two groups. Irradiated patients revealed re-stenotic lesions mainly at the stent ends, while control group patients suffered extensive re-stenotic lesions within the stent lumen and the stent ends.Our study suggests that EBI is feasible, safe and effective method for the prevention of neointimal hyperplasia at the superficial femoral artery. Further studies are deemed necessary to optimize the radiation dose and the number of fractions.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Description based on contents viewed June 24, 2007; title from title screen. Includes bibliographical references (p. 76-80).

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Nesta escolha interfere o tipo de procedimento, impacto ao paciente, risco ao profissional e experiência técnica. O acesso via artéria femoral é o mais difundido globalmente e a técnica de acesso pela artéria radial tem sido progressivamente adotada devido ao maior conforto para o paciente, menores taxas de complicações e em alguns cenários, de mortalidade. Um dos focos de interesse crescente é a exposição à radiação ionizante e medidas para minimizar o risco ao paciente e ao profissional. Escassa é a literatura disponível na área e conflitantes são seus resultados. Objetivo: Avaliar os níveis de radiação recebidos pelo médico operador de acordo com as diferentes técnicas de acesso, bem como mapear áreas de escape de radiação. Após essa etapa, o estudo visou desenvolver e validar dispositivo de radioproteção dedicado à técnica radial (TRIPTable) voltado à redução da radiação ao médico operador, comparando o seu impacto à técnica femoral e radial padrão no cenário de pacientes portadores de síndrome coronária aguda randomicamente alocados para cateterismo com intenção de tratamento percutâneo. Métodos: A fase inicial pré-clínica do estudo foi constituída de avaliação em ambiente controlado dos níveis de radiação em pontos pré-especificados de um operador simulado com phantom de água. A fase clínica do estudo foi um ensaio clínico prospectivo, randomizado, unicêntrico, comparativo entre três grupos denominados técnica femoral, técnica radial e técnica radial com dispositivo radioprotetor TRIPTable, recrutados no Hospital das Clínicas de Marília (Marília/SP) e randomizados na proporção 1:1:1 (108 pacientes - 36 por grupo) avaliando a radiação recebida pelo operador em três diferentes pontos (gônadas, tireoide e olhos). Os resultados foram comparados com o grupo controle de 108 pacientes provenientes de coorte randomizada externa entre técnica radial e femoral 1:1, utilizando critérios similares, porém com operadores cegos aos objetivos de avaliação de radiação visando detecção de vieses de técnica (efeito Hawthorne) e validação de resultados. Resultados: Não houve diferença entre o estudo e a coorte externa ou entre os grupos do estudo quanto a características clínicas, desfechos dos procedimentos ou parâmetros de exposição radiológica ao paciente. Os resultados indicam maior radiação recebida pelo operador com a técnica radial (12,5 mSv), seguida da femoral (10,1 mSv) e TRIPTable (6,8 mSv). Em relação aos locais de exposição, o território de gônadas teve maior sensibilidade radiológica com uso da técnica radial (p=0,001). Com uso da técnica femoral não houve diferença entre os três territórios (p=0,398), porém na análise ad hoc o território de gônadas foi mais sensível quando comparado à exposição aos olhos (p=0,016) e limítrofe em comparação à tireoide (p=0,056). No grupo do dispositivo TRIPTable não houve diferença significativa entre qualquer um dos territórios analisados (p=0,180). Conclusões: O estudo indica equivalência entre os resultados do procedimento entre os grupos e quanto à exposição radiológica ao paciente. Contudo, demonstrou maior impacto radiológico para o operador que utilizou a técnica radial, em comparação à técnica femoral e à técnica radial com uso do dispositivo TRIPTable. O uso do dispositivo reduziu o impacto radiológico comparado ainda à técnica femoral. Tais diferenças derivaram primordialmente da variação em território de gônadas. Os achados demonstram um campo de exposição radiológica heterogêneo ao corpo do operador, benefício do dispositivo testado e oportunidade de novas formas de desenvolvimento de medidas de radioproteção. Registros: UTN/OMS - U1111-1158-8591 Plataforma Brasil - CAAE 32767514.0.1001.5413 Clinical Trials - NCT 02200783. / Background: Interventional cardiology requires an invasive vascular access, a choice of medical operator. This choice is affected by type of procedure, patient impact, professional risk and technical experience. Interventional procedures via radial technique have progressively increased due to improved patient comfort, lower complication rates, and reduced mortality in some scenarios. One area of interest is radiation exposure and ways to minimizing it. Most studies focusing on patient radiation risk demonstrated conflicting results, and there is no consensus for increased exposure with any technique. Objective: The aim of this study was to evaluate radiological exposure under controlled radial and femoral access simulation tests, mapping radiation paths. After this stage, the study developed a radiological protection device for the transradial technique (TRIPTable), comparing its impact as compared to standard femoral and radial techniques in the setting of patients with acute coronary syndrome randomly assigned for catheterization with intent to percutaneous treatment. Methods: Radiation exposure was simulated under controlled conditions for femoral and radial techniques using a pressurized ionization chamber and water phantom. Different measurement points were defined according to standard positions to simulate radiation received by the operator in the gonads, thyroid, and eyes at different angles during real procedures. The clinical phase of the study is a prospective clinical trial, single-center, randomized, and comparing three groups (femoral technique, radial technique, and radial technique with radioprotective device), admitted in the Emergency Department of Hospital das Clinicas de Marilia (Marilia / SP – Brazil). Patients were randomized in a 1:1:1 proportion (108 patients - 36 per group) evaluating the radiation received by the operator measured by dosimetry at three different points (gonads, thyroid and eyes). As it is impossible to blind operators to study techniques, the results were compared to an external control cohort of patients including 108 individuals with similar inclusion and exclusion criteria, randomized for radial and femoral technique, but with blinded operators to radiation objectives, aiming technical bias detection (Hawthorne effect) and validation of results. Results: There was no difference between groups regarding clinical characteristics, procedures or patient radiation exposure outcomes. The results indicate higher radiation received by the operator with the radial technique (12.5 mSv) as compared to femoral technique (10.1 mSv) and TRIPTable technique (6.8 mSv). Regarding exposure locations, the gonad region had a higher radiation sensitivity with radial technique (p=0.001). With femoral technique there was no difference between the three territories (p=0.398) but the ad hoc analysis indicated higher radiosensibility in gonads when compared to eyes exposure (p=0.016) and borderline compared to thyroid exposure (p=0.056). In the TRIPTable device group there was no significant difference between any of the territories analyzed (p=0.180). Conclusions: The study indicates no difference of radiation exposure to the patients between the groups. However, there was a greater radiologic impact to the operator who used the radial technique, compared to the femoral technique and TRIPTable device technique. The device reduced the radiological impact even compared to the femoral technique. Such differences derived primarily from variation in gonads exposure. The findings demonstrate a heterogeneous radiation exposure to the operator body, device benefit and an opportunity to develop new ways to improve radiation protection. Registration: UTN/OMS - U1111-1158-8591 Plataforma Brasil - CAAE 32767514.0.1001.5413 Clinical Trials - NCT 02200783.

Orientador: Katashi Okoshi / Resumo: Introdução: A cardiologia intervencionista requer necessariamente um acesso vascular invasivo, sendo esta via de acesso uma escolha do médico operador. Nesta escolha interfere o tipo de procedimento, impacto ao paciente, risco ao profissional e experiência técnica. O acesso via artéria femoral é o mais difundido globalmente e a técnica de acesso pela artéria radial tem sido progressivamente adotada devido ao maior conforto para o paciente, menores taxas de complicações e em alguns cenários, de mortalidade. Um dos focos de interesse crescente é a exposição à radiação ionizante e medidas para minimizar o risco ao paciente e ao profissional. Escassa é a literatura disponível na área e conflitantes são seus resultados. Objetivo: Avaliar os níveis de radiação recebidos pelo médico operador de acordo com as diferentes técnicas de acesso, bem como mapear áreas de escape de radiação. Após essa etapa, o estudo visou desenvolver e validar dispositivo de radioproteção dedicado à técnica radial (TRIPTable) voltado à redução da radiação ao médico operador, comparando o seu impacto à técnica femoral e radial padrão no cenário de pacientes portadores de síndrome coronária aguda randomicamente alocados para cateterismo com intenção de tratamento percutâneo. Métodos: A fase inicial pré-clínica do estudo foi constituída de avaliação em ambiente controlado dos níveis de radiação em pontos pré-especificados de um operador simulado com phantom de água. A fase clínica do estudo foi um ensaio clíni... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Interventional cardiology requires an invasive vascular access, a choice of medical operator. This choice is affected by type of procedure, patient impact, professional risk and technical experience. Interventional procedures via radial technique have progressively increased due to improved patient comfort, lower complication rates, and reduced mortality in some scenarios. One area of interest is radiation exposure and ways to minimizing it. Most studies focusing on patient radiation risk demonstrated conflicting results, and there is no consensus for increased exposure with any technique. Objective: The aim of this study was to evaluate radiological exposure under controlled radial and femoral access simulation tests, mapping radiation paths. After this stage, the study developed a radiological protection device for the transradial technique (TRIPTable), comparing its impact as compared to standard femoral and radial techniques in the setting of patients with acute coronary syndrome randomly assigned for catheterization with intent to percutaneous treatment. Methods: Radiation exposure was simulated under controlled conditions for femoral and radial techniques using a pressurized ionization chamber and water phantom. Different measurement points were defined according to standard positions to simulate radiation received by the operator in the gonads, thyroid, and eyes at different angles during real procedures. The clinical phase of the study is a prospective cli... (Complete abstract click electronic access below) / Doutor