PACAP causes long‐term increases in sympathetic nerve activity and is necessary for the sympathetic response to acute intermittent hypoxia

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17–24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr ( n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 ± 1.3 vs. 74 ± 1.7 mmHg, P < 0.01), MSNA [9.94 ± 2.0 to 14.63 ± 1.5 bursts/min ( P < 0.05); 16.89 ± 3.2 to 26.97 ± 3.3 bursts/100 heartbeats (hb) ( P = 0.01)], and forearm vascular resistance (FVR) (35.3 ± 5.8 vs. 55.3 ± 6.5 mmHg·ml−1·min·100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

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Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00081.2013 ◽

2013 ◽

Vol 304 (11) ◽

pp. H1538-H1546 ◽

Cited By ~ 31

Author(s):

Brittany S. Luckett ◽

Jennifer L. Frielle ◽

Lawrence Wolfgang ◽

Sean D. Stocker

Keyword(s):

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Arcuate Nucleus ◽

Insulin Receptors ◽

Ventromedial Hypothalamus ◽

Intracerebroventricular Injection ◽

Sprague Dawley ◽

Nerve Activity ◽

Sympathetic Response ◽

Sprague Dawley Rats

Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275–425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.

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Acute intermittent hypoxia in ratin vivoelicits a robust increase in tonic sympathetic nerve activity that is independent of respiratory drive

The Journal of Physiology ◽

10.1113/jphysiol.2010.190454 ◽

2010 ◽

Vol 588 (16) ◽

pp. 3075-3088 ◽

Cited By ~ 52

Author(s):

Tao Xing ◽

Paul M. Pilowsky

Keyword(s):

Sympathetic Nerve ◽

Intermittent Hypoxia ◽

Sympathetic Nerve Activity ◽

Respiratory Drive ◽

Nerve Activity

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Long-term control of renal blood flow: what is the role of the renal nerves?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.5.r1534 ◽

2001 ◽

Vol 280 (5) ◽

pp. R1534-R1545 ◽

Cited By ~ 49

Author(s):

Carolyn J. Barrett ◽

Michael A. Navakatikyan ◽

Simon C. Malpas

Keyword(s):

Heart Rate ◽

Blood Flow ◽

Renal Blood Flow ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Renal Nerves ◽

Renal Vasculature ◽

Nerve Activity ◽

Renal Sympathetic

We have developed a system for long-term continuous monitoring of cardiovascular parameters in rabbits living in their home cage to assess what role renal sympathetic nerve activity (RSNA) has in regulating renal blood flow (RBF) in daily life. Blood pressure, heart rate, locomotor activity, RSNA, and RBF were recorded continuously for 4 wk. Beginning 4–5 days after surgery a circadian rhythm, dependent on feeding time, was observed. When averaged over all days RBF to the innervated and denervated kidneys was not significantly different. However, control of RBF around these mean levels was dependent on the presence of the renal sympathetic nerves. In particular we observed episodic elevations in heart rate and other parameters associated with activity. In the denervated kidney, during these episodic elevations, the increase in renal resistance was closely related to the increase in arterial pressure. In the innervated kidney the renal resistance response was significantly more variable, indicating an interaction of the sympathetic nervous system. These results indicate that whereas overall levels of RSNA do not set the mean level of RBF the renal vasculature is sensitive to episodic increases in sympathetic nerve activity.

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Effect of antenatal glucocorticoids on sympathetic nerve activity at birth in preterm sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.274.1.r160 ◽

1998 ◽

Vol 274 (1) ◽

pp. R160-R167 ◽

Cited By ~ 17

Author(s):

Jeffrey L. Segar ◽

Eugenie R. Lumbers ◽

Anne Monique Nuyt ◽

Oliva J. Smith ◽

Jean E. Robillard

Keyword(s):

Sympathetic Nerve ◽

Premature Birth ◽

Sympathetic Nerve Activity ◽

Premature Delivery ◽

Antenatal Corticosteroids ◽

Nerve Activity ◽

Fetal Sheep ◽

Corticosteroid Administration ◽

Sympathetic Response ◽

Arterial Blood

Renal sympathetic nerve activity (RSNA) increases rapidly after delivery of term fetal sheep and parallels the rise in heart rate (HR) and arterial pressure. To examine the RSNA response at birth in immature lambs, experiments were performed in chronically instrumented preterm fetal sheep (118- to 125-day gestation, term 145 days) before and after delivery by cesarean section. HR remained unchanged from fetal values at 1 and 4 h after birth, whereas mean arterial blood pressure (MABP) decreased significantly ( P < 0.05) by 4 h after delivery. RSNA significantly decreased after premature birth in all animals studied ( n = 6), achieving only 39 ± 17% of fetal RSNA ( P< 0.05; all results are mean ± SE). Because cardiovascular function after premature birth is improved by the use of antenatal corticosteroids, we also tested the hypothesis that corticosteroid administration would evoke a more pronounced sympathetic response in prematurely delivered lambs ( n = 7, 118- to 125-day gestation). After maternal administration of dexamethasone (5 mg im, 48 and 24 h before delivery), RSNA increased after birth in six of seven fetuses to 166 ± 32% of the fetal RSNA value. Dexamethasone treatment also decreased the sensitivity of baroreflex-mediated changes in HR in response to increases in MABP. Because the sympathetic response at birth is depressed in preterm compared with term lambs, we performed an additional study ( n = 8) to determine if immature sheep are capable of mounting a sympathetic response to cold. In utero cooling produced rapid and sustained increases in MABP (20 ± 4%), HR (26 ± 6%), and RSNA (282 ± 72%) (all P < 0.05), consistent with a generalized sympathoexcitation. These results suggest that sympathoexcitation is absent after premature delivery despite the presence of functional descending autonomic pathways. Furthermore, exogenous corticosteroids appear to have a maturational effect on the sympathetic response at birth, which may be one mechanism by which maternal steroid administration improves postnatal cardiovascular homeostasis.

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Baseline arterial pressure affects sympathoexcitatory responses to ventricular premature beats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.1.h153 ◽

1995 ◽

Vol 269 (1) ◽

pp. H153-H159

Author(s):

M. L. Smith ◽

K. A. Ellenbogen ◽

D. L. Eckberg

Keyword(s):

Arterial Pressure ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Diastolic Pressure ◽

Muscle Sympathetic Nerve Activity ◽

Nerve Activity ◽

Sympathetic Response ◽

Ventricular Premature Beats ◽

Ventricular Dysrhythmias ◽

Premature Beats

The seconds to minutes before sudden cardiac death are characterized by fluctuations of arterial pressure, cardiac rhythm, and probably sympathetic nerve activity. We explored the interrelations among these factors in seven patients undergoing clinical electrophysiological testing. We measured muscle sympathetic nerve activity (SNA) and arterial pressure responses to ventricular premature beats induced throughout the cardiac cycle under three conditions: 1) lowered arterial pressure and elevated SNA produced by intravenous nitroprusside, 2) baseline arterial pressure and SNA during saline infusion, and 3) elevated arterial pressure and decreased SNA activity produced by intravenous phenylephrine. Sympathetic responses to premature beats were inversely related to diastolic pressure. The magnitude of the sympathetic response was directly related to the prevailing arterial pressure and inversely related to baseline SNA. These data demonstrate that sympathoexcitation evoked by ventricular dysrhythmias is determined importantly by the prevailing arterial pressure and possibly by the background R-R interval and level of sympathetic activity. This effect may influence hemodynamic and electrophysiological stability during dysrhythmias.

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