Browsing by Subject "Vasopressin"
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Item Regulation of Secretin the Neurohypophysis(2011-05-01) McGovern, Adam A.; Tom CunninghamSecretin (SCT) exists in the hypothalamo-neurohypophysis axis of the rat. Secretin receptor null mice show altered glomerular and renal tubular morphology along with mild polydipsia and polyuria. We hypothesize SCT may play a role in the physiology of water regulation in the rat. Water deprivation (WD) and bile duct ligation (BDL) models were used. Rats were WD for 48 h and rehydrated with either water (RH+W) or 0.9% NaCl (RH+S) for 2 h before sacrifice. Sham and BDL rats were sacrificed 4 weeks after surgery. The presence of SCT and arginine-vasopressin (AVP) in the pituitary; secretin receptor (SCTR), vasopressin receptor 2 (AVP2R), and aquaporin-2 water channel (AQP-2) in the kidney were analyzed using the Western blot technique. Plasma SCT concentrations were measured by enzyme immunoassay (EIA) analysis. Our results show that there is no change in pituitary SCT content in WD rats when compared to controls or in the BDL model. There is also no change in AVP content in either model. No change occurred in plasma SCT concentration for either model. AVP2R and SCTR (at 50kDa) are significantly decreased in the BDL group compared to sham (P [less than] 0.015; P [less than] 0.004 respectively). Abundance of glycosylated and non-glycosylated AQP-2 are increased significantly for RH+W and RH+S compared to control (P [less than] 0.002; P [less than] 0.015 respectively), but neither showed a difference between sham and BDL groups. We confirm the presence of SCT in the neurohypophysis, but do not support the hypothesis that SCT acts independently of AVP to regulate water absorption in response to homeostatic challenges or disease models with increased AVP. We also show decreased abundance of the SCTR in the kidney of a model of dilutional hyponatremia in the rat.Item Regulation of Supraoptic Vasopressin Neurons during Hypernatremia and Hyponatremia(2019-05) Balapattabi, Kirthikaa; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.; Ma, Rong; Cunningham, Rebecca L.This dissertation addresses the regulatory mechanisms of arginine vasopressin (AVP) secretion during salt loading (SL) and liver failure. The experiments focused on AVP neurons located in the supraoptic nucleus (SON) of hypothalamus that, along with other hypothalamic neurons, secrete AVP. This dissertation has two sections. The first section, specific aims 1a and 1b, examines AVP secretion with SL. Salt loading is associated with increased AVP release and mean arterial pressure. The male SL (2% NaCl for 7 days) rats secrete AVP despite increase in mean arterial pressure and were used as an animal model for this aim to study altered AVP neuron regulation. Previous work has shown that SL impairs baroreceptor mediated inhibition of rat AVP neurons through brain derived neurotrophic factor (BDNF) dependent activation of tyrosine receptor kinase B (TrkB) and downregulation of K+/Cl- co-transporter (KCC2). This mechanism diminishes the GABAA mediated inhibition of SON AVP neurons by increasing intracellular chloride ([Cl]i). However, the source of BDNF leading to this ionic plasticity is unknown. In specific aim 1a, adeno-associated viral vectors with shRNA against BDNF were used to test if the SON is the source of BDNF contributing to increased AVP release and elevated mean arterial pressure in SL rats. In specific aim 1b, virally mediated chloride imaging with ClopHensorN was combined with single cell Western blot analysis by capillary based Simple Wes technology to verify the expression of KCC2 in the SON AVP neurons and to determine the role of TrkB-KCC2 mechanism in increased [Cl]i in SL male rats.In Aim 2, a more clinically relevant animal model was used to study regulatory mechanism leading to inappropriate increase in AVP secretion. Chronic bile duct ligated (BDL) rats were used as animal model of liver failure induced hyponatremia due to inappropriate AVP release. The findings and approaches from specific aim 1 were used to test the role of BDNF-TrkB-KCC2 signaling in increased AVP secretion and hyponatremia during liver failure. The experiments in this dissertation advance our understanding about the pathophysiology of AVP secretion. There are several novel findings from this work. First, SON was identified as the source of BDNF contributing to increase in [Cl]i of SON AVP neurons and AVP secretion in SL rats. Additionally, this is the first study to correlate the KCC2 protein expression in individual AVP neurons with its function using chloride imaging. Finally, these results are the first to demonstrate a mechanism that contributes to the increase in AVP secretion resulting in hyponatremia during liver failure.Item The Role of the MnPO in Body Fluid Balance and Blood Pressure Regulation(2019-05) Marciante, Alexandria B.; Cunningham, J. Thomas; Mifflin, Steve W.; Schreihofer, Ann M.; Goulopoulou, Styliani; Ma, Rong; Bugnariu, Nicoleta L.The median preoptic nucleus (MnPO) is situated on the anteroventral wall of the third ventricle (AV3V) between two circumventricular organs (CVOs) that lack a functional blood-brain barrier, the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT). The SFO and OVLT project to the MnPO and together these regions regulate neuroendocrine and autonomic function, arousal, and fluid balance. Early studies demonstrated that the MnPO and other regions in the AV3V contribute to regulating thirst associated with body fluid homeostasis, as well as several forms of neurogenic hypertension. The MnPO is key in relaying signals from the SFO and OVLT to downstream regions that control fluid intake and autonomic function; however, pathway-specific and stimulus-dependent mechanisms are not fully understood. These studies investigate how the MnPO differentially responds to models of physiological challenges that induce thirst, as well as pathway-specific mechanisms of blood pressure in a known model of hypertension. To study the role of the MnPO in thirst, rats were tested with models of cellular (hyperosmolality) and extracellular (angiotensin II, ANG II) dehydration associated with hypovolemia. Previous studies have shown that different populations of MnPO neurons are osmo- or ANG II-sensitive; however, both stimuli lead to a converging behavioral outcome: water consumption. This led to the hypothesis that osmotic challenges and ANG II activate MnPO neurons that project to different regions in a stimulus-dependent manner. Results show that the MnPO signals to specific thirst-driving regions of the brain and the activation of these regions is dependent on the stimulus. To study the role of the MnPO in regulating blood pressure, an experimental model of chronic intermittent hypoxia (CIH) associated with obstructive sleep apnea (OSA) is used to successfully mimic the oxygen deprivation associated with apneic breathing patterns patients with mild to moderate forms of OSA experience. Both patients with OSA and rodents in the CIH model develop diurnal hypertension, which is a sustained increase in blood pressure that persists into the waking hours. Hypertension involves multiple organ systems, including the central nervous system, and can be a heterogenous disease state that manifests from a number of factors, including CIH, ANG II from renin-angiotensin system (RAS), and changes in body fluid osmolality. This led to the hypothesis that pathway-specific inhibition of MnPO neurons that project to pre-autonomic neurons in the paraventricular nucleus (PVN) of the hypothalamus would block persistent hypertension. Results indicate that lesioning PVN-projecting MnPO neurons can block CIH-induced hypertension, resulting in decreases in oxidative stress and improved cardiovascular health. These findings provide new information about how the MnPO differentially regulates behavioral and physiological outcomes in a stimulus-dependent manner. These outcomes also have broad clinical implications relating to the role of the central nervous system in disease states affecting body fluid balance and blood pressure regulation.Item VASOPRESSIN INSTEAD OF EPINEPHRINE ENHANCES EFFICACY OF CPR WITHOUT CAUSING TACHYCARDIA(2014-03) Cherry, Brandon H.; Nguyen, Ahn Q.; Williams, Arthur G. Jr.; Scott, Gary F.; Hollrah, Roger A.; Ryou, Myoung-Gwi; Hoxha, Besim; Olivencia-Yurvati, Albert H.; Mallet, Robert T.Survival from cardiac arrest is highly dependent on the arterial pressure generated by cardiopulmonary resuscitation (CPR). To increase efficacy of precordial compressions, the potent vasoconstrictor epinephrine (EPI) is administered. However, EPI also elicits a robust, β1-adrenoceptor-mediated tachycardia following defibrillation, depleting the myocardium of the energy reserves it requires for recovery. We proposed that the adrenoceptor-independent vasoconstrictor vasopressin (AVP) increases arterial pressure as effectively as EPI without producing tachycardia. After 6 min pacing-induced cardiac arrest, domestic swine (25-35 kg; 10 boars, 11 sows) received precordial compressions (100/min) for 4 min, and either EPI (0.1 mg; n=5) or AVP (10 U; n=24) was injected iv at 1 min CPR. EPI and AVP similarly increased mean arterial pressure from 31±3 to 66±4 mmHg vs. 34±3 to 59±3 mmHg after 4 min CPR. The AVP-treated pigs required less countershock energy (12±2 J) to achieve defibrillation vs EPI-treated pigs (16±4 J). Post-arrest tachycardia was less intense in AVP- (133±11 bpm) than EPI-treated (174±14 bpm) pigs. Thus, AVP is as effective as EPI at enhancing CPR, but avoids EPI-induced tachycardia. Purpose (a): The purpose of this study was to test the hypothesis that the adrenoceptor-independent vasoconstrictor vasopressin increases arterial pressure as effectively as epinephrine without producing tachycardia during cardiopulmonary resuscitation (CPR). Methods (b): After 6 min pacing-induced cardiac arrest, domestic swine (25-35 kg; 10 boars, 11 sows) received precordial compressions (100/min) for 4 min, and either epinephrine (0.1 mg; n=5) or vasopressin (10 U; n=24) was injected iv at 1 min CPR. Results (c): Epinephrine and Vasopressin similarly increased mean arterial pressure from 31±3 to 66±4 mmHg vs. 34±3 to 59±3 mmHg after 4 min CPR. The vasopressin-treated pigs required less countershock energy (12±2 J) to achieve defibrillation vs epinephrine-treated pigs (16±4 J). Post-arrest tachycardia was less intense in vasopressin- (133±11 bpm) than epinephrine-treated (174±14 bpm) pigs. Conclusions (d): Vasopressin is as effective as epinephrine at enhancing CPR, but avoids epinephrine-induced tachycardia.