Eileen M. Hasser - US grants

Activation of the sympathetic nervous system plays a pivotal role in the response of an organism to stress. This activation and the resultant cardiovascular adjustments in large part determine the organism's chances for survival. Studies of sympathetic efferent discharge, plasma catacholamines, and cardiovascular function have documented this increase in activity. Recently, a potent system for modulation of sympathetic activity by endogenous opioid peptides has been described. In the conscious, intact animal, this system is apparently involved with limiting sympathetic activation during stress. Although this system may function in a variety of stressful situations, the work of Dr. James Schadt will focus on its role in hemorrhagichypotension. This work will be performed on rabbits and will use neurochemical measures to determine blood levels of essential peptides during stress and correlate these with sympathetic nervous system activity. This work is important in understanding the biological basis of stress.

Compensatory responses to dehydration include increases in plasma vasopressin (AVP), plasma renin activity (PRA) (and thus angiotensin II) and peripheral vascular resistance. AVP and angiotensin II (AII) are potent vasoconstrictors, and both act in the central nervous system to modulate control of the sympathetic nervous system (SNS). The CNS effects of both are mediated at least in part at the area postrema. AVP acts at the area postrema to augment reflex inhibition of the SNS, while AII exerts sympathoexcitatory effects at the area postrema. The integrated effects of concomitant elevations of both of these peptides at the area postrema is not known. This is especially thus od chronic increases in both AVP and AII, as occurs during dehydration. The proposed studies will address the central concept that the area postrema modulates arterial and cardiopulmonary baroreflexes during dehydration, and thus influences the regulation of the circulation in the dehydrated state. The specific hypotheses which we will test are: 1) the area postrema modulates the reflexly mediated changes in plasma AVP, AII and catecholamines in response to 48 hours of water deprivation; 2) the dehydration-induced increases in AVP and AII modulate arterial and cardiopulmonary baroreflex control of the SNS via an action at the area postrema; and 3) the area postrema modulates reflex compensation to the vasoconstrictor effects of AVP, AII and the SNS during dehydration. The role of the area postrema in neurohumoral responses to dehydration, and in mediating effects of AVP and/or AII on baroreflex function during dehydration, will be evaluated by comparing responses in conscious, area postrema lesioned and sham lesioned animals. Area postrema modulation of the vasoconstrictor effects of AVP, AII and the SNS during dehydration will be evaluated by measuring regional vascular resistance responses to blockade of AVP, AII or the SNS in area postrema lesioned animals. Experiments will examine the effects of direct activation of the area postrema, and effects of microinjection of AVP and/or AII into the area postrema on baroreflex function during dehydration. Little is known about integrative cardiovascular responses to simultaneous elevations in AVP and AII, especially when both are increased chronically. Hypovolemic states, as well as pathophysiologic conditions such as congestive heart failure and certain forms of hypertension are characterized by longterm changes in these neurohumoral factors. Therefore, it is important to obtain a clear understanding of their interactions in regulation of the circulation in order to assess their role in pathophysiological states.

DESCRIPTION: (Adapted from the application) Prolonged bed rest or weightlessness in humans results in a number of adverse cardiovascular consequences, often referred to as cardiovascular deconditioning. Prominent among these are orthostatic intolerance and decreased exercise capacity. Rat hindlimb unweighting is an animal model of cardiovascular deconditioning, and results in similar cardiovascular consequences. Cardiovascular adjustments to both orthostatic challenges and exercise require the integrated response of cardiovascular reflexes and the appropriate vascular response to reflex stimuli. Therefore, the orthostatic intolerance and decreased exercise capacity associated with cardiovascular deconditioning may be due to reflex dysfunction, vascular dysfunction, or both. The proposed studies will test the general hypothesis that hindlimb unweighting in rats results in impaired reflex control of the vasculature. The investigators postulate that arterial and cardiopulmonary baroreflex control of the sympathetic nervous system is impaired in conscious hindlimb unweighted rats. They further propose that the ability of the vasculature to respond to sympathomimetic vasoactive stimuli is compromised. There are 4 specific aims: 1) To evaluate arterial and cardiopulmonary baroreflex regulation of renal and lumbar sympathetic nerve activity in conscious rats subjected to 14 days of hindlimb unweighting, 2) To examine the interaction between arterial and cardiac baroreflex control of sympathetic nerve activity in conscious hindlimb unweighted rats, 3) To evaluate changes in afferent and/or central nervous system mechanisms in baroreflex regulation of the sympathetic nervous system, and 4) To evaluate changes in vasomotor reactivity of visceral and skeletal muscle vascular beds in conscious rats after 14 days of hindlimb unweighting.

DESCRIPTION (provided by the applicant): Prolonged exposure to bed rest or microgravity in humans, results in a number of adverse cardiovascular consequences, leading to cardiovascular deconditioning. Rat hindlimb unloading (HU) is an animal model of cardiovascular deconditioning and results in similar cardiovascular consequences including orthostatic intolerance. Blunted sympathetic vasoconstriction appears to contribute to orthostatic intolerance after bedrest or space flight. Studies in HU rats suggest that reflex activation of the sympathetic nervous system in response to hypotensive stimuli is blunted following cardiovascular deconditioning. It is unclear whether these alterations in autonomic function represent a chronic adaptation to microgravity or bedrest or are due to the acute response to return to a 1 G environment or resumption of an upright posture, respectively. The specific mechanisms that contribute to baroreflex dysfunction following deconditioning are unknown, but a number of factors are likely candidates. Activation of cardiopulmonary receptors, due to the cranial shift in blood volume during the HU period, could account for the changes in arterial baroreflex function. In addition, changes in circulating humoral agents acting at circumventricular organs, specifically vasopressin acting at the area postrema, could also produce the observed changes in baroreflex control of sympathetic activity following cardiovascular deconditioning. Furthermore, the attenuated sympathoexcitation appears to be due to altered central nervous system integration of baroreceptor afferent activity and likely involves changes in the rostral ventrolateral medulla (RVLM). The RVLM is critically important in control of the sympathetic nervous system. The diminished reflex-sympathoexcitation following deconditioning appears to be due in part to enhanced inhibition of the RVLM but could also be mediated by a reduction in excitatory influences at the RVLM. The proposed studies will investigate the factors contributing to alterations in arterial baroreflex function due to HU and the mechanisms that mediate those changes. SPECIFIC AIMS: 1. To examine mechanisms contributing to blunted arterial baroreflex control of sympathetic nerve activity in conscious hindlimb unloaded rats. 2. To evaluate mechanisms contributing to diminished activation of the RVLM after hindlimb unloading. 3. To determine whether blunted reflex control of sympathetic nerve activity in conscious rats subjected to 14 days of hindlimb unloading is due to chronic adaptations or responses to return to the horizontal position.

More than 35 million Americans are subject to hospitalization and bedrest each year. Cardiovascular deconditioning (CVD) due to bedrest or microgravity impairs cardiovascular regulation. CVD in humans and an animal model, hindlimb unloaded (HU) rats, produces autonomic impairments, including enhanced chemoreflex function, that correlate with poor prognosis in disease. The nucleus tractus solitarii (nTS) coordinates basal and reflex cardiorespiratory function via neurotransmitters/neuromodulators acting through a network of synapses which include both neurons and astrocytes (the ?tripartite synapse?). We propose that increased excitability within the nTS tripartite synapse contributes to augmented chemoreflex responses in CVD. The goal of this proposal is to determine the cellular, molecular and integrative mechanisms, including the role of the tripartite synapse, by which the nTS influences cardiorespiratory regulation in CVD. We hypothesize that nTS astrocytes tonically restrain excitation of nTS neurons, and CVD attenuates this restraint or reverses it to enhancement. The resulting increased nTS synaptic and/or neuronal activity augments chemoreflex function. Aim 1 determines the extent to which CVD alters 1) reflex and nTS neuronal responses to arterial chemoreflex stimuli; 2) nTS synaptic and neuronal activity; 3) the balance of excitatory and inhibitory modulation of nTS chemoreflex, neuronal and synaptic signaling. Aim 2 determines the magnitude by which cardiovascular deconditioning modulates the integrative role of astrocytes in the nTS tripartite synapse to 1) enhance baseline ventilation, sympathetic and neuronal activity, and responses to chemoreflex activation, and 2) neuronal and synaptic function. Aim 3 determines the extent to which CVD alters the contribution of nTS astrocyte transport mechanisms to 1) baseline and enhanced cardiorespiratory and neuronal responses to chemoreflex stimulation, 2) synaptic and neuronal function, and 3) the influence of neurotransmitters. These studies utilize a comprehensive and integrated approach, including conscious and anesthetized whole animal studies to examine physiological mechanisms, the brainstem slice preparation to determine cellular mechanisms within the nTS tripartite synapse, and molecular approaches. Proposed studies will provide valuable novel information regarding the role of plasticity of the nTS tripartite synapse in normal cardiorespiratory function, and insight into mechanisms of dysfunction in CVD. Importantly, mechanisms of cardiorespiratory dysfunction in CVD also may apply to other disease states that exhibit altered autonomic and respiratory control.