Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure.
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Animals↗
Biomedical subjects
Scott A Smith
Publications and source records attributed to Scott A Smith.
Exercise pressor reflex function is altered in spontaneously hypertensive rats.
In hypertension, exercise elicits excessive elevations in mean arterial pressure (MAP) and heart rate (HR) increasing the risk for adverse cardiac events and stroke during physical activity. The exercise pressor reflex (a neural drive originating in skeletal muscle), central command (a neural drive originating in cortical brain centres) and the tonically active arterial baroreflex contribute importantly to cardiovascular control during exercise. Each of these inputs potentially mediates the heightened cardiovascular response to physical activity in hypertension. However, given that exercise pressor reflex overactivity is known to elicit enhanced circulatory responses to exercise in disease states closely related to hypertension (e.g. heart failure), we tested the hypothesis that the exaggerated cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. To test this hypothesis, we used a rat model of exercise recently developed in our laboratory that selectively stimulates the exercise pressor reflex independent of central command and/or the arterial baroreflex. Activation of the exercise pressor reflex during electrically induced static muscle contraction in the absence of input from central command resulted in significantly larger increases in MAP and HR in male spontaneously hypertensive rats as compared to normotensive Wistar-Kyoto rats over a wide range of exercise intensities. Similar findings were obtained in animals in which input from both central command and the arterial baroreflex were eliminated. These findings suggest that the enhanced cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. Potentially, effective treatment of exercise pressor reflex dysfunction may reduce the cardiovascular risks associated with exercise in hypertension.
Animals↗
Aluminum sulfate significantly reduces the skin test response to common allergens in sensitized patients.
BACKGROUND: Avoidance of allergens is still recommended as the first and best way to prevent allergic illnesses and their comorbid diseases. Despite a variety of attempts there has been very limited success in the area of environmental control of allergic disease. Our objective was to identify a non-invasive, non-pharmacological method to reduce indoor allergen loads in atopic persons' homes and public environments. We employed a novel in vivo approach to examine the possibility of using aluminum sulfate to control environmental allergens. METHODS: Fifty skin test reactive patients were simultaneously skin tested with conventional test materials and the actions of the protein/glycoprotein modifier, aluminum sulfate. Common allergens, dog, cat, dust mite, Alternaria, and cockroach were used in the study. RESULTS: Skin test reactivity was significantly reduced by the modifier aluminum sulfate. Our studies demonstrate that the effects of histamine were not affected by the presence of aluminum sulfate. In fact, skin test reactivity was reduced independent of whether aluminum sulfate was present in the allergen test material or removed prior to testing, indicating that the allergens had in some way been inactivated. CONCLUSION: Aluminum sulfate was found to reduce the in vivo allergic reaction cascade induced by skin testing with common allergens. The exact mechanism is not clear but appears to involve the alteration of IgE-binding epitopes on the allergen. Our results indicate that it may be possible to diminish the allergenicity of an environment by application of the active agent aluminum sulfate, thus producing environmental control without complete removal of the allergen.
Journal Article↗
Cerebral autoregulation is preserved during orthostatic stress superimposed with systemic hypotension.
We sought to determine whether cerebral autoregulation (CA) is compromised during orthostatic stress superimposed with systemic hypotension. Transient systemic hypotension was produced by deflation of thigh cuffs previously inflated to suprasystolic pressure, combined with or without lower body negative pressure (LBNP). Cardiac output (CO) decreased from a baseline of 5.0+/-0.5 l/min by -8.3+/-1.7, -19.2+/-2.0, and -30.6+/-3.4% during LBNP of -15, -30, and -50 Torr, respectively. Mean arterial pressure (MAP) was maintained during LBNP, despite decreases in systolic and pulse pressures. Middle cerebral arterial blood flow velocity (VMCA) decreased significantly from a baseline of 64+/-3 to 58+/-4 cm/s (-9.7+/-2.4%) at -50 Torr of LBNP. The reduction in VMCA was associated with a decrease in regional cerebral O2 saturation. However, the percent decrease in VMCA was markedly less than that of CO. This suggests that the magnitude of the change in VMCA (an index of cerebral blood flow) is less than would be predicted, given the decrease in CO. Transient systemic hypotension decreased MAP by -21+/-2, -24+/-2, -28+/-3, and -26+/-3% at rest and during LBNP of -15, -30, and -50 Torr, respectively. Likewise, this acute hypotension resulted in decreases in VMCA of -20+/-2, -21+/-2, -24+/-25, and -19+/-2% and regional cerebral O2 saturation of -5+/-1, -6+/-1, -6+/-1, and -7+/-2% at rest and during LBNP of -15, -30, and -50 Torr, respectively. Complete recovery of VMCA to baseline values following transient hypotension (ranging from 5 to 8 s) occurred significantly earlier compared with MAP (from 10 to 12 s). No subjects experienced syncope during acute hypotension. We conclude that CA is preserved during LBNP, superimposed with transient systemic hypotension, despite the decrease in VMCA associated with sustained central hypovolemia in normal healthy individuals. This preserved CA is vital for the prevention of orthostatic syncope.
Adult↗
The mammalian exercise pressor reflex in health and disease.
The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise. In heart failure, the cardiovascular response to exercise is augmented. Owing to the peripheral skeletal myopathy that develops in heart failure (e.g. muscle atrophy, decreased peripheral blood flow, fibre-type transformation and reduced oxidative capacity), the exercise pressor reflex has been implicated as a possible mechanism by which the cardiovascular response to physical activity is exaggerated in this disease. Accumulating evidence supports this conclusion. This review therefore focuses on the role of the exercise pressor reflex in regulating the cardiovascular system during exercise in both health and disease. Updates on our current understanding of the exercise pressor reflex neural pathway as well as experimental models used to study this reflex are presented. In addition, special emphasis is placed on the changes in exercise pressor reflex activity that develop in heart failure, including the contributions of the muscle mechanoreflex and metaboreflex to this pressor reflex dysfunction.
Afferent Pathways↗
The interaction of central command and the exercise pressor reflex in mediating baroreflex resetting during exercise in humans.
Central command and the exercise pressor reflex can independently reset the carotid baroreflex (CBR) during exercise. The present investigation assessed the interactive relationship between these two neural mechanisms in mediating baroreflex resetting during exercise. Six men performed static leg exercise at 20% maximal voluntary contraction under four conditions: control, no perturbation; neuromuscular blockade (NMB) induced by administration of the neuromuscular blocking agent Norcuron (central command activation); MAST, application of medical antishock trousers inflated to 100 mmHg (exercise pressor reflex activation); and Combo, NMB plus MAST (concomitant central command and exercise pressor reflex activation). With regard to CBR control of heart rate (HR), both NMB and Combo conditions resulted in a further resetting of the carotid-cardiac stimulus-response curve compared to control conditions, suggesting that CBR-HR resetting is predominately mediated by central command. In contrast, it appears that CBR control of blood pressure can be mediated by signals from either central command or the exercise pressor reflex, since both NMB and MAST conditions equally augmented the resetting of the carotid-vasomotor stimulus-response curve. With regard to the regulation of both HR and blood pressure, the extent of CBR resetting was greater during the Combo condition than during overactivation of either central command or the exercise pressor reflex alone. Therefore, we suggest that central command and the exercise pressor reflex interact such that signals from one input facilitate signals from the other, resulting in an enhanced resetting of the baroreflex during exercise.
Adult↗
Mechanoreflex mediates the exaggerated exercise pressor reflex in heart failure.
BACKGROUND: In heart failure, exercise elicits excessive increases in mean arterial pressure (MAP) and heart rate (HR). Using a novel rat model, we previously demonstrated that this exaggerated cardiovascular responsiveness is mediated by an overactive exercise pressor reflex (EPR). Although we previously determined that abnormalities in the group IV afferent neuron population (associated with the metabolic component of the reflex) initiate the development of the exaggerated EPR in heart failure, these fibers do not mediate the enhanced circulatory responses to exercise. Therefore, we hypothesized that the augmentation in EPR activity is primarily mediated by the mechanically sensitive component of the reflex (mediated predominately by activation of group III afferent fibers). METHODS AND RESULTS: Male Sprague-Dawley rats were divided into 3 groups: sham (control), dilated cardiomyopathic (DCM), and neonatal capsaicin-treated animals (NNCAP, group IV afferent fibers ablated). Activation of the EPR by electrically induced static muscle contraction of the hindlimb resulted in larger increases in MAP and HR in DCM and NNCAP compared with sham animals. In all groups, administration of gadolinium (a selective blocker of mechanically sensitive receptors) within the hindlimb attenuated the MAP and HR responses to contraction. However, the magnitude of this reduction was greater in DCM and NNCAP compared with sham animals. CONCLUSIONS: From these data, we conclude that the muscle mechanoreflex mediates the exaggerated EPR that develops in heart failure. Moreover, these findings suggest that mechanoreflex overactivity in heart failure may be a compensatory response to functional alterations in group IV fibers. Given these findings, the muscle mechanoreflex may serve as a novel target in the treatment of the abnormal circulatory responses to exercise in heart failure.
Afferent Pathways↗
Structural basis for antagonism by suramin of heparin binding to vaccinia complement protein.
Suramin is a competitive inhibitor of heparin binding to many proteins, including viral envelope proteins, protein tyrosine phosphatases, and fibroblast growth factors (FGFs). It has been clinically evaluated as a potential therapeutic in treatment of cancers caused by unregulated angiogenesis, triggered by FGFs. Although it has shown clinical promise in treatment of several cancers, suramin has many undesirable side effects. There is currently no experimental structure that reveals the molecular interactions responsible for suramin inhibition of heparin binding, which could be of potential use in structure-assisted design of improved analogues of suramin. We report the structure of suramin, in complex with the heparin-binding site of vaccinia virus complement control protein (VCP), which interacts with heparin in a geometrically similar manner to many FGFs. The larger than anticipated flexibility of suramin manifested in this structure, and other details of VCP-suramin interactions, might provide useful structural information for interpreting interactions of suramin with many proteins.
Binding Sites↗
The capsaicin-sensitive afferent neuron in skeletal muscle is abnormal in heart failure.
BACKGROUND: In heart failure, the cardiovascular response to activation of the skeletal muscle exercise pressor reflex (EPR) is exaggerated. Group IV afferent neurons, primarily stimulated by the metabolic by-products of skeletal muscle work, contribute significantly to the EPR. Therefore, it was postulated that alterations in the activity of group IV neurons contribute to the EPR dysfunction manifest in heart failure. METHODS AND RESULTS: Group IV afferent fibers were ablated in neonatal Sprague-Dawley rats by subcutaneous administration of capsaicin. In neonatal capsaicin-treated adult animals, selective activation of the EPR, by electrically induced static muscle contraction, recapitulated the exaggerated increases in heart rate and blood pressure observed in rats with dilated cardiomyopathy (DCM). Furthermore, compared with control animals, both neonatal capsaicin-treated and DCM rats displayed a decreased pressor response to the intra-arterial administration of capsaicin within the hindlimb, a maneuver that selectively excites group IV afferent neurons. Moreover, expression of mRNA for the capsaicin receptor TRPv1, a marker of group IV fibers, was downregulated in DCM animals compared with controls. CONCLUSIONS: These findings suggest that EPR dysfunction in heart failure results in part from functional and molecular alterations in group IV fibers. Furthermore, the responsiveness of these metabolically sensitive neurons appears to be blunted in DCM, indicating that their contribution to the EPR may be reduced. This occurs despite an overall exaggeration of the EPR in heart failure. These insights into the basic mechanisms of EPR dysfunction are essential to the development of effective therapeutic strategies aimed at improving exercise capacity in heart failure.
Animals↗
Determination of nitroaromatic and nitramine explosives from a PTFE wipe using thermal desorption-gas chromatography with electron-capture detection.
A method for the detection of nitroaromatic and nitramine explosives from a PTFE wipe has been developed using thermal desorption andgas chromatography with electron-capture detection (TD-GC-ECD). For method development a standard mixture containing eight nitroaromatic and two nitramine (HMX and RDX) explosive compounds was spiked onto a PTFE wipe. Explosives were desorbed from the wipe in a commercial thermal desorption system and trapped onto a cooled injection system, which was incorporated into the injection port of the GC. A dual column, dual ECD configuration was adopted to enable simultaneous confirmation analysis of the explosives desorbed. For the desorption of 50 ng of each explosive, desorption efficiencies ranged between 80.0 and 117%, for both columns. Linearity over the range 2.5-50 ng was demonstrated for each explosive on both columns with r2 values ranging from 0.979 to 0.991 and limits of detection less than 4 ng. Desorption of HMX from a PTFE wipe has also been demonstrated for the first time, albeit at relatively high loadings (100 ng).
Aniline Compounds↗
New insight into the mechanism of cardiovascular dysfunction in the elderly: transfer function analysis.
This study sought to test the hypothesis that alterations in the relationships between (i) mean arterial pressure (MAP) and heart rate (HR), (ii) cardiac output (CO) and MAP, and (iii) total peripheral resistance (TPR) and MAP variability contribute to the diminished dynamic control of cardiovascular function with advanced age. Six-minute hemodynamic data were continuously recorded in 11 elderly (70 +/- 2 years) and 11 young (26 +/- 1 year) healthy volunteers under supine resting condition and during lower body negative pressure-induced orthostatic challenge. The data were converted using fast Fourier transform, and the ratio of cross-spectra to auto-spectra between two signals (i.e., MAP-HR, CO-MAP, TPR-MAP) was computed for transfer function analysis. In the low-frequency ranges (LF; 0.04-0.14 Hz) and high-frequency ranges (0.15-0.30 Hz), the gain and coherence of the transfer function describing the relationship between MAP-HR signals were significantly greater in younger than in older adults. The phase degree was significantly >0 in both groups under all conditions, suggesting that the MAP variability preceded the HR variability. In contrast, the coherence between CO-MAP signals in both age groups was <0.5, indicating that the beat-to-beat MAP variability was not significantly related to the CO signals. However, the transfer function gain and coherence of TPR-MAP signals were significantly greater in the young group (coherence >/=0.5 in the LF range), suggesting a more effective dynamic vasomotor control. In conclusion, the oscillations in CO-MAP signals are not significantly synchronized or not related in a simply linear fashion in both age groups. The MAP variability is more related to the oscillation of TPR signals in the young group only. Advanced age not only diminishes MAP-HR transfer function gain, but also weakens its coherence. Thus, alterations in the relationship between MAP-HR variability and TPR-MAP variability may significantly contribute to the diminished dynamic control of cardiovascular function manifest in the elderly.
Adult↗
Vaccinia virus complement control protein ameliorates collagen-induced arthritic mice.
The main objective of this study was to investigate the therapeutic efficiency of recombinant vaccinia virus complement control protein (rVCP) on collagen-induced arthritis (CIA) in DBA-1/J mice. Arthritis was induced in DBA-1J mice by injecting bovine collagen emulsified in complete Freunds adjuvant. We used rVCP to block complement activation and investigated its effect on different aspects of CIA including osteoclast formation and bone destruction. The osteoclast-like cells were detected using immunohistochemistry. Joint destruction was studied using X-ray of the intact knee joints. Cartilage destruction was monitored by staining the paraffin sections with toluidine blue. ELISA was used to measure the cytokine levels in the serum. Blocking complement activation in DBA/1J arthritic mice with rVCP resulted in significant inhibition of the clinical progression of the disease and reduction in joint destruction as revealed by X-ray analysis and toluidine blue staining of the joint sections. Inhibition of complement reduced the production of proinflammatory cytokines and the number of osteoclast-like cells in arthritic joints. In conclusion, blocking of complement in CIA by rVCP inhibits the inflammation and the formation of osteoclast-like cells and reduces cartilage destruction.
Animals↗
Intervention strategies and agents mediating the prevention of xenorejection.
Xenotransplantation, the transplantation of cells, tissues, and/or organs across species, has proven to be an enormous challenge, resulting in only limited achievements over the last century. Unlike allotransplantation, the immunologic barriers involved in xenotransplant rejection are aggressive and usually occur within minutes in a hyperacute fashion. The use of organs from phylogenetically related concordant species may not be practical. Discordant xenotransplantation is characterized by hyperacute graft rejection, and to use nonprimate discordant organs for human benefit will require manipulation of the taxonomic differences. The hyperacute rejection process is primarily due to the attachment of preformed xenoreactive antibodies to the donor vascular endothelium, which results in hyperactivation of the complement system beyond the control of the natural complement regulatory proteins. Understanding the complex and diverse immune components involved in hyperacute, acute, and accelerated rejections has resulted in the development of different hematologic and molecular strategies. Plasmapheresis has been used to remove xenoantibodies, and xenoperfusion techniques are used to create a suitable and familiar environment for the xenograft. Various molecular approaches, such as the development of transgenic animals expressing human complement regulatory proteins such as CD59 or decay accelerating factor (DAF), to downregulate complement activation or the production of pigs lacking the xenoreactive antigen by knockout of the Gal alpha-1,3-galactosyl transferase gene have also been attempted. A combination of these techniques together with the administration of soluble complement inhibitors such as the vaccinia virus complement control protein (VCP) may well contribute to prolong graft survival. However, various issues including the possible emergence of new viral infections have confounded the topic of xenotransplantation. Here the different modulatory approaches and agents mediating interventions in xenorejection are discussed.
Acute Disease↗
Infections due to community-acquired methicillin-resistant Staphylococcus aureus: an emergent epidemic in Kentucky.
In recent years, epidemics of Methicillin-Resistant Staphylococcus aureus (MRSA) infections in patients not associated with the health care system have been reported in several states. This community-acquired MRSA (CA-MRSA) is microbiologically distinct from hospital-acquired MRSA (HA-MRSA) and has a predilection to cause severe skin and soft tissue infections and a particularly virulent necrotizing pneumonia. Many patients have suffered serious morbidity and mortality because of thefailure to recognize CA-MRSA as the pathogen in these infections. There are also serious infection control implications associated with these epidemics. Here we report 15 cases of CA-MRSA infections managed by the Infectious Diseases Division at the University of Louisville and offer guidelines for diagnosis, treatment, and infection control based on our experience. Primary care and emergency physicians as well as infection control professionals need to be aware that there is an emerging epidemic of CA-MRSA infections in the state of Kentucky. Several of our current practices regarding treatment and isolation will need to be modified to prevent the morbidity and possibly mortality associated with some CA-MRSA infections.
Adult↗
Independent modification of baroreceptor and exercise pressor reflex function by nitric oxide in nucleus tractus solitarius.
It has been suggested that nitric oxide (NO) is a key modulator of both baroreceptor and exercise pressor reflex afferent signals processed within the nucleus tractus solitarius (NTS). However, studies investigating the independent effects of NO within the NTS on the function of each reflex have produced inconsistent results. To address these concerns, the effects of microdialyzing 10 mM L-arginine, an NO precursor, and 20 mM N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, into the NTS on baroreceptor and exercise pressor reflex function were examined in 17 anesthetized cats. Arterial baroreflex regulation of heart rate was quantified using vasoactive drugs to induce acute changes in mean arterial pressure (MAP). To activate the exercise pressor reflex, static hindlimb contractions were induced by electrical stimulation of spinal ventral roots. To isolate the exercise pressor reflex, contractions were repeated after barodenervation. The gain coefficient of the arterial cardiac baroreflex was significantly different from control (-0.24 +/- 0.04 beats.min(-1).mmHg(-1)) after the dialysis of L-arginine (-0.18 +/- 0.02 beats.min(-1).mmHg(-1)) and L-NAME (-0.29 +/- 0.02 beats.min(-1).mmHg(-1)). In barodenervated animals, the peak MAP response to activation of the exercise pressor reflex (change in MAP from baseline, 39 +/- 7 mmHg) was significantly attenuated by the dialysis of L-arginine (change in MAP from baseline, 29 +/- 6 mmHg). The results demonstrate that NO within the NTS can independently modulate both the arterial cardiac baroreflex and the exercise pressor reflex. Collectively, these findings provide a neuroanatomical and chemical basis for the regulation of baroreflex and exercise pressor reflex function within the central nervous system.
Animals↗
Cross-Cordillera exchange mediated by the Panama Canal increased the species richness of local freshwater fish assemblages.
Completion of the Panama Canal in 1914 breached the continental divide and set into motion a natural experiment of unprecedented magnitude by bringing previously isolated freshwater fish communities into contact. The construction of a freshwater corridor connecting evolutionarily isolated communities in Pacific and Caribbean watersheds dramatically increased the rate of dispersal, without directly affecting species interactions. Here, we report that a large fraction of species have been able to establish themselves on the other side of the continental divide, whereas no species have become extinct, leading to a local increase in species richness. Our results suggest that communities are not saturated and that competitive exclusion does not occur over the time-scale previously envisioned. Moreover, the results of this unintentional experiment demonstrate that community composition and species richness were regulated by the regional process of dispersal, rather than by local processes such as competition and predation.
Analysis of Variance↗
Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation.
Vaccinia virus complement control protein (VCP), a homolog of the regulators of the complement activation family of proteins, inhibits complement activation through mechanisms similar to human fluid-phase complement regulators factor H and C4b-binding protein. VCP has a heparin-binding activity that assists vaccinia in host interactions. Interaction with cell-surface polyanions like heparin is centrally important in the functioning of fluid-phase complement regulators and is the basis of host-target discrimination by the alternative pathway. We report the structure of VCP in complex with a heparin decasaccharide, which reveals changes in VCP that might be pertinent to complement regulation. Properties that VCP shares with fluid-phase complement regulators suggest that such conformational changes may be of relevance in the functioning of other complement regulators. Additionally, comparison of VCP-heparin interactions with potentially similar interactions in factor H might enable understanding of the structural basis of familial hemolytic uremic syndrome, attributed to mutational disruption of heparin and C3b binding by factor H.
Amino Acid Sequence↗
Vaccinia virus complement control protein reduces inflammation and improves spinal cord integrity following spinal cord injury.
Traumatic spinal cord injury (SCI) claims approximately 10,000 new victims each year in the United States alone. The injury usually strikes those under the age of 30 years, often leading to a lifetime of pain, suffering, and disability. Therapeutic agents targeting spinal cord injury are sorely lacking, and therefore our laboratory endeavored to evaluate the potential therapeutic benefits of immediate post-injury administration of the vaccinia virus complement control protein (VCP). VCP is a multifunctional anti-inflammatory protein that can inhibit both pathways of complement activation and bind heparin. Utilizing a common animal model of contusion SCI, motor function recovery tests, and immunochemical stains, we evaluated the effects of VCP injected into spinal cord tissue following injury. Results demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves hind-limb function, establishing VCP as a strong candidate for further investigation in the treatment of SCI.
Animals↗