Michael Joyner

..01). The results show that GA can attenuate NO-mediated dilation in human skin, suggesting a potential role for HSP90 in activation of eNOS in the microcirculation...

..Much work remains for those interested in the role of NO in the regulation of blood flow to the skin and skeletal muscle of humans...

..Our goal is to use selected data from our own work and that of others to stimulate debate on the nature and cause of the 'risk factor gap' associated with exercise and physical activity...

..From a physiological perspective, more information is clearly needed on the relationship between VO(2max) and running economy and the influence of running economy and body size on thermoregulation and fuel use...

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..As always, we must also ask what do the ideas about physical activity and inactivity and the conditions mentioned above not explain?..

..Arguments relevant to this set of assertions are advanced and this paper, which was based on the 2011 Adolph Lecture, represents an effort to fill the intellectual void left by reductionism and improve scientific progress...

..Thus the role of NO in two of the most extreme dilator responses seen in nature is limited and in muscle the sympathetic nerves can restrain the dilation to defend arterial blood pressure...

..Therefore, the performance of elite athletes is likely to defy the types of easy explanations sought by scientific reductionism and remain an important puzzle for those interested in physiological integration well into the future...

..Additionally, the key contributions of John Shepherd and the late David Donald (along with their colleagues) on related issues are noted...

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..In this article, we discuss the philosophy behind the themes outlined above and argue that questions, and not answers, are where the action is for both research and education...

..Lower exercise hyperaemia in older humans may be mediated in part by less NO- and PG-mediated vasodilatation during exercise...

..Taken together, our results demonstrate that NO is not obligatory for functional sympatholysis in contracting skeletal muscles of healthy men...

..In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm...

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..The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP...

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..This blunting appears to be exercise intensity-dependent...

..Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity...

..In contrast to previous reports based on systemic infusions of beta(2)-agonists, our findings indicate that regional blood flow responses to locally infused isoproterenol are significantly greater in Gly16 than in Arg16 homozygotes...

..The potential physiological and pathophysiological implications of these findings are discussed...

..Our results demonstrate that post-junctional alpha-adrenergic receptor vasoconstrictor responsiveness to endogenous noradrenaline release is not blunted during mild-to-moderate systemic hypoxia in healthy humans...

..Our findings are placed in context with data from others, and possible future areas of study are identified...

..Repeated episodes of hypoxemia may not be sufficient to drive an increase in resting sympathetic activity in the absence of additional comorbidities...

..These findings might help explain the greater skeletal muscle vasoconstrictor tone and reduced blood flow during large muscle dynamic exercise in older adults...

..These results suggest that, in healthy young subjects, the enhanced HR response to changes in systolic pressure helps maintain the stability of arterial blood pressure when alpha1-adrenergic responsiveness is reduced...

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..46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm...

..We conclude that vasoconstrictor responses mediated via both post-junctional alpha1- and alpha2-adrenergic receptors are blunted in contracting human skeletal muscles...

..There are known functional polymorphisms of the beta(2)AR, such as substitution of glycine for arginine at codon 16. We sought to determine if this variation in genotype differentially influences airway function during exercise...

..However, sex-stratified data indicate that sex-based differential correlations might exist...

..These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR...

..Further, HF patients are unable to vasoconstrict locomotor vascular beds beyond NB when presented with a respiratory load...

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..These data indicate that endothelial function in human skin is largely preserved after sympathectomy. The altered pattern of the response suggests that the nitric oxide-dependent portion may be accelerated in sympathectomized limbs...

..Furthermore, the contribution of sympathetic alpha-adrenergic vasoconstriction to basal forearm vascular tone is reduced with age in healthy men...

..We examined the influence of metaboreceptor stimulation on ventilation with and without maintaining end-exercise end-tidal CO(2) levels...

..Further, they discuss how these changes in sympathetic a-adrenergic control of skeletal muscle blood vessels have important physiological and clinical implications for the aging human...

..The aim of the current study was to determine if ACE genotype is associated with altered pulmonary function and exercise intolerance in patients with treated CHF...

..59), and wasted left ventricular energy (r = -0.58; P<0.01 for all). Our results suggest another possible mechanism by which young women are protected against the development of cardiovascular disease...

..01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia...

..To provide a brief overview of the main techniques to measure muscle blood flow in humans and highlight some of the strengths and weaknesses associated with each technique...

..The NOS + COX-independent dilation does not appear sensitive to feedback inhibition from NO in the human forearm...

..Although interindividual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the sex discrepancy requires further investigation...

..These findings may have important implications for understanding how hypertension and other disorders of blood pressure regulation occur in men and women...

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..7 vs. -21.4 +/- 5.2%; P = 0.28) and 20% (-13.4 +/- 3.5 vs. -18.8 +/- 4.5%; P = 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine...

..The relationship between error signal and burst incidence may provide important insight into the control of muscle sympathetic nerve activity across sexes and in various populations...

..However, some differences in insulin sensitivity in GB remain compared with L. Residual insulin resistance may be related to excess total body fat or abnormal lipolysis and requires further study...

..05 vs. aminophylline). Our data indicate that adenosine contributes to compensatory vasodilation in an NO-independent manner during exercise with acute hypoperfusion...

..We conclude that exercise-induced dehydration causes post-exercise changes in the baroreflex control of blood pressure that may contribute to, rather than offset, orthostatic intolerance...

..L-NMMA during hypoxic exercise only blunted the compensatory vasodilator response in the young group (P <0.05). Our data suggest that ageing reduces the compensatory vasodilator response to hypoxic exercise via blunted NO signalling...

..However, the source of the NO becomes less dependent on ?-adrenergic mechanisms as exercise intensity increases...

..Our studies suggest that functionally significant variant sequence in the human PNMT gene might contribute to individual variation in levels of circulating epinephrine during exercise...

..05 before vs. after Aph). We conclude that there may be reduced Ado receptor responsiveness or sensitivity in nonresponders. Furthermore, Ado may play a limited role exercise hyperemia in both subgroups...

..22 +/- 4%), and at 20% exercise (-22 +/- 5 vs. -14 +/- 4%) between hypoxia and normoxia, respectively. Thus sympatholysis is not augmented by moderate hypoxia nor does it contribute to the increased blood flow during hypoxic exercise...

..This may suggest possible genotype-related differences in baseline receptor function or density which causes phenotypic differences at rest that are sustained during short-term exercise...

..The failure of DIP to augment exercise hyperemia under these conditions suggests that ADO concentrations may not rise enough during rhythmic handgripping to have a major impact on these responses...

..Gly16, respectively, means+/-SD). These data suggest that subjects homozygous for Arg at amino acid 16 of the beta2AR have a greater susceptibility for lung fluid accumulation relative to subjects homozygous for Gly at this position...

..8) to a similar degree. Thus the preservation of cutaneous active vasodilation in subjects with CF is not associated with an enhanced NO-dependent vasodilation...

..This study provides evidence that dietary Na+ modulates effects of the Arg16Gly polymorphism on cardiovascular function...

..28 +/- 0.03; P < 0.01). These results suggest that the Arg16Gly polymorphism of the beta2AR is associated with differences in natriuretic response to rapid saline infusion, which may influence long-term regulation of blood pressure...

..The similar vasoconstrictor responses to both drugs after prazosin might be explained by the presynaptic effects on norepinephrine release...

..Furthermore, the Arg16/Gly beta2-receptor polymorphism has no significant influence on the FBF or cardiovascular responses to mental stress...

..The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure...

..The results indicate that GPX1 may represent a potential therapeutic target for enhancement of regenerative capacity of EPCs in old subjects...

..60), and 75 W (R(2) = 0.32) (P < 0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance...

..To quantify the energy efficiency of locomotion and free-living physical activity energy expenditure of transfemoral amputees using a mechanical and microprocessor-controlled prosthetic knee...

..22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle...

..Similar data for patients undergoing major spine surgery, however, are not available...

..We sought to determine whether genetic variation of the ADRB2 influenced ADRB2 density and, consequently, resting cardiovascular function...

..05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans...

..However, some subjects are sensitive to triple blockade, but they are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals...

..Finally, our data support the concept that neither Ado nor nitric oxide is obligatory for exercise hyperemia...

..Our study was designed to examine the effects of pioglitazone versus glipizide on body water, body composition, and hemodynamic parameters in the presence of comparable glycemic control between groups...

..Our data suggest that the reduced dilator effects of PGI(2) in older individuals are attributable to a reduction in the contribution of endothelial-derived NO versus alterations in the direct effects of PGI(2) on vascular smooth muscle...

..These observations suggest that NO is released by contracting muscles or that a portion of the dilation caused by ischemic metabolites is NO dependent...

..PGs contribute modestly and transiently, suggesting a redundant signal compensates for the loss of vasodilating PGs, and (3). NO and PG signals appear to contribute independently to forearm exercise hyperaemia...

..Furthermore, the modified Oxford method does not appear to alter the properties of the baroreflex...

..It is important for women to include regular exercise in their daily routines, particularly because regular physical activity has been implicated in the prevention of osteoporosis, breast cancer, heart disease, and depression...

..In contrast, nicotine decreases SkBF responses to prolonged heating by activating noradrenergic nerves...

..04). Neither GLP-1 nor SU altered NTP-induced vasodilatation. These data demonstrate that GLP-1 per se has direct beneficial effects on endothelium-dependent vasodilatation in humans that are differentially modulated by SU...

..02). We conclude midodrine improves blood pressure and TPR during exercise and dramatically improves the recovery of MAP after exercise...

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..We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans. ..

..We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans. ..

..We propose novel and innovative strategies to address a number of currently unresolved issues and controversies related to these topics in humans. ..

..In summary, this overall approach will permit us to understand how normotensive is maintained in humans with high baseline sympathetic activity and set the stage for understanding how these mechanisms might fail in hypertension. ..

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..Data from these patient- oriented studies have implications related to understanding the contribution of endothelial function in a variety of common diseases. ..

..These vasodilating mechanisms may have significance in a variety of disease states associated with endothelial and autonomic dysfunction. ..

..In summary, this overall approach will permit us to understand how normotensive is maintained in humans with high baseline sympathetic activity and set the stage for understanding how these mechanisms might fail in hypertension. ..