Physiology - Theses
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ItemIdentification of the phenotype of the angiotensin II type 1A receptor-expressing neurons involved in modulating the baroreceptor-heart rate reflex( 2016)Blood pressure (BP) regulation requires a complex interaction between different physiological systems to ensure adequate tissue blood flow under different physiological conditions. One of these is the baroreceptor reflex which modulates heart rate (HR) and total peripheral resistance (TPR) to modulate BP homeostasis. Circulating angiotensin II (ANG II) acts via its type 1 receptor (AT1R) to attenuate the barorereceptor-heart rate (HR) response. It is currently unknown which AT1R –expressing cell type mediates this modulatory effect of ANG II on the baroreflex. Thus, overarching aim of this thesis is to investigate which cell types, involved in the modulation of the baroreceptor reflex express the AT1R. To achieve this aim, I used a combination of genetic tools to remove AT1Rs from specific cell populations. In chapter three, the baroreceptor-HR response was investigated in the global AT1AR knockout (AT1AR-KO) and wildtype (AT1AR-WT) mice under artificial ventilation and isoflurane anaesthesia. Baroreceptors were activated by changes in blood pressure induced by bolus injections or slow infusions of phenylephrine (PhE) or sodium nitroprusside (SNP) to increase or decrease the blood pressure respectively. No impairment in the baroreceptor-HR response was observed in AT1AR-KO mice. In chapter four, I have attempted to generate a brain-specific knock out of the AT1ARs using the conditional, CRE-recombinase-mediated deletion. Unfortunately, I was unable to demonstrate any obvious reduction in the expression of AT1ARs in the brains of these mice. The baroreceptor-HR response was intact in these animals. An abberant tachycardiac response to systemic ANG II was observed, but the cellular basis for this could not be determined. The nucleus of the solitary tract (NTS) is the first synapse of the baroreceptor afferent neurons. It has a high density of AT1Rs and is invovlved in modulation of baroreceptor-HR response by ANG II. However, little is known about the properties of the AT1R-expressing neurons in the NTS. Chapter five addresses this issue using a transgenic mouse where the AT1AR- promoter drives GFP expression. AT1AR is widely expressed in many subregions of the NTS in cells resembling neurons. Co-expression of the AT1AR-GFP and either Phox2b or tyrosine hydroxylase (TH), occurred in a distinct pattern in different subregions of the NTS. This suggests that AT1R-expressing neurons in the NTS are a heterogenous population with a complexity that reflects the diverse function of ANG II in the NTS. In chapter six, the role of subpopulations of AT1R-expressing cells in the NTS in modulating the sensitivity of the baroreceptor-HR responses was investigated. I observed that the sensitivity was significantly enhanced in mice in which the AT1AR was deleted from Phox2-expressing neurons using recombinant viral approaches, but was un altered in transgenic mice with AT1AR deletion from TH-expressing neurons. This suggests that AT1ARs on TH-, Phox2+ cells tonically inhibit the baroreceptor-HR response in adult mice. The PhE induced baroreceptor-HR responses was significantly enhanced in AT1AR-FL mice that received bilateral injections of Lv-PRSx8-CRE in the NTS but was unaltered in the ThCRE+ x AT1AR-FL mice. This suggested that AT1ARs on TH-, Phox2+ cells tonically inhibits the baroreceptor-HR responses in adult mice. In conclusion, we have found that the AT1R-expressing cells in the NTS are a heterogeneous population of cells. Amongst these, the AT1AR on TH-, Phox2+ cells attenuate the baroreceptor-HR response. Further investigation is required to fully understand the functional properties of other AT1R-expressing cells in the NTS.