The long range goal of the principal investigator is to examine mechanisms that control peripheral blood flow. This proposal examines the arterial chemoreflex (sympathoexcitatory), its modulation by the lung mechanoreflex (sympathoinhibitory) and peripheral vascular effects of hypoxemia in humans. Our hypotheses are that 1) During hypoxemia (with spontaneous breathing) sympathetic vasoconstrictor traffic and norepinephrine (NE) release from nerve terminals is increased, yet adrenergic vasoconstriction does not occur and forearm vascular resistance decreases. The rise in plasma NE is attenuated because NE clearance rises during hypoxemia. Using a tritiated NE infusion technique, we will explore the mechanism of increased NE clearance during hypoxemia. 2) The forearm vasodilation observed during hypoxemia is not due to sympathetic neural withdrawal but may be secondary to cholinergic vasodilation and/or local vasodilator mechanisms. In experiments with intra-arterial infusion of atropine (cholinergic blockade) and aminophylline (adenosine receptor blockade) we will explore the mechanism(s) of vasodilation induced by hypoxemia. 3) The sympathoinhibitory effect of ventilation is crucial in opposing sympathoexcitation evoked by hypoxemia. We will measure muscle sympathetic nerve activity (MSNA, peroneal microneurography) and forearm and skin blood flow (plethysmography, laser Doppler velocimetry) to examine the effects of altered breathing with/without simultaneous chemoreceptor stimulation. 4) Periodic breathing, such as seen in patients with obstructive sleep apnea, is accompanied by striking hemodynamic oscillations. Marked blood pressure elevations occur immediately after apnea and may in part be mediated by hypoxemia or absent lung mechanoreflex activity (apnea). To determine the role of the sympathetic nervous system in this response, we will measure MSNA during simulated apnea (voluntary breathholding), and apnea during sleep (spontaneous). Periodic (Cheyne-Stokes) breathing is also very common in heart failure, especially during sleep. If in heart failure, hemodynamic oscillations similar to sleep apnea occur, these intermittent increases in left ventricular afterload may further impair circulatory function. To determine whether these reflexes are important in heart failure, we will perform microneurography studies in these patients. These studies will be conducted in an active clinical research environment using a multidisciplinary approach. The findings will provide new insight into mechanisms of circulatory control and may have important implications in disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Research Training Review Committee (RTR)
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Pennsylvania State University
Internal Medicine/Medicine
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United States
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Leuenberger, U A; Hardy, J C; Herr, M D et al. (2001) Hypoxia augments apnea-induced peripheral vasoconstriction in humans. J Appl Physiol 90:1516-22
Silber, D H; Sinoway, L I; Leuenberger, U A et al. (2000) Magnetic stimulation of the human motor cortex evokes skin sympathetic nerve activity. J Appl Physiol 88:126-34
Leuenberger, U A; Gray, K; Herr, M D (1999) Adenosine contributes to hypoxia-induced forearm vasodilation in humans. J Appl Physiol 87:2218-24
Shoemaker, J K; Hogeman, C S; Leuenberger, U A et al. (1998) Sympathetic discharge and vascular resistance after bed rest. J Appl Physiol 84:612-7
Silber, D H; Sutliff, G; Yang, Q X et al. (1998) Altered mechanisms of sympathetic activation during rhythmic forearm exercise in heart failure. J Appl Physiol 84:1551-9
MacLean, D A; Sinoway, L I; Leuenberger, U (1998) Systemic hypoxia elevates skeletal muscle interstitial adenosine levels in humans. Circulation 98:1990-2
Waradekar, N V; Sinoway, L I; Zwillich, C W et al. (1996) Influence of treatment on muscle sympathetic nerve activity in sleep apnea. Am J Respir Crit Care Med 153:1333-8
Sinoway, L; Shenberger, J; Leaman, G et al. (1996) Forearm training attenuates sympathetic responses to prolonged rhythmic forearm exercise. J Appl Physiol 81:1778-84
Haque, W A; Boehmer, J; Clemson, B S et al. (1996) Hemodynamic effects of supplemental oxygen administration in congestive heart failure. J Am Coll Cardiol 27:353-7
Leuenberger, U; Jacob, E; Sweer, L et al. (1995) Surges of muscle sympathetic nerve activity during obstructive apnea are linked to hypoxemia. J Appl Physiol 79:581-8

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