Joel E. Dimsdale - US grants

This study examines the interaction of dietary salt and psychological stressors on blood pressure and the physiological responses of plasma norepinephrine, epinephrine, renin, aldosterone, renal blood flow, and adrenergic receptor sensitivity. We shall study 4 groups of 20 men each: Whites with and without mild hypertension; and Blacks with and without mild hypertension. Our major hypotheses are: 1. that high salt intake increases the blood pressure response to psychological stressors, particularly in Blacks; 2. that hypertensive subjects' alpha and beta receptors are more sensitive to ambient levels of plasma catecholamines; 3. that hypertensive subjects respond to stressors with a fall in renal blood flow; 4. that hypertensive subjects respond to stressors not only with greater blood pressure elevation but also with greater increases in plasma catecholamines, renin, and aldosterone; 5. that suppressed hostility is associated with hypertension. Subjects will be studied at two extremes of dietary salt intake: 10 meq Na/day and 200 meq Na/day. All subjects will be studied twice, after stabilizing on each of the two diets. Diets will be administered and monitored at the Clinical Research Center of Massachusetts General Hospital. Subjects will be studied at rest, after postural challenge, and after psychological stressors.

This study examines the effect of angiotensin converting enzyme inhibition and dietary salt on physiological responses to behavioral stressors. It is difficult to tease apart the roles of the sympathetic nervous system, the renin-angiotensin system, and dietary salt. For instance, under low salt conditions, there is activation of both the sympathetic nervous system and the renin- angiotensin system. As a result, observing an increased pressor response to stressors in patients on high salt intake is not straightforward. A beginning way to understand this system is to block production of angiotensin II with an angiotensin covering enzyme inhibitor (captopril). Thirty hypertensive and 30 normotensive white men will be admitted for two 5-day hospitalizations on a Clinical Research Center while they consume a low salt diet (10 meq/d). These subjects will participate in a randomized crossover design employing either placebo on the initial hospitalization or captopril. Patients will be studied at rest, while they are exposed to behavioral stressors, and during infusions of norepinephrine. The following physiological variables will be monitored: blood pressure, heart rate, plasma and urinary catecholamines, renin, aldosterone, angiotensin II, atrial natriuretic factor, urinary sodium, and the slope of the dose response curve relating infused norepinephrine to blood pressure. The investigators will also have obtained data from another project on an additional 60 subjects, studied on the same reactivity protocol, but who are hospitalized on a high salt diet (200 meq/d). The reactivity of these subjects will be compared to that elicited by other subjects on a combination of salt depletion plus captopril. Thus the effects of salt intake will be studied while blocking the activation of the renin-angiotensin system on the low salt diet.

There is a high co-morbidity between sleep apnea and essential hypertension. This study will test the hypothesis that apneic episodes predispose to hypertension by repeated nighttime arousals that raise blood pressure to daytime levels via activation of the sympathetic nervous system and release of stress hormones. Plasma and urinary catecholamines, renin, neuropeptide Y, atrial natriuretic factor, blood pressure, and cortisol will be examined during sleep, resting wakefulness, and after mild behavioral stressors. Beta adrenergic receptors on lymphocytes and the response to adrenergic agonists will be characterized. This study will determine if apneic hypertensives have an excessive response to the stress of hypoxia or to combined hypoxia plus breathholding. Mild hypoxia will be induced, and the effects of hypoxia will be examined on norepinephrine metabolism, baroreceptor functioning, and sensitivity to infused isoproterenol. Eighty unmedicated patients will be studied: 20 hypertensives with sleep apnea, 20 hypertensives without apnea, 20 normotensives with sleep apnea, and 20 normotensives without apnea. All patients will be admitted for a 2 day stay in the Clinical Research Center.

There is a high co-morbidity between sleep apnea and essential hypertension. This study will test the hypothesis that apneic episodes predispose to hypertension by repeated nighttime arousals that raise blood pressure to daytime levels via activation of the sympathetic nervous system and release of stress hormones. Plasma and urinary catecholamines, renin, neuropeptide Y, atrial natriuretic factor, blood pressure, and cortisol will be examined during sleep, resting wakefulness, and after mild behavioral stressors. Beta adrenergic receptors on lymphocytes and the response to adrenergic agonists will be characterized. This study will determine if apneic hypertensives have an excessive response to the stress of hypoxia or to combined hypoxia plus breathholding. Mild hypoxia will be induced, and the effects of hypoxia will be examined on norepinephrine metabolism, baroreceptor functioning, and sensitivity to infused isoproterenol. Eighty unmedicated patients will be studied: 20 hypertensives with sleep apnea, 20 hypertensives without apnea, 20 normotensives with sleep apnea, and 20 normotensives without apnea. All patients will be admitted for a 2 day stay in the Clinical Research Center.

There is a high co-morbidity between sleep apnea and essential hypertension. This study will test the hypothesis that apneic episodes predispose to hypertension by repeated nighttime arousals that raise blood pressure to daytime levels via activation of the sympathetic nervous system and release of stress hormones. Plasma and urinary catecholamines, renin, neuropeptide Y, atrial natriuretic factor, blood pressure, and cortisol will be examined during sleep, resting wakefulness, and after mild behavioral stressors. Beta adrenergic receptors on lymphocytes and the response to adrenergic agonists will be characterized. This study will determine if apneic hypertensives have an excessive response to the stress of hypoxia or to combined hypoxia plus breathholding. Mild hypoxia will be induced, and the effects of hypoxia will be examined on norepinephrine metabolism, baroreceptor functioning, and sensitivity to infused isoproterenol. Eighty unmedicated patients will be studied: 20 hypertensives with sleep apnea, 20 hypertensives without apnea, 20 normotensives with sleep apnea, and 20 normotensives without apnea. All patients will be admitted for a 2 day stay in the Clinical Research Center.

[Note: This UCSD GCRC protocol utilized the UVA GCRC VAX computer for (continued) access to CLINFO software for data analysis.] This study examines the effect of salt and stress on blood pressure regulation with particular emphasis on the sympathetic nervous system and the renin angiotensin system. Patients are studied on a low-salt diet (10 mEq. sodium/day) during 2 hospitalizations where they receive, in a double-blind fashion, either placebo or an angiotensin-converting enzyme inhibitor. COMPUTER ONLY.

This study examines the sympathetic nervous system in hypertensives with sleep apnea. In order to study this adequately, comparisons will be made between hypertensives and normotensives, with and without sleep apnea.

This project examines the effect of continuous positive airways pressure (CPAP) treatment on the sympathetic nervous system (SNS) of sleep apneic patients. In previous studies we have documented that apneics have increased SNS tone, as inferred by urinary catecholamines, beta adrenergic receptors, preejection period, Heather index, cardiac acceleration index. Such individuals also demonstrate alterations in baroreflex functioning (increased pressor sensitivity). Numerous other studies have reported that CPAP treatment lowers the blood pressure of apneic patients. The mechanism and time course of such blood pressure lowering is uncertain. We will enroll 60 patients with sleep apnea and characterize their blood pressure and SNS activity. Patients will then be randomized to receive a one week trial on either CPAP or placebo-CPAP (insufficient CPAP pressure to reduce the respiratory disturbances). Their blood pressure and sympathetic nervous system activity will be studied after 1 day and after 7 days on CPAP (or placebo-CPAP). End points will include: ambulatory blood pressure, baseline blood pressure, blood pressure in response to behavioral stressors, plasma and urinary catecholamines, measures of cardiac SNS tone as inferred from impedance cardiography, adrenergic receptor characteristics, and baroreflex functioning.

This study examines the role of dietary salt and psychological stress in blood pressure regulation in blacks and whites. After achieving salt balance on a 200 mEq NA diet and on a 10 mEq NA diet, the subjects are examined at rest and in response to behavioral stressors. Plasma catecholamines, renin, aldosterone, renal blood flow, and peripheral receptor sensitivity are studied.

Determine the pharmacological and psychological characteristics of individuals who have caffeine sensitivity by contrasting 3 groups of patients, habitual coffee drinkers who experience no unpleasant side effect from coffee, individuals who complain of unpleasant side effects from coffee and individuals who neither consume coffee or have a history of caffeine sensitivity.

DESCRIPTION (adapted from investigator's abstract): This competing renewal examines the effect of chemoreceptor (CHEMO) and sympathetic nervous system (SNS) physiology in four groups of individuals: apneics and non-apneics, with and without hypertension. A total of 80 individuals will be studied in terms of their CHEMO and SNS function, sleep physiology, and quality of life. They will then be randomized to receive either nocturnal oxygen supplementation or nocturnal room-air supplementation and they will be restudied after 24 hours and after one week. Studies will include measurement of plasma and urinary catecholamines, beta adrenergic receptors on lymphocytes, plasma endothelin-1. CHEMO activity will be characterized while breathing room-air, while stimulating CHEMO with a brief period of hypoxia, and while blocking CHEMO with a brief period of hyperoxia. Using tritiated norepinephrine, norepinephrine release rate will be calculated during each of these CHEMO manipulations. Using impedance cardiography, cardiac hemodynamics will be characterized at rest and in response to behavioral stressors. The study will measure heart rate and tidal volume responses to infused isoproterenol. Baroreflexes will be characterized after stimuli that transiently increase and decrease blood pressure. Blood pressure will be characterized with ambulatory blood pressure monitoring. Sleep will be characterized with polysomnography. The effect of nocturnal oxygen treatment will be studied in terms of patient satisfaction, compliance, and quality of life.

DESCRIPTION (adapted from the investigator's abstract): This competing renewal examines how blood pressure regulation differs between blacks and whites. There is increasing evidence suggesting that blood pressure decreases (or "dips") less at nighttime in certain groups of individuals and that such relative non-dipping of blood pressure is related to adverse health outcomes. Data suggest that non-dipping is found more frequently in Blacks. We will study 80 blacks and 80 whites in an effort to understand the psychological and physiological correlates of nocturnal BP dipping. Patients' sleep and ambulatory blood pressure will be studied at home and in the Clinical Research Center environment. Physiological characterization will include 24-hour urinary norepinephrine, beta-adrenergic receptors on lymphocytes, hemodynamic responses to behavioral stressors, heart rate and blood pressure responses to infused isoproterenol. Psychological characterization will include assessment of life stressors and job stress, mood, anger/hostility, and social desirability.

DESCRIPTION (provided by applicant): The goal of this R21 application is to refine an experimental design to examine the impact of commonly used pain medications on sleep and next-day fatigue. However, before such studies can be conducted in patients with acute or chronic pain associated with cancer or other severe chronic illness, crucial information is needed to optimize the study design. This proposal seeks to answer certain experimental methodological design questions that can be safely, quickly, and inexpensively addressed in healthy volunteers. This R21 application will generate data guiding the research design and power estimates for subsequent RO1 applications intended to address the impact of pain medication on sleep and fatigue in patients with acute or chronic pain. There are 5 specific aims: 1. Characterize the effect of a typical nighttime dose of MS-Contin and methadone on cytokines, polysomnographic sleep and on rest/activity patterns in healthy volunteers: 2. Characterize daytime fatigue the day after drug administration with self-reported measure of fatigue and mood 3. Characterize neuropsychological performance on the day after drug administration. 4. Estimate the covariance structure of sleep measures to assess the comparative advantages of a crossover or parallel groups design. 5. Evaluate the necessity of repeated first nights and whether this is the optimum design for follow-up studies. Over a two-year period, 50 healthy volunteer subjects will be examined with polysomnography, actigraphy, and neuropsychological tests. Data will be collected on self-reported mood and fatigue, as well as proinflammatory cytokine levels (IL-6, IL-1beta, and TNF-alpha. The study design involves a double-blind, placebo-controlled crossover. Each individual will be admitted to the UCSD GCRC on 3 pairs of nights. Each admission will feature an acclimation night in the sleep laboratory followed by a night providing placebo, MS-Contin (15 rag) or methadone (5 mg). On the morning after each dosing subjects will complete fatigue and mood ratings and will perform a brief neuropsychological test battery. They will also undergo actigraphy monitoring for 3 continuous days to examine whether there are subtle lingering effects of the drugs. Blood levels ofproinflammatory cytokines will be obtained at various points before and after drug dosing and the next morning to test the hypothesis that opioid-induced changes in these cytokines are associated with sleep disruption and increased fatigue.

therapy adverse effect; human therapy evaluation; methadone; drug adverse effect; morphine; fatigue; sleep; drug screening /evaluation; drug abuse chemotherapy; opiate alkaloid; drug addiction antagonist; actigraphy; human subject; neuropsychological tests; polysomnography; clinical research;

human therapy evaluation; physiologic stressor; glutamate receptor; psychopharmacology; drug screening /evaluation; psychophysiology; emotional crisis; prodrugs; angers; catecholamines; cortisol; heart rate; behavioral /social science research tag; human subject; clinical research;

DESCRIPTION (provided by applicant): This study examines the role of inflammatory factors underlying the physiological and psychological symptoms associated with obstructive sleep apnea. Inflammatory markers (C reactive protein, interleukin-6, tumor necrosing factor alpha) will be examined in blood and urine in 80 patients with obstructive sleep apnea and in 25 normal controls. The study will examine the relationship between inflammatory markers, procoagulant markers, and hallmark signs of sleep apnea such as the respiratory disturbance, intermittent oxygen desaturation, elevated sympathetic nervous system activity as well as depressive symptoms, neuropsychological impairment, and quality of life. The 80 patients with sleep apnea will then be randomized for 3 weeks of treatment to either CPAP or sub-therapeutic CPAP. Treatment effects will be studied in terms of effects on procoagulant markers and on the relationship between inflammatory factors, the respiratory disturbance, intermittent oxygen desaturation, elevated sympathetic nervous system activity as well as depressive symptoms, neuropsychological impairment, and quality of life.

sleep apnea; sympathetic nervous system; hypertension; clinical research; human subject;

DESCRIPTION (provided by applicant): Stroke survivors frequently complain of fatigue, depressive symptoms, and decreased cognitive functioning. These burdens complicate the recovery and rehabilitation from stroke. While there may be many contributing factors to these burdens, one factor in particular may be both terribly common and yet readily susceptible to intervention. Consistent reports from around the world demonstrate that >50% of stroke patients have obstructive sleep apnea (OSA), a disorder that is also associated with fatigue, depressive symptoms, and decreased cognitive functioning. OSA is also associated with increases in inflammatory products which themselves are associated with the same array of burdens. This study will examine 225 inpatients at a stroke rehabilitation center. Patients will be characterized in terms of fatigue, depressive symptoms, and problems with cognitive functioning as well as inflammation. Their sleep will be studied. Patients with OSA will be randomized to 10 days treatment double blind with either continuous positive airways pressure (CPAP) treatment or to sub-therapeutic CPAP treatment. After 10 days of treatment, the OSA patients as well as the stroke patient without OSA will be restudied in terms of their subjective burdens (fatigue, depressive symptoms, and cognitive functioning) and inflammation. The study will shed light on the impact of OSA on stroke patients'burdens of fatigue, depressive symptoms, and decreased cognitive functioning. It will clarify the possible role of inflammation on these burden symptoms, and it will test if treatment of OSA with CPAP has a specific effect to decrease burdens as well as inflammation. Keywords: obstructive sleep apnea, stroke, inflammation, cognition, depressive symptoms. PUBLIC HEALTH RELEVANCE: Strokes are commonly associated with burdens of fatigue, depressive symptoms, and cognitive problems. Obstructive sleep apnea has similar symptoms and is also very common in stroke patients. This study will determine if treating apnea in stroke patients will improve these burdens.