Cardiovascular
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21705
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Browsing Cardiovascular by Author "Cunningham, J. Thomas"
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Item A Vital role for Median Preoptic AT1a Receptors in the Sustained Hypertension of Chronic Intermittent Hypoxia(2016-03-23) Cunningham, J. Thomas; Shell, BrentPurpose The hypoxemia from Sleep Apnea (SA) results in hypertension during both the hypoxic sleeping period and the normoxic waking period. This pathophysiological sustained hypertension persists during waking hours and is a source of numerous cardiovascular sequlae. In order to better understand the neurological changes that underlie this disease state, our lab utilizes Chronic Intermittent Hypoxia (CIH) to model the hypoxemia and generate the hypertension of SA sufferers. Previously, our lab has shown that the Median Preoptic Nucleus increases in both neuronal activity and Angiotensin Type 1a Receptor (AT1aR) RNA expression in response to CIH. The MnPO is situated in a critical location that allows it to receive inputs from nuclei outside of the blood brain barrier and provide inputs to regions that control sympathetic outflow, and therefore blood pressure. The ability to modulate sympathetics based upon peripheral inputs coupled with increased activity and AT1aR expression leads us to hypothesize that increased Angiotensin signaling to the MnPO is essential for the sustained component of hypertension from CIH. Methods Male Sprague-Dawley rats were microinjected in the MnPO with either a virus to knockdown AT1aR expression (shAT1a) or a scramble virus (SCR) and instrumented with radio telemetry a week later. Radio telemetry provides continuous recording of cardiovascular variables. After a week of surgery recovery the animals were monitored for a 5 day baseline period before experiencing 7 days of CIH. The morning of the final day, the animals were either perfused with formaldehyde for immunohistochemistry (IHC) or their brains were snap frozen for quantitative PCR. Results Rodents injected in the MnPO with the shAT1a did not exhibit the sustained component of hypertension compared to SCR animals (P Conclusions Overall, this data indicates that the increase in AT1aR expression in the MnPO is essential for the development of the sustained component of CIH hypertension. The shAT1a virus successfully prevents the increase in AT1aR expression and this leads to normal waking blood pressure in the CIH exposed rodents. IHC results indicate that there is less activity in the MnPO and RVLM of the rodents most likely related to reduced sympathetic outflow. This data lends support to optimizing our current treatment regiment through blood brain barrier AT1aR blockers and ACE inhibitors. Future treatment methods could focus solely on preventing Angiotensin as a peptide neurotransmitter in the MnPO to ameliorate neurogenic hypertension.Item Role of Chronic Intermittent Hypoxia and Hypercapnia Induced Hypertension in Regulation of Blood Pressure(2016-03-23) Cunningham, J. Thomas; Little, Joel; Marciante, Alexandria B.Role of Chronic Intermittent Hypoxia and Hypercapnia Induced Hypertension in Regulation of Blood Pressure Purpose Sleep apnea is a prevalent disease characterized by momentary cessations in respiration leading to sustained hypertension. The hypertension experienced can be mimicked by periodic decreases in oxygen or chronic intermittent hypoxia (CIH) in humans and animal models. More recently, CIH has been combined with hypercapnia (CIH-H) to determine if an increase in circulating carbon dioxide, which is also experienced by patients that suffer from sleep apnea, contributes to neural adaptations related to sustained hypertension. CIH has been shown to have a significant effect on increased blood pressure due to increased sympathetic outflow from initiation and maintenance of hypertension. However, it is not known if the additional hypercapnic component significantly affects blood pressure or central autonomic control. Methods Male Sprague-Dawley rats are instrumented with radio telemetry one week after arrival. The radio telemetry provides information regarding cardiovascular variables continuously over a specified period of time. Animals were monitored for recovery for one week and then acclimated to the CIH or CIH-H rooms for 6 days, and monitored during this period for baseline data before experiencing 7 days of CIH, CIH-H or normoxic conditions. The CIH exposure is applied for 8 hours during the light (nocturnal) period from 8:00 AM to 4:00 PM, during which time hypoxia is produced using 3 min on-3 min off cycles that reduces oxygen from 21% to 10% to then being flushed with room air, so the inspired oxygen rises back to 21% before the cycle repeats. During CIH-H, rats are exposed to the same conditions with the addition of carbon dioxide that is raised from 0% to 8% during hypoxia to also produce hypercapnia. Results Rodents exposed to hypoxic and hypercapnic conditions did exhibit a greater increase in blood pressure than rodents exposed to only hypoxic conditions in the light period. The difference was not sustained during the return to normoxic conditions. Conclusions The results are consistent with previous studies which showed periods where there were greater increases in blood pressure in CIH-H animals than those exposed to hypoxia alone. Both CIH and CIH-H produced a greater increase in blood pressure during the light period. The difference did not appear to be sustained when rats were breathing room air.Item Role of Median Preoptic AT1a Receptors in Control of Thirst Regulation(2016-03-23) Cunningham, J. Thomas; Farmer, Gef; Shell, BrentPurpose Thirst is an essential mechanism for organisms to maintain osmotic and blood volume homeostasis and is therefore tightly regulated. Angiotensin II (Ang II) has long been known to stimulate thirst by both its action peripherally as a circulating hormone, and centrally acting as a peptide neurotransmitter. Peripherally circulating Ang II can elicit thirst by stimulating the Subfornical Organ (SFO), which in turn stimulates other hypothalamic nuclei regulating blood volume homeostasis such as the Median Preoptic Nucleus (MnPO) and Paraventricular Nucleus presumably through Ang II signaling. These hypothalamic nuclei then activate higher cognitive centers resulting in thirst. Central Ang II administered via intracerbroventricular (ICV) infusion also induces thirst by directly stimulating regions such as the MnPO through the Angiotensin Type 1 receptor and following a similar signaling pathway as peripheral Ang II only ignoring the circumventricular organs. Methods Male Sprague-Dawley rats are microinjected in the MnPO with either a virus to knockdown AT1aR expression (shAT1a) or a scramble virus (SCR) and instrumented with radio telemetry a week later. Our lab microinjected an adeno-associated virus with short hairpin RNA matched to the Angiotensin Type 1a receptor (At1aR) into the MnPO to test whether Ang II was necessary for thirst signaling in the MnPO. We hypothesized that Ang II was necessary for the thirst response to peripherally circulating Ang II as well as ICV injected central Ang II. Sprague Dawley rats were separated into subcutaneous (SC) and ICV Ang II administration groups. The SC group was pretested for their drinking response to 2mg/kg Ang II, and those animals that drank in response to the SC Ang II administration were utilized in the study. All animals were injected with the shAt1aR virus on Day 0, and were allowed to recover before drinking tests on day 14 and day 18. ICV animals were microinjected with the virus on Day 0 as well and instrumented with a chronic lateral ventricle cannula. These animals were administered 2ng Ang II in 1ul aCSF. Results Unexpectedly, we found that knockdown of AT1aR in the MnPO did not reduce drinking in the subcutaneous animals (p [greater than] .05), but did significantly reduce drinking in the ICV animals (P Conclusions Peripheral generation of thirst through Ang II may be predominantly mediated through glutamatergic neurotransmission from the SFO which only uses Ang II as a co-transmitter. Mechanistic understanding of thirst generation in the hypothalamus is critical for pharmacological manipulation with currently available pharmaceuticals as well as for development of future compounds.