Complete or partial obstruction of the duodenum by the superior mesenteric artery (SMA) is a rare cause of bowel obstruction. SMA syndrome results from the compression of the 3rd part of the duodenum between the superior mesenteric artery and the abdominal aorta. Causes include anatomical variation in the superior mesenteric artery, trauma, burns, surgeries, malignancy, and rapid weight loss. Diagnosis of SMA syndrome in patients may be difficult, as the clinical findings often resemble other forms of small bowel obstructions. This syndrome was first described in the literature by Carl Freiherr von Rokitansky in 1861. Subsequently, David Wilke provided a comprehensive description of the disease in a series of 75 patients. There has been skepticism about the existence of SMA syndrome due to scant literature reports and non-specific symptomatology. However, modern cross-sectional imaging has confirmed the existence of this rare syndrome. Here we present the case of a 50-year-old female with longstanding symptoms of gastrointestinal discomfort, weight loss, nausea, and vomiting. She underwent an exhaustive gastrointestinal workup until a diagnosis of SMA syndrome was made. We elected to proceed with a minimally invasive three-port laparoscopic, trans-mesenteric side-to-side duodenojejunostomy. The patient was discharged on postoperative day one after tolerating a regular diet. On one month follow-up, our patient reported improvement in symptoms with no postprandial pain or nausea and normal bowel movements. In conclusion, we report a case of superior mesenteric artery syndrome in a patient with recurrent abdominal pain and nausea. CT scan has the highest sensitivity for the diagnosis of SMA syndrome, findings suggestive of the diagnosis include an abnormal aortomesenteric angle and distance. While supplemental tube feeds and gastric drainage may resolve the condition without the need for surgery, this often takes many weeks to months to be effective. Minimally invasive surgical bypass is an attractive option because of the rapidity of symptom resolution, lack of need for long-term invasive tubes, short inpatient length of stay, and high success rate.

Kepenų arterijų anatominiai variantai yra dažni. Viena dažniausių aberantinių (netipiškai atsišakojančių) kepenų arterijų atsišakojimo vietų yra viršutinė pasaito arterija. Pastarosios arterijos kraujotaka yra įtakojama daugybės fiziologinių ir patologinių veiksnių. Literatūroje taip pat aprašyti pavieniai atvejai apie iš viršutinės pasaito arterijos atsišakojančios aberantinės kepenų arterijos įtaką viršutinės pasaito arterijos hemodinamikai, tačiau didesnės apimties įrodymais pagrįstų tyrimų šioje srityje iki šiol nebuvo atlikta. Todėl šio tyrimo tikslas buvo įvertinti, ar aberantinė kepenų arterija, atsišakojanti iš viršutinės pasaito arterijos, reikšmingai įtakoja pastarosios kraujagyslės hemodinamiką. Šiame tyrime kompiuterinės tomografijos angiografijos pagalba įvertinti kepenų arterijų anatominiai variantai, atrinkti pacientai doplerio ultragarso tyrimams. Pastaruoju metodu tirta viršutinės pasaito arterijos kraujotaka pacientams, kurių vieni turėjo aberantinę kepenų arteriją, atsišakojančią iš viršutinės pasaito arterijos, o kiti turėjo įprastą kepenų arterijų anatomiją. Vertinta aberantinės kepenų arterijos, atsišakojančios iš viršutinės pasaito arterijos, įtaka pastarosios arterijos hemodinamikai (rezistentiškumui). Remiantis tyrimo duomenimis nustatyta, kad kepenų arterijų anatominiai variantai yra dažni. Aberantinė kepenų arterija, atsišakojanti iš viršutinės pasaito arterijos, reikšmingai mažina pastarosios arterijos rezistentiškumą. Pateiktos praktinės... [toliau žr. visą tekstą] / Anatomical variants of hepatic arteries are frequent. One of the most common origins of aberrant (atypically branching) hepatic arteries is superior mesenteric artery. Many physiologic and pathologic features influence hemodynamics of the latter artery. There were some sporadic cases in literature about the influence of aberrant hepatic artery arising from superior mesenteric artery to the hemodynamics of the latter artery, but no evidence based large extent studies were performed. Therefore the aim of this study was to evaluate how significant the aberrant hepatic artery branching from the superior mesenteric artery influences the hemodynamics of superior mesenteric artery. Anatomical variants of the hepatic arteries were evaluated by computed tomography angiography also the candidates for Doppler ultrasound were selected. Doppler ultrasound was used to evaluate the hemodynamics of the superior mesenteric artery in patients with aberrant hepatic artery arising from the superior mesenteric artery and in those with typical hepatic artery anatomy. The influence of the aberrant hepatic artery arising from superior mesenteric artery to the hemodynamics (resistance) of the superior mesenteric artery was assessed. The results of the investigation show that anatomical variants of the hepatic arteries are frequent. The aberrant hepatic artery arising from superior mesenteric artery significantly lowers resistance of the superior mesenteric artery. Practical recommendations were set... [to full text]

<p>Acute thrombo-embolic occlusion of the superior mesenteric artery (SMA) with intestinal infarction is a lethal disease, difficult to diagnose in time, with unknown incidence and cause-specific mortality. The aim of this thesis was to characterize the disease and to develop diagnostic methods. </p><p>Two laboratory studies were conducted on patients with suspected acute SMA occlusion. A pilot-study showed that the fibrinolytic marker D-dimer was elevated in six patients with the disease. In the subsequent study including 101 patients, D-dimer was the only elevated coagulation marker in nine patients with the disease. In a prospective study 24 patients (median age 84 years) were identified, of whom four were diagnosed at autopsy, despite an autopsy-rate of 10%. One-fourth were initially nursed in non-surgical wards. Length of the intestinal infarction was a predictor for death. An analysis of patients from the three studies showed that D-Dimer was elevated in all 16 tested patients with the disease.</p><p>Sixty patients with acute SMA occlusion underwent intestinal revascularisation and were registered in the Swedish Vascular Registry (SWEDVASC). One-year survival-rate was 40%. Previous vascular surgery was a negative risk-factor.</p><p>A population-based study was conducted in Malmö, based on an autopsy-rate of 87%. Among 270 patients with the disease, 2/3 were diagnosed only at autopsy and 1/2 were managed in non-surgical wards. The incidence was 8.6 per 100000 person years. The age-standardized incidence increased exponentially without gender differences. The diagnosis was the cause of death in 1.2% among octogenarians and beyond. Thrombotic occlusions were located proximally within the SMA and associated with extensive intestinal infarctions. Synchronous embolism, often multiple, occurred in 2/3 of the patients with embolic occlusions.</p><p>Conclusions: A normal D-dimer at presentation most likely excludes the diagnosis. Acute SMA occlusion was more frequent than previously estimated from clinical series. The patients were often nursed in non-surgical wards.</p>

Acute thrombo-embolic occlusion of the superior mesenteric artery (SMA) with intestinal infarction is a lethal disease, difficult to diagnose in time, with unknown incidence and cause-specific mortality. The aim of this thesis was to characterize the disease and to develop diagnostic methods. Two laboratory studies were conducted on patients with suspected acute SMA occlusion. A pilot-study showed that the fibrinolytic marker D-dimer was elevated in six patients with the disease. In the subsequent study including 101 patients, D-dimer was the only elevated coagulation marker in nine patients with the disease. In a prospective study 24 patients (median age 84 years) were identified, of whom four were diagnosed at autopsy, despite an autopsy-rate of 10%. One-fourth were initially nursed in non-surgical wards. Length of the intestinal infarction was a predictor for death. An analysis of patients from the three studies showed that D-Dimer was elevated in all 16 tested patients with the disease. Sixty patients with acute SMA occlusion underwent intestinal revascularisation and were registered in the Swedish Vascular Registry (SWEDVASC). One-year survival-rate was 40%. Previous vascular surgery was a negative risk-factor. A population-based study was conducted in Malmö, based on an autopsy-rate of 87%. Among 270 patients with the disease, 2/3 were diagnosed only at autopsy and 1/2 were managed in non-surgical wards. The incidence was 8.6 per 100000 person years. The age-standardized incidence increased exponentially without gender differences. The diagnosis was the cause of death in 1.2% among octogenarians and beyond. Thrombotic occlusions were located proximally within the SMA and associated with extensive intestinal infarctions. Synchronous embolism, often multiple, occurred in 2/3 of the patients with embolic occlusions. Conclusions: A normal D-dimer at presentation most likely excludes the diagnosis. Acute SMA occlusion was more frequent than previously estimated from clinical series. The patients were often nursed in non-surgical wards.

Acute occlusion of the superior mesenteric artery (SMA) is a condition associated with high mortality and morbidity. The aim of this thesis is to evaluate diagnostic and therapeutic approaches for acute SMA occlusion. In a prospective study of patients with suspected intestinal ischemia, no biomarker was sufficiently accurate to detect this condition. In a second retrospective study, pancreatic amylase and troponin-I were elevated in a substantial proportion of patients with verified SMA occlusion. In an experimental animal model of acute SMA occlusion, microarray studies of ischemic small bowel wall were used to characterize the mRNA response to ischemia. Thrombospondin, Monocyte Chemoattractant Protein 1 and Gap Junction Alpha 1 were consistently up-regulated in all pigs with intestinal ischemia. Genes encoding previously proposed biomarkers for intestinal ischemia were either up-regulated, such as lactate dehydrogenase and creatine kinase, or down-regulated, such as intestinal fatty acid binding protein and glutathione S-transferase. In a study of the role of computed tomography in the diagnosis of SMA occlusion, it was shown that computed tomography with intravenous contrast was associated with improved survival. A retrospective analysis of all acute SMA revascularizations in Sweden 1999-2006 revealed that D-dimer was elevated in all 35 measured cases.  Endovascular surgery was associated with better outcome than open surgery, both in short and in long term. The presence of postoperative short bowel syndrome was a strong independent risk-factor for decreased long-term survival. Conclusions: Data affirm that D-dimer may serve as an exclusion test for acute SMA occlusion, whereas elevated troponin-I and pancreatic amylase are potential diagnostic pitfalls. Contrast-enhanced computed tomography of the visceral arteries seems to be the best diagnostic method. Endovascular surgery is an option to open surgery in selected cases, and was associated with favourable outcome.

Anatomical variants of hepatic arteries are frequent. One of the most common origins of aberrant (atypically branching) hepatic arteries is superior mesenteric artery. Many physiologic and pathologic features influence hemodynamics of the latter artery. There were some sporadic cases in literature about the influence of aberrant hepatic artery arising from superior mesenteric artery to the hemodynamics of the latter artery, but no evidence based large extent studies were performed. Therefore the aim of this study was to evaluate how significant the aberrant hepatic artery branching from the superior mesenteric artery influences the hemodynamics of superior mesenteric artery. Anatomical variants of the hepatic arteries were evaluated by computed tomography angiography also the candidates for Doppler ultrasound were selected. Doppler ultrasound was used to evaluate the hemodynamics of the superior mesenteric artery in patients with aberrant hepatic artery arising from the superior mesenteric artery and in those with typical hepatic artery anatomy. The influence of the aberrant hepatic artery arising from superior mesenteric artery to the hemodynamics (resistance) of the superior mesenteric artery was assessed. The results of the investigation show that anatomical variants of the hepatic arteries are frequent. The aberrant hepatic artery arising from superior mesenteric artery significantly lowers resistance of the superior mesenteric artery. Practical recommendations were set... [to full text] / Kepenų arterijų anatominiai variantai yra dažni. Viena dažniausių aberantinių (netipiškai atsišakojančių) kepenų arterijų atsišakojimo vietų yra viršutinė pasaito arterija. Pastarosios arterijos kraujotaka yra įtakojama daugybės fiziologinių ir patologinių veiksnių. Literatūroje taip pat aprašyti pavieniai atvejai apie iš viršutinės pasaito arterijos atsišakojančios aberantinės kepenų arterijos įtaką viršutinės pasaito arterijos hemodinamikai, tačiau didesnės apimties įrodymais pagrįstų tyrimų šioje srityje iki šiol nebuvo atlikta. Todėl šio tyrimo tikslas buvo įvertinti, ar aberantinė kepenų arterija, atsišakojanti iš viršutinės pasaito arterijos, reikšmingai įtakoja pastarosios kraujagyslės hemodinamiką. Šiame tyrime kompiuterinės tomografijos angiografijos pagalba įvertinti kepenų arterijų anatominiai variantai, atrinkti pacientai doplerio ultragarso tyrimams. Pastaruoju metodu tirta viršutinės pasaito arterijos kraujotaka pacientams, kurių vieni turėjo aberantinę kepenų arteriją, atsišakojančią iš viršutinės pasaito arterijos, o kiti turėjo įprastą kepenų arterijų anatomiją. Vertinta aberantinės kepenų arterijos, atsišakojančios iš viršutinės pasaito arterijos, įtaka pastarosios arterijos hemodinamikai (rezistentiškumui). Remiantis tyrimo duomenimis nustatyta, kad kepenų arterijų anatominiai variantai yra dažni. Aberantinė kepenų arterija, atsišakojanti iš viršutinės pasaito arterijos, reikšmingai mažina pastarosios arterijos rezistentiškumą. Pateiktos praktinės... [toliau žr. visą tekstą]

Made available in DSpace on 2015-05-14T12:59:31Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4097090 bytes, checksum: 20afefc885332713d2591aa778f7c7c0 (MD5) Previous issue date: 2012-02-27 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The essential oils are volatile organic constituents found in aromatic plants, which present several monoterpenes, such a-terpineol. Studies have demonstrated some biologic activities such as hypotensive and vasorelaxant (Guedes et al., 2004). In the present work the cardiovascular effects of a-terpineol was investigated and the pharmacodynamics of this effect was characterized. Wistar Kyoto and spontaneously hypertensive rats (SHR) were anaesthetized and polyethylene catheters were inserted into the low abdominal aorta and inferior vena cava for blood pressure measurements and administration of drugs. Isolated superior mesenteric rings (1-2 mm) were suspended by cotton threads for isometric tension recordings in Tyrode s solution (37°C, gassed with 95% O2 and 5% CO2), under 0.75g resting tension were measured by using pressure transducers, coupled to a computer set and CVMS software Miobath-4, WPI, Sarasota, EUA. In addition, the bioavailability of NO and eNOS, AKT and AMPK activity were quantified when exposing cells to α-terpineol in the cultured endothelial cells. In both SHR and normotensive rats, i.v. bolus injections of α-terpineol (1 20 mg/kg) decreased mean arterial pressure (MAP) in a dose-related manner, WKY (-103, -399, -5211, -6212 mmHg, n=10) and SHR (-375, -577, -715, -844 mmHg, n=9) associated with tachycardia. However, hypotensive and tachycardic responses were significantly attenuated after L-NAME (20 mg/kg, i.v.). The -terpineol demonstrated improves the baroreflex sensitivity. In intact isolated rat mesenteric rings -terpineol (10-12 10-5M) induced concentration-dependent relaxation of the contractions induced by phylephrine (10M) WKY Emax= 60  4 or SHR Emax= 53.7 ± 3, p<0.05, n=9). After endothelium removal the vasorelaxant elicited by -terpineol was significantly attenuated WKY [Emax= 20.5  1*] and SHR [Emax= 16.1 ± 3*, p<0.05, n=8]. Similar results were obtained in the presence of L-NAME 100M, a competitive antagonist of NOS, hydroxocobalamin 30 μM, a NO scavenger or ODQ 10μM, a selective inhibitor of soluble guanylyl cyclase. In addition, in endothelial cells, a-terpineol increased eNOS activation and NO levels by phosphorylation of PI3K/ AKT and AMPK pathway. However, atropine (1ηM) or indometacin (10 μM) had no effect on the a-terpineol -induced vasorelaxation. Furthermore, vasorelaxation was significantly attenuated in the presence of 20 mM KCl a modulator K+ efflux or several blocking of potassium channels: 1mM 4-aminopirimidine, 10 M glibenclamide, 1 mM tetraethylammonium and carybdotoxin plus apamin (0.2uM). In conclusion, the present study demonstrated that a-terpineol induced hypotensive effect, probably due to a decrease of peripheral vascular resistances, which seems to be mediated by endothelium derived relaxant factors, at least NO induced. These results suggest that vasorelaxant response, almost completely mediated by the endothelium, likely via NO release and activation eNOS by PI3K and AMPK with consequently activation of NO-cGMP pathway and potassium channels activation at least, KCa, KV, and KATP are involved in the vasorelaxant effect induced by a-terpineol. / Os óleos essenciais são componentes voláteis orgânicos encontrados em plantas aromáticas, que apresentam vários monoterpenos, como o α-terpineol. Estudos têm demonstrado algumas atividades biológicas, tais como hipotensivas e vasorelaxantes (Guedes et al., 2004). No presente trabalho, estudaram-se os efeitos cardiovasculares do α-terpineol e caracterizou-se a farmacodinâmica destes efeitos. Para isso foram utilizados ratos normotensos Wistar (WKY) e espontaneamente hipertensos (SHR), empregando técnicas combinadas in vivo, in vitro, e cultivo de células endoteliais. Para determinar a medida direta da pressão arterial, foram implantados cateteres na artéria aorta e veia cava inferior para administração de drogas em ratos WKY e SHR. Adicionalmente, foram realizados estudos para avaliar a reatividade vascular, assim, animais foram sacrificados e a artéria mesentérica superior foi isolada. Os anéis foram mantidos em cubas com solução de Tyrode, e gaseificada com carbogênio. Os anéis foram fixados a um transdutor de força, o qual estava acoplado a um sistema de aquisição de dados (Miobath-4, WPI, Sarasota, EUA) a uma tensão de 0,75 g por 1h. Após este período as preparações, foram pré-contraídas com 10 μM de fenilefrina (FEN) e, em seguida, concentrações crescentes de a-terpineol (10-12-10-5 M) foram adicionadas cumulativamente. Adicionalmente, realizamos experimentos para quantificação da produção de NO e determinação da atividade da eNOS, AKT e AMPK em cultivo de células endoteliais, utilizando as técnicas de citometria de fluxo e western blotting. Assim, observamos que a-terpineol (1, 5, 10 e 20 mg/kg i.v., randomicamente) produziu uma hipotensão dose-dependente em ratos WKY (-103, -399, -5211, -6212 mmHg, n=10) e SHR (-375, -577, -715, -844 mmHg, n=9, respectivamente), associada a taquicardia. A resposta hipotensora foi atenuada significantemente, após o tratamento com L-NAME (20 mg/kg, i.v), sugerindo que esse efeito pode ser decorrente de uma diminuição da resistência periférica., α-terpineol demonstrou melhorar a sensibilidade do barorreflexo. A resposta vasorelaxante foi significativamente atenuada quando comparada aos anéis na presença (WKY Emax= 60  4 e SHR Emax= 53,7 ± 3, p<0,05, n=9) e na ausência do endotélio funcional [WKY Emáx= 20,5  1 e SHR Emáx=16,1 ± 3, p<0,05, n=8]. Em anéis pré-contraídos com FEN na presença de L-NAME (100 μM), Hidroxicobalamina (30 μM) e ODQ (10 μM), a resposta relaxante foi atenuada significantemente, sugerindo uma participação da via NO-GMPc. Adicionalmente, a-terpineol aumentou os níveis de produção de NO e a atividade da eNOS por fosforilar vias como a PI3K e AMPK. No entanto, na presença de atropina (1 mM) ou indometacina (10 uM), a resposta vasorelaxante de a-terpineol não foi alterada indicando que os receptores muscarínicos e metabólitos da enzima Ciclooxigenase parecem não estar envolvidos. KCl (20mM) foi capaz de atenuar o efeito de a-terpineol, e preparações com endotélio vascular incubados com glibenclamida (10 uM) e 4-aminopiridina (1 mM), tetraetilamônio (1 mM) e caribdotoxina + apamina (0,2 μM). Deste modo, concluímos que resposta vasorelaxante promovida pelo a-terpineol é dependente de endotélio e envolve a via L-Arginina-NO-GMPc por aumentar a fosforilação da eNOS por vias PI3K e AMPK, produção de NO e EDHF com participaçãode canais para potássio do tipo KCa, KV e KATP em SHR e WKY e estes efeitos são responsáveis por eventos in vivo.

Made available in DSpace on 2015-05-14T13:00:05Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1204463 bytes, checksum: 3201c67d583f13a718e1d142910fb5c4 (MD5) Previous issue date: 2008-03-04 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The essential oils are volatiles organic constituents found in aromatic plants, which present several monoterpenes. a-terpineol is an important chemical constituent of the essential oil of many plants.. Studies have demonstrated some biologic activities such as antifungal and antispasmodic. In the present work the cardiovascular effects of a-terpineol were investigated in normotensive rats. Male Wistar rats (250-350 g) were anaesthetized and polyethylene catheters were inserted into the low abdominal aorta and inferior vena cava for blood pressure measurements and administration of drugs. Arterial pressure and heart rate were measured by using a pressure transducers coupled to a computer set and CVMS software. Isolated superior mesenteric rings (1-2 mm) were suspended by cotton threads for isometric tension recordings in Tyrode s solution (37°C, gassed with 95% O2 and 5% CO2), under 0.75g resting tension. In normotensive non-anaesthetized rats (n=6), a-terpineol (1, 5, 10, 20, 30 mg/Kg i.v., randomly) injections produced hypotension (-8,6 ± 2,25; - 18,35 ± 4,35; -33,25±6,0; -51,2±4,5 e -49,5±6,5 mmHg, n=6 , respectively followed by tachycardia (44,6±5,3; 24,5±8,4; 109,8±7,3; 113,2±12,4 e 35,8±14,0 bpm, n=6, respectively). However, hypotensive and tachycardic responses were significantly attenuated after L-NAME (20 mg/Kg ,i.v.) administration i.v (-1,5±0,6; -4,9±2,0; - 6,9±2,8; -22,0±9,0 e -22,1±9,0 mmHg, n=4). In intact isolated rat mesenteric rings a- terpineol (10-12 10-5M) induced concentration-dependent relaxation of the contractions induced by phylephrine (10μM) [Emax=62.41±13.79%]. After endothelium removal the vasorelaxant elicited by a-terpineol was significantly attenuated [Emax= 20.08±4.95]. Similar results were obtained in the presence LNAME 100 or 300 μM, a competitive antagonist of NOS, hydroxocobalamin 30 μM, a NO scavenger or ODQ 10μM, a selective inhibitor of soluble guanylyl cyclase [Emax= 18.33± 3.85% Emax= 23.24± 3.93% Emax= 23.49±7.05 Emax= 20.79 ± 1.06% respectively, p<0,001]. Furthermore, vasorelaxation was significantly attenuated in the presence of 20 mM KCl a modulator K+ efflux [Emax=23.07±14.36%] or several blocking of potassium channels: 1mM 4-aminopirimidine [Emax=26.48±10.50 %], 10 μM glibenclamide [Emax=27.97±3.7%], was not significantly modified after 1 mM tetraethylammonium [Emax=55.40±17.56%]. In conclusion, the present study demonstrated that a-terpineol induced hypotensive effect, probably due to a decrease of peripheral vascular resistances, which seems to be mediated by endothelium derived relaxant factors, at least NO.induced. These results suggest that vasorelaxant response, almost completely mediated by the endothelium, likely via NO release and activation of NO-cGMP pathway and consequently by potassium channels activation at least, KV, and KATP are involved in the vasorelaxant effect induced by a-terpineol. / Os monoterpenos são voláteis, freqüentemente encontrados nos os óleos essenciais e possui um elevado potencial terapêutico. O a-terpineol é um terpenóide com baixa toxicidade, e componente majoritário de óleos essenciais de muitas espécies vegetais. Os efeitos cardiovasculares de a-terpineol foram estudados em ratos usando técnicas combinadas in vivo e in vitro. Foram utilizados ratos Wistar que foram cirurgiados para implantação dos cateteres na artéria aorta e veia cava inferior para a medida direta da pressão arterial. Para os estudos de reatividade vascular os animais foram sacrificados e a artéria mesentérica superior foi isolada. Os anéis foram mantidos em cubas com solução de Tyrode, (37º C) e gaseificada com carbogênio. Os anéis foram fixados a um transdutor de força (FORT 10, WPI, Sarasota, EUA), o qual estava acoplado a um sistema de aquisição de dados (Miobath-4, WPI, Sarasota, EUA) a uma tensão de 0,75 g por 1h. Após este período as preparações, foram pré-contraídas com fenilefrina (FEN) 10 μM em seguida as concentrações crescentes de a-terpineol (10-12-10-5 M), foram adicionadas cumulativamente. Em ratos normotensos não-anestesiados, a-terpineol (1, 5, 10, 20 e 30 mg/Kg i.v., randomicamente) produziu uma hipotensão dose-dependente (- 8,6±2,25; -18,35±4,35; -33,25±6,0; -51,2±4,5 e -49,5±6,5 mmHg, n=6 respectivamente) associada a taquicardia (44,6±5,3; 24,5±8,4; 109,8±7,3; 113,2± 12,4 e 35,8±14,0 n=6, respectivamente). A resposta hipotensora foi atenuada significantemente, após o tratamento com L-NAME 20 mg/Kg, i.v (-1,5±0,6; -4,9±2,0; -6,9±2,8; -22,0±9,0 e -22,1±9,0 mmHg, n=4, respectivamente), sugerindo que esse efeito pode ser decorrente de uma diminuição da resistência periférica acompanhada por uma resposta taquicárdica provavelmente de origem reflexa. A resposta vasorelaxante foi significativamente atenuada quando comparada aos anéis na presença (Emáx=62,41±13,79%) e na ausência (Emáx= 20,08±4,95%) (p<0,001) do endotélio funcional e em contrações com KCl 80 mM não foi alterado significativamente. Em anéis pré-contraídos com FEN na presença de L-NAME 100 μM e 300 μM, Hidroxicobalamina 30 μM e ODQ 10 μM a resposta relaxante foi atenuada significantemente, sugerindo uma participação de FRDEs. No entanto na presença de atropina (1 hM) e indometacina (10 μM) a resposta vasorelaxante de a- terpineol não foi alterada indicando que os receptores muscarínicos e metabólitos da enzima cicloxigenase parecem não estar envolvidos nesta resposta vasorelaxante. Em anéis na presença ou na ausência do endotélio, KCl 20mM foi capaz de atenuar o efeito de a-terpineol, e preparações com endotélio vascular incubados com glibenclamida (10 μM) e 4-aminopiridina (1 mM) a resposta vasorelaxante também foi atenuada, mas não foi alterada significantemente na presença de tetraetilamônio (1 mM). Deste modo, constatou-se que, a resposta vasorelaxante promovida pelo a- terpineol é dependente de endotélio e parece envolver a participação do NO, através da via L-Arginina-NO-GMPc e conseqüente ativação de canais para potássio do tipo KV e KATP.

Made available in DSpace on 2015-05-14T13:00:14Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2088369 bytes, checksum: 2e3d2793391ca047954511fc5b3ad4ec (MD5) Previous issue date: 2010-03-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The organic nitrates are the most commonly nitric oxide (NO) donors used in the treatment of cardiovascular diseases, mainly due the pronounced vasodilator effect. The purpose of this study was to evaluate the vascular effects of tetrahydrofurfuryl nitrate (NTHF), an organic nitrate derivated from the sugarcane s synthetic route. In rat mesenteric artery rings, pre-contracted with phenylephrine 10 &#956;M, NTHF induced concentration-dependent (1 pM-10 &#956;M) vasodilatation, with intact endothelium (Maximum Response = 84 ± 5.3%, pD2 = 7.86 ± 0.22) or endothelium removal, NTHF effects were no attenuated (MR = 100 ± 6.1%, pD2 = 7.39 ± 0.15), suggesting an independent mechanism of endothelium-derived vasoactive factors. The subsequent experiments were performed in rings without endothelium. After pre-incubation of 3 mM NAC, a reactive oxygen species (ROS) scavenger, the response was potentiated (pD2 = 8.32 ± 0.18), a common profile of compounds producing NO. However, when pre-incubated with L-NAME 100 &#956;M, a NOS inhibitor, there was a decrease in the potency (pD2 = 6.62 ± 0.15), suggesting an involvement of this enzyme in the NTHF vascular response. By using scavenger NO radical, hydroxocobalamin 30 &#956;M or carboxy-PTIO 300 &#956;M, the efficacy was attenuated (MR = 66 ± 9.2% and 32 ± 6.2%, respectively), suggesting an involvement of this NO form in the NTHF vasodilator response. In the presence of cyanamide 1 mM, an aldehyde dehydrogenase (ALDH) inhibitor, or ODQ 10 &#956;M, a soluble guanylate cyclase (sGC) inhibitor, there was a significative maximum response s reduction (MR = 29 ± 9.5% and 22 ± 4.6, respectively), indicating an involvement of these enzymes in the NTHF vasodilator mechanism. After exposure to high concentrations of extracellular K+, KCl 80 or 20 mM, the NTHF effect was significantly attenuated (MR = 49 ± 3.8%; 59 ± 9.5%, respectively), a characteristic of substances that act by activating K+ channels. This effect was confirmed after the use of tetraethylammonium (TEA) 3 mM (MR = 31 ± 5.0%), a non-selective K+ channel blocker. In the presence of TEA 1 mM, which at this concentration selectively blocks the BKCa, the vasodilatation was significantly attenuated (MR = 38 ± 8.3%), suggesting the involvement of these channels in the nitrate vasorelaxant effect. This hypothesis was reinforced following the use of 4-aminopyridine 1 mM (MR = 81 ± 8.5%), a KV blocker, glibenclamide 10 &#956;M (MR = 97 ± 9.0%), a KATP blocker, or BaCl2 30 &#956;M (MR = 94 ± 4.9%), a KIR blocker, which did not alter the NTHF vasodilator response. After NTHF (10 &#956;M) incubation for 60 min, the vasodilatation was not changed, indicating that in this concentration this nitrate does not induce vascular tolerance. In conclusion, the NTHF cause vasodilatation, probably by promoting the NO radical release, involving the activation of NOS, ALDH, sGC and BKCa. / Os nitratos orgânicos são compostos doadores de óxido nítrico (NO) mais utilizados no tratamento de distúrbios cardiovasculares, principalmente, devido ao pronunciado efeito vasorrelaxante. A finalidade deste estudo foi avaliar os efeitos vasculares do nitrato tetra-hidrofurfurílico (NTHF), um nitrato orgânico proveniente da rota sintética da cana-de-açúcar. Em anéis de artéria mesentérica superior de rato, pré-contraídos com fenilefrina 10 &#956;M, o NTHF promoveu vasodilatação de maneira dependente de concentração (1 pM-10 &#956;M), com o endotélio vascular intacto (Emáx = 84 ± 5,3%; pD2 = 7,86 ± 0,22) ou removido (Emáx = 100 ± 6,1%; pD2 = 7,39 ± 0,15), sugerindo um mecanismo independente dos fatores vasoativos derivados do endotélio. Todos os experimentos subsequentes foram realizados com remoção do endotélio. Após pré-incubação com N-acetilcisteína 3 mM, um sequestrador de espécies reativas do oxigênio, a resposta foi potencializada (pD2 = 8,32 ± 0,18), um perfil peculiar de substâncias que produzem NO. Entretanto, ao serem pré-incubados com L-NAME 100 &#956;M, um inibidor da NO sintase (NOS), houve uma diminuição da potência (pD2 = 6,62 ± 0,15), sugerindo a participação desta enzima no efeito vasodilatador do NTHF. Ao utilizar sequestradores de NO radicalar, hidroxocobalamina 30 &#956;M ou carboxi-PTIO 300 &#956;M, a eficácia do efeito vasorrelaxante do NTHF foi atenuada (Emáx = 66 ± 9,2% e 32 ± 6,2%, respectivamente), indicando o envolvimento desta forma do NO na vasodilatação do nitrato em estudo. Na presença de cianamida 1 mM, um inibidor da aldeído desidrogenase (ALDH), e do ODQ 10 &#956;M, um inibidor da ciclase de guanilil solúvel (sGC), a resposta máxima foi reduzida significativamente (Emáx = 29 ± 9,5% e 22 ± 4,6, respectivamente), indicando a participação destas enzimas no mecanismo vasorrelaxante do NTHF. Após a exposição a concentrações elevadas de K+ extracelular, KCl 80 ou 20 mM, o efeito do NTHF foi significantemente atenuado (Emáx = 49 ± 3,8% e 59 ± 9,5%, respectivamente), sendo esta uma característica de substâncias que agem por ativar canais para K+. Este efeito foi confirmado após utilização de tetraetilamônio (TEA) 3 mM (Emáx = 31 ± 5,0%), que nesta concentração bloqueia de modo não seletivo os canais para K+. Ao utilizar TEA 1 mM (Emáx = 38 ± 8,3%), que nesta concentração bloqueia seletivamente os BKCa, a vasodilatação foi atenuada de modo significante, sugerindo a participação destes canais neste efeito vasorrelaxante. Esta hipótese foi reforçada após a utilização de 4-aminopiridina 1 mM (Emáx = 81 ± 8,5%), um bloqueador dos KV, glibenclamida 10 &#956;M (Emáx = 97 ± 9,0%), um bloqueador dos KATP, ou BaCl2 30 &#956;M (Emáx = 94 ± 4,9%), um bloqueador dos KIR, que não alteraram a resposta vasodilatadora do NTHF. Após a incubação durante 60 min com o NTHF (10 &#956;M), o vasorrelaxamento não foi alterado, sugerindo que nesta concentração este nitrato não induz tolerância vascular. Em conclusão, o NTHF causa vasodilatação, provavelmente, por promover a liberação de NO radicalar, envolvendo a ativação da NOS, ALDH, sGC e de BKCa.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The p- cymene is a monoterpene aromatic biosynthetic which has many biological properties , including cardiovascular. Em system actions on the in vivo study, p- cymene showed hypotensive activity through a central effect. Therefore, we sought to investigate the effect of p-cymene on the peripheral vascular resistance in the superior mesenteric artery of rats Rats were sacrificed by exsanguination under anesthesia and the superior mesenteric artery was removed, sectioned and kept in vats containing nutrient solution Tyrode. For recording of isometric contractions, each ring was suspended by cotton thread attached to a force transducer connected to a data acquisition system. In mesenteric artery rings with functional endothelium precontracted with phenylephrine (FE) (control), p- cymene (10-8 - 3x10 -2M) induced relaxation (Emáx = 77.1 ± 3.53% , n = 5) in a concentration-dependent manner not was attenuated after removal of endothelium (Emáx = 72 ± 4.03 %, n = 7) or pre-contracted with 80 mM KCl (Emáx = 79.37 ± 5.25 % n = 6) , suggesting a possible effect independent of the endothelium and surrounding channels for Ca2 +. In preparations without functional endothelium and pre-contracted with FEN and incubated with tetraethylammonium (TEA), tetraethylammonium (TEA), a blocker of non-selective for K+ channels, p- cymene induced relaxation (Emáx = 50.56 ± 4.09 %, n = 8) which was not significantly different from that obtained without functional endothelium in rings pre-contracted with FEN without blocking . Thus, possibly there is no involvement of K + channels for this purpose. Furthermore, incubation with p- cymene (3x10-3, 10-2 and 3x10-2M) was able to antagonize the contractions induced by CaCl2 (3x10-7 - 3x10-2M), and sodium orthovanadate (Na3VO4) (10-5 - 3x10-2M) a non-selective inhibitor of protein tyrosine fosfatase.These results it can be concluded that p- cymene produces vasorelaxant effect independent of the endothelium. The pharmacological evidence suggest that the mechanism of action of p- cymene vasorelaxant involves channels for Ca2+ and voltage sensitive desensitization of the Ca2+ contractile elements. / O p-cimeno é um monoterpeno aromático biossintético que apresenta inúmeras propriedades biológicas, incluindo ações sobre o sistema cardiovascular. Em estudo in vivo, o p-cimeno demonstrou atividade hipotensora, através de um efeito central. Diante disso, buscou-se investigar o efeito do p-cimeno sobre a resistência vascular periférica em artéria mesentérica superior de ratos. Para tanto, ratos Wistar foram eutanasiados por dessangramento sob anestesia e a artéria mesentérica superior foi removida, seccionada e mantidas em cubas contendo solução nutritiva de Tyrode. Para o registro das contrações isométricas, cada anel foi suspenso por linha de algodão fixada a um transdutor de força conectado a um sistema de aquisição de dados. Em anéis de artéria mesentérica com endotélio funcional pré-contraídos com fenilefrina (FEN) (controle), o p-cimeno (10-8 - 3x10-2M) induziu relaxamento (Emáx = 77,1 ± 3,53%; n = 5) de maneira dependente de concentração.Este efeito não foi atenuado após a remoção do endotélio (Emáx =72 ± 4,03%, n = 7) ou pré-contraído com KCl 80 mM (Emáx = 79,37 ± 5,25%; n = 6), sugerindo um possível efeito independente do endotélio e envolvendo canais para Ca2+. Em preparações sem endotélio funcional pré-contraídos com FEN e incubadas com tetraetilamônio (TEA), um bloqueador não seletivo dos canais para K+, o p-cimeno induziu relaxamento (Emáx= 50,56 ± 4,09%; n= 8), que não foi significativamente diferente daquele obtido em anéis sem endotélio funcional pré-contraídos com FEN sem o bloqueador. Portanto, possivelmente, não há participação dos canais para K+ neste efeito. Além disso, a incubação com o p-cimeno (3x10-3, 10-2 e 3x10-2M) foi capaz de antagonizar as contrações induzidas por CaCl2 (10-7 - 3x10-2M) e Ortovanadato de Sódio (Na3VO4) (10-5 - 3x10-2M), um inibidor não-seletivo de proteínas tirosina-fosfatase. Diante desses resultados, pode-se concluir que o p-cimeno produz efeito vasorelaxante independente do endotélio. As evidências farmacológicas sugerem que o mecanismo de ação vasorelaxante do p-cimeno envolve canais para Ca2+ sensíveis à voltagem e dessensibilização de elementos contráteis ao Ca2+.