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Hypertension is a major risk factor for developing cardiovascular, renal and nervous system pathologies. Refractory hypertension is prevalent at approximately 30% despite diet, lifestyle and multiple pharmacologic interventions. Blood pressure can be influenced at the level of the nervous system, at the level of the kidney, and at the level of the vasculature. This document describes investigations performed into each of these systems during the development of hypertension using a model of human essential hypertension, the spontaneously hypertensive rat (SHR), by a proteomic approach of 2-dimensional gel electrophoresis and mass spectrometry. A transgenic mouse model with deficits in p75 neurotrophin receptor (NTR), which has been implicated in hypertension, was similarly investigated. Proteomics is a scientific strategy that is not entirely hypothesis driven, rather it has the hypothesis that functional and phenotypic changes in pathophysiology are reflected at the protein level. Proteomics compares the proteome of a disease state, treatment, temporal state, to an appropriate control to determine changes in the level of protein present and its biochemical properties. Proteome changes in the SHR mesenteric arteries included the novel observation of increased CLIC1 association with the adventitia in the SHR, the decreased expression of HSP90 alpha and beta in the SHR, and the presence of an additional protein spot for tropomyosin beta and MLC20 in the SHR. These proteome changes are suggestive of an increased contractile state in the mesenteric resistance arteries of SHR. In the renal proteome, there was a decrease of alpha-2μ globulin and a decrease in MAWDBP in the SHR demonstrating molecular changes in the kidney before known pathological changes. In superior cervical ganglia, sstereological measurement showed significant increases in the number of sympathetic neurons in both lines of p75NTR-deficient mice, relative to wild type mice with an enhanced survival of sympathetic neurons associated with shifts toward the more basic isoforms of Annexin V in the proteomes of p75NTR-deficient mice. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2014-02-11 15:35:00.525

Increasingly, individuals in New Zealand are taking "herbal highs" with little knowledge of their possible long-term effects. Benzylpiperazine (BZP) is the predominant base drug in most herbal highs. The limited research into BZP has suggested that it produces similar effects to amphetamine, but could be 10 times less potent. There are to date, however, no long-term behavioural studies of BZP exposure. This study therefore, investigated effects of BZP exposure in adolescent male and female rats on subsequent measures of anxiety-like behaviours in adulthood. One group of experimental animals was treated daily with BZP, whereas another group received the same total amount of drug via a four day "binge" regime. The results suggested that, when observed in a Y-maze, social interaction test and a light/dark emergence test, BZP-treated rats were more anxious than control animals. In the Y-maze, male controls were more active than female controls, but BZP-treated females were more active than treated males. Results of this interaction indicate that the male rats may have been more affected by the administration of BZP during adolescence than females. Additionally, rats given the binge dose regime showed significantly increased anxiety in the Y-maze relative to the daily-exposed or control rats'. This suggests that larger quantities of BZP over a shorter time frame produce more detrimental effects than smaller quantities of BZP over a longer time frame. Overall, it would appear that the administration of BZP to adolescent animals produces behavioural changes in emotionality that are detectable in adulthood.

Children and adolescents are regular consumers of caffeine, and their consumption is increasing. Caffeine has been shown to affect the later behaviour of rats and mice when exposed to the drug daily before birth and during the lactational period of development. However, to date, little research has investigated the effects caffeine consumption may have on adolescent brain development, and the behavioural consequences of this. The present study, therefore, investigated the effects of repeated caffeine exposure on adolescent rats on behavioural measures of anxiety. During middle and later adulthood, the rats’ activity and emotional reactivity were assessed by means of frequencies of rearing, ambulation, immobility, defaecation and urination recorded in an open field, as well as their occupancy of corners and centre squares of the field, and their partial emergence and latencies to fully emerge from a small darkened chamber into a brightly lit arena. The results showed that those rats treated with caffeine were probably more emotionally reactive than untreated controls, as suggested by more immobility, defaecation and urination. There were also effects on rearing and ambulation that might have arisen from increased impulsivity. Overall, the results suggest that exposure to caffeine during adolescence produces some small but significant increases in emotionality in adulthood. This study may have clinical implications, as it is possible that people exposed to caffeine as adolescents, may show increased anxiety later in life.

Zugl.: Dresden, Techn. Univ., Diss., 2008

Proefschrift Maastricht. / Auteursnaam op omslag: Jos C.S. Kleinjans. Lit.opg.

Proefschrift Universiteit Maastricht. / Met lit. opg., bibliogr. - Met samenvatting in het Nederlands.

Proefschrift Maastricht. / Met lit.opg. - Met een samenvatting in het Nederlands.

Proefschrift Universiteit Maastricht. / Met lit. opg., bibliogr. - Met samenvatting in het Nederlands.