Hypertension is associated with autonomic nervous system dysfunction. Elevated sympathetic outflow and alterations in the baroreceptor reflex sensitivity may play an important role in the initiation and maintenance of high blood pressure. Previous work from this laboratory has demonstrated that endothelial derived genes are differentially expressed in key brainstem nuclei in hypertensive rats. In addition, angiotensin II acting at the nucleus tractus solitarii has been shown to attenuate the baroreflex through a vascular-neuronal signalling mechanism involving the release of nitric oxide. This evidence has led to the hypothesis that alterations in brainstem microvascular gene expression are causative to hypertension in animals and man.

I have studied the GNB3 gene as a candidate gene for hypertension and left ventricular mass in a systematic and comprehensive manner. I have carried out association studies in three independent populations - A case-control study with well characterised hypertensive and their matched controls; a twin study looking at echocardiographic LV mass; and a large family based study analysing blood pressure and ECG LV mass. In addition I have also looked at three additional candidate genes including ACE, aldosterone synthase and beta-1 adrenoceptor. Though these studies concluded that there was no association between the C825T polymorphism and blood pressure or LV mass, I have demonstrated a significant heritability of various electrocardiographic measures of LV mass and an interaction between GNB3, ACE and SF1 explaining the variability of continuous measures of LV mass in this population. I studied the functional aspects of the GNB3 polymorphism by measuring platelet aggregation in normal human volunteers, using it as a marker of G-protein related signal transduction. However, there was also no association between epinephrine or platelet activating factor induced platelet aggregation and the GNB3 genotype. Finally, I performed molecular studies using cells transfected with b3 (wild-type) and b3-s (splice-variant) of GNB3 along with a fusion construct of a2AGi, and measuring of GTPase activity and calcium signalling. There was no significant difference between b3 or b3-s transfected cells, in terms of epinephrine stimulated GTPase activity, onset-delay of calcium release and time-to-peak of calcium signal. However, cells expressing b3-s showed a significantly lower rate of calcium release compared to cells expressing b3. These results indicate that the G protein b3-s subunit has no functional difference or possible slightly reduced effect compared to the wild type.

Includes copies of author's previously published works. / Bibliography: leaves 106-122. / xiii, 123 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines the relationship between circulating adrenaline (AD) and blood pressure. Results suggest that the elevation of circulating AD in hypertensive rats is a consequence rather than a cause of their hypertension. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1995