Considerable evidence indicates that hypoxia has lasting effects on ventilation that persist long after termination of the exposure. Although some evidence also exists that changes in sympathetic nervous system activity (SNA) persist after hypoxic exposure, the time domains of these changes and the mechanisms that underlie these alterations of SNA are poorly defined. In this proposal, we intend to better define the time course and the mechanisms of the SNA response following hypoxia in normal human volunteers. Our preliminary data suggest that: 1) brief hypoxic exposures (20 min to 2 hours) result in postexposure sustained sympathoexcitation despite producing no change in chemosensitivity; and, 2) intermediate duration hypoxic exposures (8 hours) result in sympathoinhibition despite apparently increased chemosensitivity. Based on these and other findings, and recognizing the crucial modulatory role of baro and chemoreflexes on SNA, we have formulated three hypotheses. First, we hypothesize that brief exposures to hypoxia produce sustained sympathoexcitation primarily through engagement of arterial baroreflex mechanisms. Second, we hypothesize that intermediate exposure to hypoxia produces sympathoinhibition because baroreflex stimulation occurs as arterial pressure increases and incomplete ventilatory acclimatization fails to counter the decrease in SNA. Finally, we hypothesize that long-term hypoxic exposure produces sustained sympathoexcitation in humans primarily through chemoreflex, rather than baroreflex, mechanisms. We will test these hypotheses in a series of investigations designed to test the role of baroreflexes and peripheral chemoreflexes in the alterations of SNA following hypoxic exposures of varying durations. We will use intra-arterial a-receptor blockade to test for sustained vasodilation and we will use phenylephrine and nitroprusside to assess baroreflex sensitivity. We will use hyperoxia and progressive isocapnic hypoxia to assess chemoreflex activation. In all studies we will use peroneal microneurography and catecholamine measurements to quantify SNA. By further characterizing the time domains and the mechanisms of SNA after hypoxic exposure, these studies will have implications for normal physiology (altitude acclimatization) and for pathophysiology (obstructive sleep apnea).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072648-04
Application #
7077725
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Golden, AL
Project Start
2003-08-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
4
Fiscal Year
2006
Total Cost
$408,036
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Gilmartin, G S; Lynch, M; Tamisier, R et al. (2010) Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 299:H925-31
Tamisier, R; Gilmartin, G S; Launois, S H et al. (2009) A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure. J Appl Physiol (1985) 107:17-24
Weiss, Matthew D; Tamisier, Renaud; Boucher, Judith et al. (2009) A pilot study of sleep, cognition, and respiration under 4 weeks of intermittent nocturnal hypoxia in adult humans. Sleep Med 10:739-45
Hunt, Brian E; Tamisier, Renaud; Gilmartin, Geoffrey S et al. (2008) Baroreflex responsiveness during ventilatory acclimatization in humans. Am J Physiol Heart Circ Physiol 295:H1794-801
Gilmartin, Geoffrey S; Tamisier, Renaud; Curley, Matthew et al. (2008) Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans. Am J Physiol Heart Circ Physiol 295:H778-85
Thomas, Robert Joseph; Tamisier, Renaud; Boucher, Judith et al. (2007) Nocturnal hypoxia exposure with simulated altitude for 14 days does not significantly alter working memory or vigilance in humans. Sleep 30:1195-203
Tamisier, Renaud; Hunt, Brian E; Gilmartin, Geoffrey S et al. (2007) Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans. Am J Physiol Heart Circ Physiol 293:H3027-35
Przyklenk, Karin; Whittaker, Peter (2007) Adaptation of a photochemical method to initiate recurrent platelet-mediated thrombosis in small animals. Lasers Med Sci 22:42-5
Tamisier, Renaud; Anand, Amit; Nieto, Luz M et al. (2005) Arterial pressure and muscle sympathetic nerve activity are increased after two hours of sustained but not cyclic hypoxia in healthy humans. J Appl Physiol 98:343-9
Tamisier, Renaud; Norman, Daniel; Anand, Amit et al. (2004) Evidence of sustained forearm vasodilatation after brief isocapnic hypoxia. J Appl Physiol 96:1782-7

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