Mechanisms of the contribution of vasopressin to the development of hypertension
|dc.contributor.advisor||Brown, Colin Hamilton|
|dc.contributor.author||Korpal, Aaron Kumar|
|dc.identifier.citation||Korpal, A. K. (2017). Mechanisms of the contribution of vasopressin to the development of hypertension (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/7593||en|
|dc.description.abstract||Plasma vasopressin levels are paradoxically elevated in some hypertensive patients. Vasopressin is secreted from the posterior pituitary gland by magnocellular neurosecretory cells (MNCs) located in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus in response to action potential discharge. Vasopressin acts at vasopressin 1 (V1) receptors on vascular smooth muscle cells to cause potent vasoconstriction, and vasopressin 2 (V2) receptors in the kidneys to promote antidiuresis. We have previously shown that vasopressin MNC activity is increased early in the development of hypertension in transgenic Cyp1a1-Ren2 rats. Angiotensin II-dependent hypertension is induced in these rats by dietary administration of indole-3-carbinol (I3C), to activate a knocked-in mouse Ren-2 renin gene. To investigate the contribution of vasopressin to hypertension, tail-cuff plethysmography was used to show that mean systolic blood pressure was significantly lower in V1 receptor antagonist-treated rats on day seven of hypertension compared to non-hypertensive controls. To investigate intrinsic mechanisms of increased vasopressin MNC activity in hypertension, extracellular single-unit recordings of SON vasopressin MNCs were made from urethane-anaesthetized rats. Vasopressin MNC firing rate was significantly higher in hypertensive Cyp1a1-Ren2 rats on day seven of I3C-treatment (I3C-7) compared to non-hypertensive controls. Stimulation of the baroreflex inhibited 6/6 vasopressin MNCs in Ord-7 rats but only 3/8 vasopressin MNCs in I3C-7 rats, demonstrating that baroreflex-inhibition of vasopressin MNCs is blunted in hypertension. Baroreflex-inhibition of vasopressin MNCs is mediated by γ-aminobutyric acid (GABA)-ergic inputs and so bicuculline (BIC), an antagonist of ionotropic GABAA receptors, was dialysed over the SON. BIC significantly lowered vasopressin MNC firing rate in I3C-7 rats compared to non-hypertensive controls, showing the response of vasopressin MNCs to GABA shifts towards excitation in hypertension. Because a similar change in vasopressin MNCs in salt-loaded rats is underpinned by brain-derived neurotrophic factor (BDNF) signalling, immunohistochemical analysis was used to stain for BDNF in MNCs and fibres within magnocellular hypothalamic nuclei but showed that BDNF expression in these structures was similar in hypertensive rats (I3C-7) and non-hypertensive controls. To determine whether microglial activation or breakdown of the blood-brain barrier (BBB) contribute to the development of hypertension, immunohistochemical analysis of Iba1 (a microglial marker) and TfR (a protein constituent the BBB) expression in the PVN and SON was carried out. Microglia exhibited a relatively ramified morphology, and the immunostained area for Iba1 was similar between I3C-7 rats and controls in both nuclei, indicating that microglial activation does not occur during the development of hypertension and, therefore, is unlikely to contribute to increased vasopressin MNC activity. The mean number and staining intensity of microvessels with TfR was similar between I3C-7 rats and controls in these nuclei, indicating that the BBB remains intact in magnocellular hypothalamic nuclei during the development of hypertension and so is unlikely to present a route for blood-borne factors to increase vasopressin MNC activity. To determine whether microglial activation, or breakdown of the BBB occur later in the development of hypertension, analyses of Iba1 and TfR were repeated on day twenty-eight (I3C-28), when severe hypertension was established. Microglia exhibited a relatively ramified morphology, and the immunostained area for Iba1 was similar between I3C-28 rats and controls in both nuclei, indicating that microglial activation does not occur in the magnocellular hypothalamic nuclei and is therefore unlikely to contribute to established hypertension in Cyp1a1-Ren2 rats. The number of TfR-labelled microvessels in the PVN and SON was significantly lower in I3C-28 rats compared to controls, suggesting that the BBB is disrupted within magnocellular hypothalamic nuclei in chronic severe hypertension. In conclusion, vasopressin is recruited early in the development hypertension in Cyp1a1-Ren2 rats to exacerbate hypertension. This is a result of increased vasopressin MNC activity, which is (at least partially) due to blunting of baroreflex-inhibition by an excitatory shift in the response of vasopressin MNCs to GABA. Microglial activation and BBB breakdown are unlikely to cause increased vasopressin MNC activity, as they are unchanged at the time vasopressin MNC activity is increased. Nevertheless, BBB patency is compromised in chronic severe hypertension, indicating that this mechanism could contribute to the maintenance of established hypertension in Cyp1a1-Ren2 rats.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||Mechanisms of the contribution of vasopressin to the development of hypertension|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
Files in this item
There are no files associated with this item.
This item is not available in full-text via OUR Archive.
If you would like to read this item, please apply for an inter-library loan from the University of Otago via your local library.
If you are the author of this item, please contact us if you wish to discuss making the full text publicly available.