A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Master of Science in Medicine, 2016 / Although it is well known that an increase in sodium intake (Na+) increases BP and is involved in the development of salt-sensitive hypertension (SS-HTN), the mechanism responsible for this increase in BP is uncertain. Further while low dietary potassium (K+) is also associated with the development of SS-HTN it is uncertain to what extent dietary potassium (K+) affects Na+-induced increases in BP. The purpose of this study was to determine whether Na+-induced increases in BP and target organ changes are altered by reductions in K+ intake. Four-month-old male Sprague-Dawley (SO) rats were randomly assigned to three dietary intervention groups for six weeks: a normal Na+ (0.3%), normal K+ (1.6%) group (CON, n=12), a high Na+ (6%), normal K+ (1.6%) group (NK+-HNa+, n=12) and a high Na+ (6%), low K+ (0.01%) group (LK+-HNa+, n=12). Tail-cuff BP, body weight, food and water intake were measured weekly. At termination, urine parameters, right kidney weight as well as left ventricular dimensions and function were measured. Vascular reactivity of the mesenteric and renal arteries was also assessed using a wire-myograph. During the diet intervention, water intake was significantly higher in the NK+-HNa+ and LK+-HNa+ groups compared to the CON group (P<0.0001). Although food intake was significantly lower in the NK+-HNa+ and LK+-HNa+ groups compared to the CON group during the first week (P=0.03 and P=0.05 respectively), no significant differences in body weight were observed between the groups (P>0.05). The urinary Na+/K+ ratio was higher in the LK+ HNa+ compared to the CON and NK+ -HNa+ groups (P<0.001). Following the 6 week dietary intervention, the systolic BP was significantly higher in the NK+-HNa+ and the LK+-HNa+ groups compared to the CON group (P=0.05 and P=0.04 respectively). The diastolic BP was significantly higher in the NK+-HNa+ and LK+-HNa+ groups compared to the CON group (P=O.05 and P=O.02, respectively). The increase in BP was not different between the NK+-HNa+ and LK+-HNa+ groups (P>O.05). In the mesenteric arteries, there was a significant increase in vascular responsiveness to phenylephrine in the NK+-HNa+ group compared to the CON group (P=O.02). However the vascular responsiveness to phenylephrine in the mesenteric arteries was similar between the NK+-HNa+ and LK+-HNa+ groups (P=O.82). No significant differences in vascular reactivity were observed in the renal arteries between the three groups. No significant differences were observed in the left ventricular dimensions and function between the different diet groups (P>O.05). In conclusion, 6 weeks of high Na+ intake increases BP, induces greater phenylephrine-induced contractions in mesenteric arteries but does not affect heart dimensions and function. The greater phenylephrine-induced contractions with a high Na+ intake may be responsible for the increase in BP. However a reduction in dietary K+ intake does not have any effect on the high Na+-induced changes in BP or mesenteric artery reactivity. / AC2016

Orientador: Cláudio Aparecido Casatti / Resumo: As teneurinas (Tens) são proteínas transmembrana do tipo II, constituídas de quatro membros homólogos (Ten-1-4). Estas proteínas são expressas principalmente durante a neurogênese do sistema nervoso central (SNC) e estão envolvidas primariamente no estabelecimento dos circuitos neuronais. Tens apresentam vários sítios de clivagens intracelular e extracelular que resultam em peptídeos bioativos, destacando-se os peptídeos associados aos terminais carboxila das teneurinas (Teneurin C-terminal-Associated Peptides, TCAPs). As latrofilinas (LPHN1-3) representam receptores associados à proteína G, sendo os principais receptores endógenos das Tens. A interação da Ten-2 com a LPHN-1 resulta na modulação nos níveis de cálcio intracelular, fato este que pode estar desbalanceado durante episódios epileptogênicos. O principal propósito deste estudo foi verificar possíveis alterações na imunorreatividade e na expressão gênica da Ten-2 no SNC em um modelo de epilepsia induzida por cloreto de lítio-cloridrato de pilocarpina em ratos adultos. Adicionalmente, as expressões gênicas do TCAP-2 e LPHN1 também foram analisadas, visto que são as principais proteínas correlacionadas à Ten-2. Para isto, ratos adultos (Rattus norvegicus; n=49) foram submetidos a indução de status epilepticus (SE) com cloreto de lítio (127 mg/kg) e cloridrato de pilocarpina (40 mg/kg) e divididos em grupos controles, grupos 2, 5 e 14 dias após SE e grupos epilepsia crônica (35 e 75 dias). Amostras do SNC destes animais... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Teneurins (Tens) are a type II transmembrane protein family composed of four homologous members (Ten-1-4). These proteins are primarily present in the central nervous system (CNS) during neurogenesis and exert an important role in the development and establishment of neuronal circuits. Tens have several intra- and extracellular cleavage sites, originating bioactive peptides, such as the carboxyl-terminal peptides named Teneurin C-terminal-Associated Peptides (TCAPs). Latrophilins (LPHN1-3) represent G protein-coupled receptors and are considered the main endogenous receptors for Tens. The Ten-2-LPHN-1interaction results in intracellular calcium modulation in neurons and this system can be changed during epilepsy induction. The main purpose of this study was to verify possible alterations in immunoreactivity and gene expression of Ten-2 in the CNS from an adult rat model of lithium chloridepilocarpine-induced epilepsy. In addition, TCAP-2 and LHPN1 gene expressions were also analyzed, as they are the main Ten-2 related proteins. For this, adult male (Rattus norvegicus; n = 49) were submitted to status epilepticus (SE) induced by intraperitoneal administration of lithium chloride (127 mg/kg) and pilocarpine hydrochloride (40 mg/kg). Subsequently, the animals were divided into control groups, 2-, 5- and 14-day groups after SE, as well as chronic epilepsy group (35-75 days). Samples were submitted to immunohistochemistry technique to identify Teneurin-2-like immunoreactive (Ten-2... (Complete abstract click electronic access below) / Doutor