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Item Cardiac Parasympathetic Dysfunction in Morphine Addiction(1997-12-01) Napier, Leslie D.; Caffrey, James L.; Raven, Peter B.; Gwirtz, Patricia A.Napier, Leslie D., Cardiac Parasympathetic Dysfunction in Morphine Addiction. Doctor of Philosophy (Biomedical Sciences), December, 1997, 137 pp., 9 tables, 22 figures, references, 163 titles. The effects of chronic morphine treatment on parasympathetic control of the heart and associated cellular mechanisms were examined using a canine model. Vagal bradycardia was significantly blunted in dogs treated for one week with subcutaneous morphine pellets. In a separate group of dogs, heart rate and high frequency fluctuations in heart rate declined during the first three hours of subcutaneous morphine infusion consistent with the vagatonic action of acute morphine. Heart rate remained below baseline on Day 2 of the morphine infusion but had returned to normal by Day 10. Ambient sympathetic tone was increased on Days 2 and 10, and plasma catecholamines were elevated on Day 2. The intrinsic heart rates on Days 2 (160 bpm) and 10 (162 bpm) of morphine treatment were lower than the pre-treatment rate (182 bpm). Suggested mechanisms include a fundamental change in sinoatrial nodal cell function or attenuated tachycardia induced by vasoactive intestinal peptide co-released with acetylcholine from post-ganglionic parasympathetic neurons. The time to 50% maximal bradycardia during vagal nerve stimulation was increased with chronic and acute morphine suggesting an effect on the rate of acetylcholine synthesis, release or degradation. Muscarinic receptor density in left ventricular and right atrial sarcolemmal membranes from dogs treated chronically with morphine were 34% and 17% higher, respectively, than in control animals. Chronic morphine had no effect on basal or MnCl2-stimulated cyclase activity in either region. Similarly, maximal β-adrenergic and muscarinic receptor/G-protein coupling to adenylate cyclase were not altered by chronic morphine. Atrial norepinephrine content was higher than that in the ventricles and was unaltered by morphine. Ventricular norepinephrine was decreased with chronic but not acute morphine treatment. Epinephrine was evenly distributed throughout the myocardium and was reduced in both the atria and the ventricles by either acute or chronic morphine. This pattern suggests that morphine may reduce extraneuronal uptake of catecholamines. Collectively these studies show that chronic morphine treatment and the accompanying persistent vagal activity may reduce parasympathetic function. This attenuated function, however, is short-lived since sympathetic systems adapt with compensatory responses masking, or perhaps reversing, initial parasympathetic deficits.Item Cardiovascular Metrics Associated With Prevention of Aging-Related Parkinsonian Signs Following Exercise Intervention in Sedentary Older Rats(Frontiers Media S.A., 2021-12-15) Kasanga, Ella A.; Little, Joel; McInnis, Tamara R.; Bugnariu, Nicoleta; Cunningham, J. Thomas; Salvatore, Michael F.Preservation of motor capabilities is vital to maintaining independent daily living throughout a person's lifespan and may mitigate aging-related parkinsonism, a progressive and prevalent motor impairment. Physically active lifestyles can mitigate aging-related motor impairment. However, the metrics of physical activity necessary for mitigating parkinsonian signs are not established. Consistent moderate intensity (~10 m/min) treadmill exercise can reverse aging-related parkinsonian signs by 20 weeks in a 2-week on, 2-week off, regimen in previously sedentary advanced middle-aged rats. In this study, we initiated treadmill exercise in sedentary 18-month-old male rats to address two questions: (1) if a rest period not longer than 1-week off exercise, with 15 exercise sessions per month, could attenuate parkinsonian signs within 2 months after exercise initiation, and the associated impact on heart rate (HR) and mean arterial pressure (MAP) and (2) if continuation of this regimen, up to 20 weeks, will be associated with continual prevention of parkinsonian signs. The intensity and frequency of treadmill exercise attenuated aging-related parkinsonian signs by 8 weeks and were maintained till 23 months old. The exercise regimen increased HR by 25% above baseline and gradually reduced pre-intervention MAP. Together, these studies indicate that a practicable frequency and intensity of exercise reduces parkinsonian sign severity commensurate with a modest increase in HR after exercise. These cardiovascular changes provide a baseline of metrics, easily measured in humans, for predictive validity that practicable exercise intensity and schedule can be initiated in previously sedentary older adults to delay the onset of aging-related parkinsonian signs.Item Correlation Between Palpated Pulse Rates Taken by Non-medically Trained Military Reservist and Medically Trained Military Reservist(2004-05-01) Baum, Stephen H.; Laura S. LangBaum, Stephen H., Correlation Between Palpated Pulse Rates Taken by Non-medically Trained Military Reservist and Medically Trained Military Reservist. Masters in Public Health (Social and Behavioral Sciences), May 2004, 41 pp., 9 tables, 4 figures, reference list, 32 titles. The Air National Guard (ANG) is interested in assessing a new fitness testing procedure using the modified Harvard Step Test and "non-medically" trained military reservist to assess peer heart rate/pulse measures before and after participation in the step test. Additionally, the use of "non-medically" trained individuals to provide biometric testing procedures has implications for public health and health promotion practitioners. The purpose of this study was to determine if a statistically significant difference was present between pulse rates taken by "non-medically" and "medically" trained military reservist. The results of this study indicate that no statistically significant difference exists between pulse rates when measured concomitantly by "non-medically" trained or "medically" trained individuals.Item Effects of Compression of the Fourth Ventricle on Sleep Latency(2003-05-01) Holland, Bradly Shane; Michael Smith; Russel Gamber; Scott StrollHolland, Bradly Shane, Effects of Compression of the Fourth Ventricle on Sleep Latency. Master of Science (Clinical Education and Research), May 2003, pp, 2 tables, 3 figures, references. Hypothesis: Compression of the fourth ventricle decreases sleep latency independent of therapeutic touch. Methods: Subjects participated in CV-4 treatment, sham treatment, and control. Order was randomized. Electrocardiogram and electroencephalogram tracings, heart rate, and blood pressure were recorded. After the treatments, data were collected for 30 minutes. Data were collected during the control for 30 minutes. After the first two treatments, subjects had a one hour recovery period. Results: The ANOVA showed a difference between groups (F=28.462, power=.998, p [less than] .001). Pairwise comparison showed sleep latency was shorter for CV-4 than sham or control. There was no difference between sham and control. For total percent sleep, an ANOVA showed a difference between groups (F=20.5, power=.982, p=.001). Pairwise comparison revealed differences between control and CV-4, control and sham, but not CV-4 and sham. Conclusions: CV-4 shortens sleep latency independent of light touch.Item Impact of Age on Cognitive Testing Practice Effects and Cardiorespiratory Responses(Sage Publications, 2024-02-27) Reddy, Priyanka M.; Abdali, Kulsum; Ross, Sarah E.; Davis, Sandra; Mallet, Robert T.; Shi, XiangrongObjective: This study tested the hypothesis that healthy aging attenuates cognitive practice effects and, consequently, limits the familiarity-associated reductions in heart rate (HR) and breathing frequency (BF) responses during retesting. Methods: Twenty-one cognitively normal older and younger adults (65 +/- 2 vs. 26 +/- 1 years old) participated in the study. Mini-Mental State Examination (MMSE), Digit-Span-Test (DST), Trail Making Test (TMT-B), and California Verbal Learning Test (CVLT-II) were administered twice at 3-week intervals, while HR and BF were monitored by electrocardiography and plethysmography, respectively. Results: Cognitive performances were not affected by the age factor, and the retest factor only affected CVLT-II. HR and BF increased only in the younger adults (p < .01) during cognitive tests; retesting attenuated these responses (retest factor p < .01). Long-delay free-recall in CVLT-II was unchanged in cognitively normal older versus younger adults. Healthy aging did not diminish short-term memory assessed by DST and CVLT-II short-delay or long-delay free-recalls. Conclusions: Only CVLT-II, but not MMSE, DST or TMT-B, demonstrated cognitive retesting practice effects in the younger and older adults. Cognitive testing at 3-week intervals in cognitively normal older and younger subjects revealed divergent cardiorespiratory responses to MMSE, DST, and TMT-B cognitive testing, particularly HR, which increased only in younger adults and to a lesser extent during retesting despite the absence of practice effects.Item Interactive Effects of Mental and Physical Stress on Cardiovascular Control(1998-08-01) Westerholm, Erin Carpenter; Smith, Michael; Raven, Peter B.; Shi, XiangrongWesterholm, Erin C., Interactive Effects of Mental and Physical Stress on Cardiovascular Control. Master of Science (Biomedical Sciences, Integrative Physiology), August, 1998, 42 pp., 1 table, 13 figures, 35 references. Mental task and exercise often occur together. Physiological responses to each of these stressors have been studied independently, yet the interactive effects of these stressors are unknown. Hypothesis: Combined mental and physical stress will produce a synergistic interaction. Methods: Twelve healthy subjects were studied by measuring cardiovascular responses to five minutes of static left handgrip alone (25-35% of maximal handgrip strength), mental arithmetic alone, and combined stimuli in random order. Sympathetic nerve activity (SNA, microneurography), mean arterial blood pressure (MAP, Finapres), heart rate (HR, ECG), and vascular resistance (Doppler) were measured. Results: Physical and combined stressors significantly changed SNA, MAP, HR, and FVR. SNA responses to handgrip and the combined stimuli exceeded responses to mental arithmetic alone (p [less than] 0.05), yet no significant difference existed between responses to handgrip alone and the combined stimuli (p=0.33). The three stimuli increased heart rate similarity (p [less than] 0.0006). Conclusion: The data refuted the hypothesis: mental task did not synergistically interact or even add to the stress response elicited by handgrip exercise. Thus these data suggest that mental task and static exercise interact in a redundant manner.Item Leucine-Enkephalin and Sympathetic Control of Heart Rate(2001-12-01) Stanfill, Amber; Caffrey, James L.; Downey, H. Fred; Shi, XiangrongStanfill, Amber A., Leucine-enkephalin and Sympathetic Control of Heart Rate. Master of Science (Biomedical Sciences), December, 2001, 51 pp., 1 table, 4 figures, references, 48 titles. The following study examined the role of leucine-enkephalin in the sympathetic regulation of the cardiac pacemaker. Leucine-enkephalin (0.3 mM) was administered, by microdialysis into the interstitium of the sinoatrial node in 10 mongrel dogs in conjunction with either sympathetic nerve stimulation or infused norepinephrine. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and stimulated to produce graded (low, 20-30; high 40-50 bpm) increases in heart rate. Once stimulation frequencies were determined, leucine-enkephalin (0.3mM) was added to the dialysis inflow and perfused at 5: 1/min thereafter. The sympathetic stimulations were repeated after 5 and 20 min exposure to leucine-enkephalin. The resulting increases in heart rate during sympathetic stimulation were attenuated at both low (18.2 ±1.3 to 11.4 ±1.4 bpm) and high (45 ±1.5 to 22.8 ±1.5 bpm) frequency stimulation. The degree of inhibition was nearly identical after 20 minutes exposure providing no evidence for a progressively evolving response and for desensitization. Vagal function was also evaluated at 5 and 20 min by stimulating the right cervical vagus at 1 and 3 Hz. Leucine-enkephalin reduced the vagal bradycardia approximately 50% at both time intervals. The administration of the delta-selective opioid antagonist, naltrindole, restored only one third of the sympathetically medicated tachycardia. The same dose of naltrindole completely reversed the coincident vagolytic of leucine-enkephalin. These observations suggested that the sympatholytic effect was either non-opioid or mediated by a different opioid receptor subtype. Study two was conducted to determine if the sympatholytic effect was prejunctional and post-junctional in character. Norepinephrine was added to the dialysis inflow into the SA node in a concentration (6-9 μM) sufficient to produce an intermediate increase in heart rate. The average increase in heart rate was 35.2 ±1.8 bpm. Leucine-enkephalin was then combined with norepinephrine and sympathetic and parasympathetic responses were recorded at 5-min intervals for 20 minutes. The tachycardia mediated by added norepinephrine was unaltered by leucine-enkephalin or the subsequent addition of naltrindole. At the same time intervals, vagal control of heart rate was reduced by more than 50% and then completely restored by naltrindole. When combined with observations in study one, the data support the conclusion that the local nodal sympatholytic effect of leucine-enkephalin was the result of a reduction in the effective interstitial concentration of norepinephrine and not the result of a post-junctional interaction between leucine-enkephalin and norepinephrine.Item Local Enkephalins Modulate Vagal Control of Heart Rate(2001-05-01) Jackson, Keith E.; James L. Caffrey; H. Fred Downey; Michael W. MartinJackson, Keith E., Local Enkephalins Modulate Vagal Control of Heart Rate. Doctor of Philosophy (Biomedical Sciences), May 2001; 112pp; 7 tables; 22 figures; bibliography, 99 titles. Endogenous opioids, such as enkephalins, were first investigated for their ability to modulate pain. A body of evidence now supports opioid actions in many facets of regulation, including the cardiovascular system. Our laboratory is particularly interested in the ability of opioids to modulate autonomic function. Specifically, the role of the endogenous encephalin, methionine-enkephalin-arginine-phenylalanine (MEAP) was investigated to determine its ability to modulate parasympathetic function in the canine. To investigate MEAP’s response in the sinoatrial (SA) node a novel application of microdialysis was employed, whereby microdialysis was employed, whereby microdialysis probes were fabricated as described by Dr. David Van Wylen (38), and implanted in the SA node. After implantation of the probe, there was a significant attenuation of vagal function during the nodal application of MEAP. Specifically, vagally mediated bradcardia was reduced as compared to control, during the nodal application of MEAP. This inhibition of the vagus by MEAP was blocked by naltrindole, a selective delta antagonist. These data suggested that the vagolytic effects of MEAP were elicited via a delta opioid receptor. To test the hypothesis that MEAP’s effects were elicited through a delta opioid receptor mechanism, selective agonists and antagonists for the opioid receptors were utilized. An attenuation of vagal bradycardia was only observed during the infusion of a very selective delta opioid receptor agonist, deltorphin. A mu and kappa agonist showed no significant differences from control. Deltorphin was observed to elicit vagolytic effects in a similar concentration range as MEAP. However, deltorphin was more efficacious that MEAP. There was a significant attenuation of the deltorphin and MEAP’s vagolytic effects, during the co-infusion of the selective delta antagonist, naltrindole. The mu and kappa antagonists were both ineffective. These data further demonstrate that the observed vagolytic effect is linked to a delta opioid receptor. Endogenous MEAP. A series of experiments were undertaken to determine if endogenous MEAP could be demonstrated in the SA node and is so, was it similarly vagolytic. A preconditioning-like protocol was performed to produce intermittent local nodal ischemia to increase the local concentration of endogenous MEAP. The resulting MEAP was measured and was observed to be elevated during the periods of local nodal ischemia and return to control during reperfusion. Contrary to expectations an augmentation of vagal function was observed, during vagal stimulation. The augmented vagal bradycardia was only observed during ischemia, when MEAP was elevated and returned to control during each subsequent reperfusion. Therefore, there was a correlation between elevated MEAP concentrations and augmented vagal bradycardia. The delta antagonist, naltrindole, prevented the augmented vagal response, during nodal ischemia Glibenclamide, a selective KATP channel blocker, partially reversed the augmented vagal response. These data confirm that delta opiate receptors are involved in the augmented vagal bradycardia and that the mechanism may involve the activation of a KATP channel.Item Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed(2000-08-01) Pearlman, Eric Brian; Barbara Barron; Patricia A. Gwirtz; Michael L. SmithPearlman, Eric B., Met-Enkephalin-Arg-Phe (MERF) and Metabolism of MERF Across the Canine Heart Vascular Bed. Master of Science (Biomedical Science), August, 2000, 37 pp., 3 tables, 11 figures, references, 20 titles. Methionine enkephalin arginine phenylalanine (MERF) has been shown to be co-stored with catecholamines in vesicles. The catecholamines appear to decrease the degradation rate of 3H-MERF in vitro. The aim of this study is to investigate the spillover and metabolism of MERF across the canine heart vascular bed. I hypothesize that 3H-MERF is either degraded in the plasma or taken up and degraded by the heart. I further hypothesize that the exogenous catecholamine, isoproterenol, inhibits or reduces the rate of MERF degradation. Mongrel dogs were anesthetized and instrumented to record cardiovascular parameters, infuse 3H-MERF, and obtain blood samples across the heart. Blood samples were taken before and after stopping 3H-MERF infusion to evaluate kinetics, show steady state, and test the effect of treatments. Steady state concentration of 3H-MERF was observed after 30 min of infusion. Chromatography separated intact from degraded 3H-MERF. Three experimental groups were used: control, propranolol plus isoproterenol, and propranolol only. Blockade of β-receptors was necessary to prevent changes in coronary blood flow. Propranolol bolus (0.2 mg/kg) was administered IV at 50 min. 3 μg/min isoproterenol or 0.5 ml/min normal saline was infused starting at 70 min until the end of sample collection. The 3H-MERF venous-arterial (V-A) difference prior to treatment was negative, indicating degradation in the plasma or uptake and degradation by the heart. The 75 min V-A difference was used to calculate the effect of the infusions on the degradation or uptake of the 3H-MERF; this value was unchanged by any treatment. Spillover of 3H-MERF was significantly lower in the propranolol + isoproterenol dogs (p [less than] 0.05) compared to propranolol only treatment at 75 min. Heart rate was significantly lower for the propranolol only group compared to control. Blood pressure and change in coronary flow were unchanged. In conclusion, isoproterenol does not affect the metabolism of 3H-MERF across the canine heart vascular bed. Propranolol, however, does increase the intact 3H-MERF in the plasma, but additional β adrenergic blockade agents need to be investigated to determine the mechanism by which this takes place.Item Opioid and Nitric Oxide Interaction in the Control of Heart Rate(2002-12-01) Farias III, Martin; James Caffrey; Fred H. Downey; Patricia GwirtzFarias III, Martin, Opioid and Nitric Oxide Interaction in the Control of Heart Rate. Doctor of Philosophy (Biomedical Sciences), December 2002, 130 pp, 2 tables, 30 figures. Understanding of the role endogenous opioids play as modulators of parasympathetic function has increased. The endogenous opioid, methionine-enkephalin arginine phenylalanine (MEAP) attenuates vagal control of heart rate when delivered by microdialysis directly in the canine sinoatrial node. This effect was mimicked by the δ-2 agonist, deltorphin-II indicating involvement by a δ-opioid receptor. The nodal delivery of the δ-antagonist naltrindole abolished the effect of deltorphin-II, further supporting the delta character of the receptor. Although the findings suggested that the opioid receptor mediating vagolysis was delta in character, the exact subtype of δ-receptor remained in question. Selective agonist and antagonists for δ-1 and δ-2 opioid receptors were employed to determine which subtype of δ-receptor mediated MEAP vagolysis. In these experiments, vagolysis produced by the nodal delivery of MEAP was unaltered by the highly selective δ-1 antagonist BNTX but abolished by the δ-2 antagonist, naltriben. Nodal delivery of deltorphin-II attenuated vagal bradycardia similar to MEAP while δ-1 agonists, DPDPE and TAN-67 failed to interrupt vagal bradycardia. TAN-67 actually improved vagal transmission and this effect was reversed by BNTX. These data indicate that δ-2 opioid receptors in the sinoatrial node and vagolytic and support the presence of vagotonic δ-1-opioid receptors in the same location. Nitric Oxide/Opioid Interaction. The hypothesis that intranodal nitric oxide synthase (NOS) modulates vagal transmission and that MEAP attenuates vagal bradycardia via the interruption of the NOS-cGMP pathway was tested. The general (L-NAME) and neuronal (7-nitroindazole) NOS inhibitors each attenuated vagal bradycardia and both effects were reversed by adding excess of the NOS substrate, L-arginine. These findings suggested that nNOS was a necessary component of vagal bradycardia in the canine sinoatrial node. Various probes of the NOS-cGMP pathway (L-arginine, SNAP, cGMP, and IBMX) were employed to determine if MEAP interrupted this pathway to produce vagolysis. The delivery of MEAP into the sinoatrial node for sixty minutes exerted a consistent vagolytic effect during vagal simulations. When MEAP was combined with a NOS pathway components, the vagolytic effect was reversed after 15-45 minutes of treatment. These findings suggested that MEAP exerted its effect by interacting with the NOW-cGMP system. The site of convergence maybe cAMP since the phosphodiesterase inhibitor, IBMX (by allowing the accumulation of cAMP) reversed the vagolytic effect of MEAP. To rule out a postjunctional effect, MEAP and the NOS inhibitors were combined with the direct acting muscarinic agonist, methacholine. The bradycardia produced by methacholine was unaltered by MEAP or nNOS inhibitors. This suggested that the effect of NOS inhibitors and MEAP were prejunctional. In summary, the cumulative findings suggest that MEAP, by activating δ-2-opioid receptors, attenuated vagal bradycardia prejunctionally, through modulating the cAMP component of the NOS-cGMP pathway in the canine sinoatrial node.Item Peripheral and Central Muscarinic Cholinergic Receptors in Arterial Blood Pressure Regulation(1999-12-01) Wray, David Walter; Shi, Xiangrong; Gwirtz, Patricia A.; Raven, Peter B.Wray, David Walter, Peripheral and Central Muscarinic Cholinergic Receptors in Arterial Blood Pressure Regulation. Master of Science (Biomedical Sciences), December, 1999, 70 pp., 7 tables, 8 illustrations, references, 83 titles. This study was designed to test the hypothesis that an age-related vagal dysfunction compromises arterial blood pressure (ABP) regulation. Changes in heart rate (HR) and ABP during lower body negative pressure (LBNP) were compared between ten elderly (≥60 yrs) and ten young (≤30 yrs) adults. A separate, young group (n=10) was also assessed following muscarinic cholinergic (MC) blockade with atropine (central and peripheral receptor blockade) or glycopyrrolate (peripheral receptor blockade) to simulate vagal dysfunction. During the onset of LBNP -40 too, orthostatic hypotension (OH) was observed in both the older subjects and the post-blockade younger subjects, with a diminished HR response. Furthermore, the reflex response to hypertensive stimuli was augmented in the post-blockade younger subjects, also associated with a diminution in HR response. We concluded that age-related or pharmacologically stimulated vagal dysfunction compromises ABP regulation during hypotensive and hypertensive stimuli, and that the difference between atropine and glycopyrrolate was insignificant.Item Resetting of the Carotid Arterial Baroreflex during Dynamic Exercise(1997-08-01) Bryant, Kristin Hannah Norton; Peter B. Raven; James Caffrey; Thomas YorioByrant, Kristin, Resetting of the Carotid Arterial Baroreflex during Dynamic Exercise Doctor of Philosophy (Biomedical Sciences), August, 1997; 121 pp; 8 tables; 20 figures, bibliography, 82 titles. Following the initial response to the onset of dynamic exercise, prolonged exercise at a constant workload is characterized by a progressive decrease in stroke volume (SV) and mean arterial pressure (MAP) and concomitant rise in heart rate (HR). These data raise the question as to whether there is a loss of baroreflex regulation of arterial blood pressure during prolonged dynamic exercise. However, we propose that the carotid barareflex (CBR) is continually reset during prolonged exercise, with the operating point being shifted toward the reflex threshold, in relation to a progressive increase in central command activity as motor fibers are recruited in response to muscle fatigue. Therefore, the baroreflex is unresponsive to the fall in MAP. In order to investigate the hypothesis, volunteer subjects performed one hour of dynamic leg cycling exercise at 65% of maximal oxygen uptake (VO2max) with: I) no intervention; and ii) maintenance of cardiac filling volume via continuous infusion of a 6% dextran in saline solution to counteract the fall in SV. At 10 and 50 minutes of exercise, CBR stimulous-response curves were generated using the neck pressure/neck suction technique. The maintenance of cardiac filling volume and thus SV resulted in a diminished drift in MAP. However, indices of central command such as HR, VO2 and ratings of perceived exertion (RPE) increased to the same extent regardless of exercise condition. Furthermore, there was augmented resetting of the CBR at 50 minutes of exercise as compared to 10 minutes under both exercise conditions. In order to further investigate the effects of central command on baroreflex control of blood pressure, a second investigation was designed to demonstrate the effects of exercise type and intensity on CBR function. Stimulus-response relationships were compared during dynamic exercise at a wide range of exercise intensities performed with either leg exercise alone or leg exercise combined with arm exercise. Increases in exercise intensity to maximal exercise resulted in increases in indices of central command such as HR and VO2 as well as an augmentation of the magnitude of the lateral shift in the CBR stimulus-response curve (with the operating point being shifted further toward the threshold of the reflex) relative to the activation of central command. In addition, the performance of combined arm and leg exercise elicited an augmented shift in the carotid-vasomotor stimulus-response relationship as compared to leg exercise alone at the same exercise intensity. As arm exercise compared to leg exercise performed at the same absolute VO2 results in an increased lactate accumulation in the venous system, the augmented resetting of the CBR is likely due to a disproportionate activation of the muscle metaboreflex component of the muscle pressor reflex. Therefore we propose that the central command is the primary mechanism by which the CBR is reset at the onset of dynamic exercise through feed-forward control. However, additional, feed-back modulation can be exerted by the muscle pressor reflex upon the development of mechanical or chemical error signals in the exercising muscle.Item Sustained δ1-Opioid Receptor Stimulation Down Regulates δ2-Opioid Receptor Responses(2005-05-01) Deo, Shekhar H.; James L. Caffrey; Michael Smith; H. Fred DowneyDeo, Shekhar., Sustained δ1-opioid receptor stimulation down regulates δ2-opioid receptor responses. Master of Science (Integrative Physiology), May 2005, 49 pp., 2 tables, 8 figures, references, 25 titles. Ultra-low doses of methionine-enkephalin-arginine-phenylalanine (MEAP) improve vagal transmission (vagotonic) and decrease the heart rate by the stimulating δ1-opioid receptors (OR) within the sinoatrial (SA) node. Higher doses of MEAP (5 nmol/min) acting on δ2-opioid receptors interrupt vagal transmission (vagolytic) and reduce the decline in heart rate. Repeated occlusion of the SA node artery produced a vagotonic response during a subsequent prolonged ischemia that was reversed by selective δ1-opioid receptor antagonist, 7-benzylidenaltrexone (BNTX). 2-Methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67); a selective δ1-OR agonist has been used experimentally to mimic ischemic preconditioning in the heart. The following study was designed to test the hypothesis that sustained δ1-opioid receptor stimulation reduces the δ2-opioid receptor response. The cervical vagi were isolated and ligated and the right vagus was stimulated at frequencies chosen to produce a two-step decline in heart rate of about 25 and 50 beats per min (bpm). A microdialysis probe was introduced into the SA node such that the porous window was in the nodal interstitium. In study one, the selective δ2-OR agonist, deltorphin II was introduced (1.67 nmol/min) into the dialysis inflow to evaluate the δ2-OR response before and after the infusion of TAN-67 (1.67 nmol/min). The vagolytic effect (% inhibition) of deltorphin after TAN-67 infusion was significantly reduced during both low (76% to 22%) and high (80% to 21%) frequency vagal stimulation. In study two, BNTX (1.67 nmol/min), a selective δ1-OR antagonist was mixed with TAN-67 (1.67 nmol/min) in an equimolar ratio and introduced into the dialysate inflow. By blocking the effects of TAN-67, BNTX preserved the deltorphin response suggesting that the earlier attrition of the response was mediated by δ1-receptor activity. In study three, TAN-67 was omitted to perform a time control study. Unexpectedly, some loss of δ2-response was apparent in the absence of added TAN-67, So study 4 was designed in which BNTX (1.67 nmol/min) was infused for the period of time similar to that of saline in study 3. Like study 2, BNTX prevented the loss of the deltorphin response, suggesting that the attenuated response seen in study 3 was also mediated by δ1-activity. Two additional studies were conducted to determine the effects of TAN-67 alone and the duration of the experiment without prior exposure to deltorphin. Another time control was conducted in which the initial deltorphin evaluation prior to the vehicle treatment was omitted. In that study (Study 5) a very robust vagolytic response was observed when deltorphin was first tested after 2.5 hours. In study six, TAN-67 was substituted for saline and the subsequent δ2-evaluation at 2.5 hour was eroded compared to that in study 5. When BNTX was added to deltorphin after erosion of the vagolytic response, the vagolytic response was not restored. This observation support the conclusion that sustained δ1-stimulation desensitizes or down regulates δ2-mediated responses through a heterologous mechanism. Collectively the six studies support the conclusion that the loss of δ2-mediated vagolytic response was a result of reduction in the number of δ2-receptors mediated by sustained δ1-receptor stimulation.Item Sympathetic Cardiac Influence and Arterial Blood Pressure Instability(2002-09-01) Formes, Kevin John; Shi, Xiangrong; Downey, H. Fred; Gwirtz, Patricia A.Formes, Kevin John, Sympathetic Cardiac Influence and Arterial Blood Pressure Instability. Master of Science (Biomedical Sciences) September 2002, 51 pp., 3 tables, 5 illustrations, 36 references. This study was designed to determine the role of β1-adrenoreceptors in arterial blood pressure (ABP) regulation during an orthostatic challenge. Metoprolol was used to block β1-adrenoreceptors. Atropine, a peripheral and central acting muscarinic blocker, was used to inhibit vagal influences on heart rate. Lower body negative pressure (LBNP) was used to stimulate an orthostatic hypotensive stimulus before and after receptor blockade. Metoprolol administration significantly increased baroreflex sensitivity (BRS) and significantly decreased the reflex increase baroreflex sensitivity (BRS) and significantly decreased the reflex increase in plasma renin activity (PRA) in response to a hypotensive stimulus. Therefore we suggest that the attenuation of PRA is counterbalanced by an increased heart rate reserve, which allows the heart rate to increase more in response to decreases in venous return. This increase in cardiac responsiveness was abolished with the administration of atropine. Therefore, we conclude that acute administration of metoprolol causes (i) improved ABP stability, as indicated by a diminished augmentation of low frequency (LF) ABP variability and (ii) attenuates the increase in PRA during LBNP induced central hypovolemic challenge.Item Wearing a Football Helmet Exacerbates Thermal Load During Exercise in Thermoneutral and Hyperthermic Exercise(2004-12-01) Brothers, Robert Matthew; Smith, Michael; Raven, Peter B.; Shi, XiangrongBrothers, Robert Matthew, Wearing a Football Helmet Exacerbates Thermal Load During Exercise in Thermoneutral and Hyperthermic Conditions. Masters of Science (Integrative Physiology), December, 2004, 42 pp., 1 table, 4 illustrations, 55 titles in References. This investigation tested the hypothesis that wearing a football helmet during intense exercise leads to a significant increase in core temperature as indicated by esophageal temperature (Tes), head skin temperature (Th) and heart rate (HR) when compared to a similar bout of exercise performed while no helmet was worn. It was found that in both the helmet and no helmet exercise protocol there was a significant increase in the above variables when compared to baseline. The helmet condition, however, resulted in a significantly greater increase in these variables when compared to the no helmet condition. Furthermore, this effect of the helmet was further increased in a hyperthermic environment when compared to the thermoneutral environment.