Two experimental goals of the original award were to determine if pulmonary stretch reflexes and/or systemic O2 levels modulate sympathetic (vasoconstrictor) nerve activity to skeletal muscle (MSNA) under resting conditions and during acute exercise in healthy humans. The findings to date indicate that: 1) vagal lung inflation feedback mediates most of the within- breath variation in MSNA observed at rest; 2) sustained, but not brief, systemic hypoxia stimulates MSNA at rest and potentiates the response to forearm muscle contractions; and 3) even brief systemic hyperoxia inhibits MSNA under resting conditions, but has no obvious effect on the response to forearm contractions. This renewal application proposes to extend these findings by determining: a) if vagal lung inflation reflexes inhibit the increase in total minute MSNA during more conventional (i.e., large-muscle) dynamic exercise; b) if respiratory-related (within-breath) variation in vasoconstrictor and/or sudomotor skin sympathetic nerve activity (SSNA) is observed under resting conditions, and whether vagal lung inflation feedback modulates SSNA at rest or during acute exercise: c) if peripheral chemoreceptors mediate the systemic O2 influence on MSNA at rest, and the mechanisms underlying the potential O2 modulatory effects on MSNA during large- muscle, dynamic exercise; and d) if systemic O2 levels influence vasoconstrictor and/or sudomotor SSNA at rest and during exercise, and if so, the nature of the underlying mechanisms. The target tissue effects of respiratory-linked changes in nerve activity will also be established. It is hypothesized that both phasic pulmonary vagal feedback and peripheral chemoreflexes exert physiologically significant modulatory influences on MSNA and SSNA at rest and during dynamic exercise. Moreover, it is postulated that, as in anesthetized animals, vasoconstrictor SSNA is regulated in an antagonistic manner to both MSNA and sudomotor SSNA in the conscious human. To test these concepts, continuous recordings of sympathetic nerve activity (via microneurography), arterial blood pressure, heart rate, breathing frequency and volume, end-tidal O2 and CO2, whole limb and skin blood flow, and skin electrical conductance (index of sweat gland activity) will be made at rest and during cycling exercise while tidal volume or systemic O2 levels (and end-tidal CO2) are manipulated under rigorously controlled laboratory conditions. Vasoconstrictor and sudomotor SSNA will be examined selectively by changing the ambient temperature. Studies will be performed primarily in normal human subjects; however the role of vagal lung inflation feedback will also be investigated in experiments on denervated lung transplant patients. Both within-breath and steady-state analyses will be performed on all variables. The proposed studies will provide substantial new information on respiratory modulation of sympathetic nerve activity in conscious humans. Such data should enhance our understanding of autonomic circulatory control in both physiological (e.g., altitude) and pathophysiological (e.g., cardiopulmonary disease) states.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Seals, Douglas R (2003) Habitual exercise and the age-associated decline in large artery compliance. Exerc Sport Sci Rev 31:68-72
Jones, Pamela Parker; Shapiro, Linda F; Keisling, Gretchen A et al. (2002) Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men? J Physiol 540:701-6
Clevenger, Christopher M; Parker Jones, Pamela; Tanaka, Hirofumi et al. (2002) Decline in insulin action with age in endurance-trained humans. J Appl Physiol 93:2105-11
Bell, C; Seals, D R; Monroe, M B et al. (2001) Tonic sympathetic support of metabolic rate is attenuated with age, sedentary lifestyle, and female sex in healthy adults. J Clin Endocrinol Metab 86:4440-4
Jones, P P; Shapiro, L F; Keisling, G A et al. (2001) Altered autonomic support of arterial blood pressure with age in healthy men. Circulation 104:2424-9
van Pelt, R E; Dinneno, F A; Seals, D R et al. (2001) Age-related decline in RMR in physically active men: relation to exercise volume and energy intake. Am J Physiol Endocrinol Metab 281:E633-9
Schiller, B C; Casas, Y G; Desouza, C A et al. (2001) Maximal aerobic capacity across age in healthy Hispanic and Caucasian women. J Appl Physiol 91:1048-54
Monroe, M B; Seals, D R; Shapiro, L F et al. (2001) Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans. Am J Physiol Endocrinol Metab 280:E740-4
Dinenno, F A; Jones, P P; Seals, D R et al. (2000) Age-associated arterial wall thickening is related to elevations in sympathetic activity in healthy humans. Am J Physiol Heart Circ Physiol 278:H1205-10
Dinenno, F A; Jones, P P; Seals, D R et al. (1999) Limb blood flow and vascular conductance are reduced with age in healthy humans: relation to elevations in sympathetic nerve activity and declines in oxygen demand. Circulation 100:164-70

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