Sympathetic nervous control of the cerebral circulation in sleep

Cerebral vessels are extensively innervated by sympathetic nerves arising from superior cervical ganglia, and these nerves might play a protective role during the large arterial pressure surges of active sleep (AS). We studied lambs (n=10) undergoing spontaneous sleep-wake cycles before and after bilateral removal of the superior cervical ganglia (SCGx, n=5) or sham ganglionectomy (n=5). Lambs were instrumented to record cerebral blood flow (CBF, flow probe on the superior sagittal sinus), carotid arterial pressure (P(ca)), intra-cranial pressure (P(ic)), cerebral perfusion pressure (Pcp=Pca-Pic) and cerebral vascular resistance (CVR). Prior to SCGx, CBF (mL min-1) was significantly higher in AS than in Quiet Sleep (QS) and Quiet Wakefulness (QW) (17+/-2, 13+/-3, and 14+/-3 respectively, mean+/-SD, P<0.05). Following SCGx, baseline CBF increased by 34, 31, and 29% respectively (P<0.05). CVR also decreased in all states by approximately 25% (P<0.05). During phasic AS, surges of Pca were associated with transient increases in Pcp, Pic and CBF. Following SCGx, peak CBF and Pic during surges became higher and more prolonged (P<0.05). Our study is the first to reveal that tonic sympathetic nerve activity (SNA) constricts the cerebral circulation and restrains baseline CBF in sleep. SNA is further incremented during arterial pressure surges of AS, limiting rises in CBF and Pic, possibly by opposing vascular distension as well as by constricting resistance vessels. Thus, SNA may protect cerebral microvessels from excessive distension during AS, when large arterial blood pressure surges are common.     

Sympathetic Withdrawal Augments Cerebral Blood Flow During Acute Hypercapnia in Sleeping Lambs

Study Objectives:

Cerebral sympathetic activity constricts cerebral vessels and limits increases in cerebral blood flow (CBF), particularly in conditions such as hypercapnia which powerfully dilate cerebral vessels. As hypercapnia is common in sleep, especially in sleep disordered breathing, we tested the hypothesis that sympathetic innervation to the cerebral circulation attenuates the CBF increase that accompanies increases in PaCO₂ in sleep, particularly in REM sleep when CBF is high.

Design:

Newborn lambs (n = 5) were instrumented to record CBF, arterial pressure (AP) intracranial pressure (ICP), and sleep-wake state (quiet wakefulness (QW), NREM, and REM sleep). Cerebral vascular resistance was calculated as CVR = [AP-ICP]/CBF. Lambs were subjected to 60-sec tests of hypercapnia (FiCO₂ = 0.08) during spontaneous sleep-wake states before (intact) and after sympathectomy (bilateral superior cervical ganglionectomy).

Results:

During hypercapnia in intact animals, CBF increased and CVR decreased in all sleep-wake states, with the greatest changes occurring in REM (CBF 39.3% ± 6.1%, CVR −26.9% ± 3.6%, P < 0.05). After sympathectomy, CBF increases (26.5% ± 3.6%) and CVR decreases (−21.8% ± 2.1%) during REM were less (P < 0.05). However the maximal CBF (27.8 ± 4.2 mL/min) and minimum CVR (1.8 ± 0.3 mm Hg/ min/mL) reached during hypercapnia were similar to intact values.

Conclusion:

Hypercapnia increases CBF in sleep and wakefulness, with the increase being greatest in REM. Sympathectomy increases baseline CBF, but decreases the response to hypercapnia. These findings suggest that cerebral sympathetic nerve activity is normally withdrawn during hypercapnia in REM sleep, augmenting the CBF response.

Citation:

Cassaglia PA; Griffiths RI; Walker AM. Sympathetic withdrawal augments cerebral blood flow during acute hypercapnia in sleeping lambs. SLEEP 2008;31(12):1729–1734.     

Contribution of galanin to stress-induced impairment of insulin secretion in swimming mice

This study examines the potential role of the neuropeptide, galanin, in stress-induced inhibition of insulin secretion in swimming mice. Firstly, the pancreatic and adrenal content of galanin-like immunoreactivity was determined in mice after swimming stress. It was found that pancreatic content was significantly lower in stressed mice than in resting controls, both after 2 (P < 0.05) and 6 (P < 0.025) minutes of swimming, suggesting partial release of pancreatic galanin during stress. In contrast, the adrenal content of galanin-like immunoreactivity did not change during the swimming stress. Gel filtration of tissue extracts indicated that (1) mouse pancreas contains two forms of galanin-like immunoreactivity; one co-eluting with synthetic porcine galanin (centred on K_av of 0.70) and another with a larger molecular weight (centred on K_av, of 0.30), and (2) mouse adrenal contains a small void volume-peak and a larger peak of immunoreactivity, the latter co-eluting with synthetic galanin. Secondly, the effects of swimming stress on plasma glucose and insulin levels were compared in mice that received high titre rabbit anti-galanin serum with those in mice receiving normal rabbit serum. In normal rabbit serum-pretreated swimming mice, glucose-induced insulin levels were only 50% of resting controls (P < 0.01). Immunoneutralization of galanin with specific antiserum abolished this swimming stress-induced inhibition of glucose-stimulated insulin levels. This was accompanied by a modestly enhanced rate of glucose disappearance. These findings suggest that pancreatic galanin is released during swimming stress in mice and that endogenous galanin makes a major contribution to stress-induced impairment of insulin secretion.     

Effect of arm-cranking on leg blood flow and noradrenaline spillover during leg exercise in man

Controversy exists whether recruitment of a large muscle mass in dynamic exercise may outstrip the pumping capacity of the heart and require neurogenic vasoconstriction in exercising muscle to prevent a fall in arterial blood pressure. To elucidate this question, seven healthy young men cycled for 70 minutes at a work load of 5540%VO_2max. At 30 to 50 minutes, arm cranking was added and total work load increased to (mean ± SE) 82 ± 4% of Vo_2max. During leg exercise, leg blood flow average 6.15 4.511 minutes^-1, mean arterial blood pressure 137 ± 4 mmHg and leg conductance 42.3 ± 2.2 ml minutes^-1 mmHg^-1. When arm cranking was added to leg cycling, leg blood flow did not change significantly, mean arterial blood pressure increased transiently to 147 ± 5 mmHg and leg vascular conductance decreased transiently to 33.5 ± 3.1 ml minutes^-1 mmHg^-1. Furthermore, arm cranking doubled leg noradrenaline spillover. When arm cranking was discontinued and leg cycling continued, leg blood flow was unchanged but mean arterial blood pressure decreased to values significantly below those measured in the first leg exercise period. Furthermore, leg vascular conductance increased transiently, and noradrenaline spillover decreased towards values measured during the first leg exercise period. It is concluded that addition of arm cranking to leg cycling increases leg noradrenaline spillover and decreases leg vascular conductance but leg blood flow remains unchanged because of a simultaneous increase in mean arterial blood pressure. The decrease in leg vascular conductance observed when arm cranking increased mean arterial blood pressure could be regarded more as a measure to prevent overperfusion than a measure to maintain arterial blood pressure.     

Variable effects of β-adrenoceptor blockade on muscle blood flow during exercise

The role of β-adrenoceptors in exercise-induced muscle hyperaemia was investigated. Exercise was performed with a small and a large muscle mass: knee extension (KE) and bicycle exercise (BE). Seven healthy subjects performed light and maximal KE and eight subjects performed stepwise dynamic BE to exhaustion before and after acute i.v. administration of propranolol (0.15 mg kg^-1). Leg blood flow was measured by a bolus dye dilution technique. During KE at low and high power leg blood flow was reduced by 8.7 and 10.5% after propranolol was administered, mean arterial blood pressure (MAP) was reduced at low, but not at high power resulting in increased leg vascular resistance (LVR) during high intensity. During BE propranolol reduced leg blood flow and increased LVR at low power, but not at high power. At high BE intensity LVR did not change with increasing power and was slightly decreased after propranolol was administered. In this situation oxygen uptake was close to maximum and the concentration of catecholamines was 3–5 times higher compared with KE. There was no significant effect of propranolol on lactate release or arterial-femoral venous (a-fv) differences for adrenaline or noradrenaline. We conclude that β-adrenoceptors modulate local vasodilation in skeletal muscles during exercise independently of local muscle energy demand, but that the effect is highly dependent on active muscle mass since a-adrenergic activity during maximal BE seemed to disguise any effect of propranolol on LVR.     

Contribution of liver nerves,glucagon, and adrenaline to the glycaemic response to exercise in rats

The contribution of hepatic sympathetic innervation, glucagon and adrenaline to the glycaemic response to exercise was investigated in rats. Hepatically denervated (LDX) or sham operated (SHAM) rats with permanent catheters were therefore submitted to swimming with or without infusion of somatostatin in combination with adrenodemedul–lation. Blood samples were taken for measurements of blood glucose, plasma free fatty acids (FFA), adrenaline (A), noradrenaline (NA), insulin and glucagon. Liver denervation by itself did not influence glucose levels during exercise. Infusion of somatostatin in SHAM animals, which inhibited the exercise–induced glucagon response, led to enhanced sympathoadrenal outflow (measured as plasma A and NA) and a reduced blood glucose during exercise, suggesting that glucagon serves as a powerful mediator of the glycaemic response during swimming. Infusion of somatostatin in LDX animals failed to enhance plasma NA levels and led to a more pronounced reduction in blood glucose levels. This indicates that liver nerves do contribute to the glycaemic response to exercise when glucagon secretion is suppressed. Reduced blood glucose levels after adrenodemedullation revealed that adrenal A is another important mediator of the glucose response to exercise. Infusion of somatostatin in adreno–demedullated SHAM or LDX animals was not accompanied with increased NA outflow, suggesting that adrenal A is necessary to allow the compensatory increased outflow of NA from sympathetic nerves. In conclusion, the study shows that pancreatic glucagon and adrenal A are the predominant factors influencing the glycaemic response to exercise, whereas a role of the sympathetic liver nerves becomes evident when glucagon secretion is suppressed.     

The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress

Aim: The prompt increase in peripheral vascular resistance, mediated by sympathetic α‐adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasoconstriction is preserved in spinal cord‐injured individuals (SCI). This study aimed at assessing the contribution of both central and local sympathetically induced α‐adrenergic leg vasoconstriction to head‐up tilt (HUT) by including healthy individuals and SCI, who lack central sympathetic baroreflex control over the leg vascular bed. Methods: In 10 controls and nine SCI the femoral artery was cannulated for drug infusion. Upper leg blood flow (LBF) was measured bilaterally using venous occlusion strain gauge plethysmography before and during 30° HUT throughout intra‐arterial infusion of saline or the non‐selective α‐adrenergic receptor antagonist phentolamine respectively. Additionally, in six controls the leg vascular response to the cold pressor test was assessed during continued infusion of phentolamine, in order to confirm complete α‐adrenergic blockade by phentolamine. Results: During infusion of phentolamine HUT still caused vasoconstriction in both groups: leg vascular resistance (mean arterial pressure/LBF) increased by 10 ± 2 AU (compared with 12 ± 2 AU during saline infusion), and 13 ± 3 AU (compared with 7 ± 3 AU during saline infusion) in controls and SCI respectively. Conclusion: Effective α‐adrenergic blockade did not reduce HUT‐induced vasoconstriction, regardless of intact baroreflex control of the leg vasculature. Apparently, redundant mechanisms compensate for the absence of sympathetic α‐adrenoceptor leg vasoconstriction in response to postural stress.     

Efferent renal nerve stimulation inhibits the antihypertensive function of the rat renal medulla when studied in a cross-circulation model

The aim of this study was to investigate the effects of renal nerve stimulation on the humoral renal antihypertensive system. An isolated kidney (IK) was perfused at normal or high arterial pressures from a normotensive assay rat by means of a perfusion pump. Perfusion pressure (PP) to the IK was 90 mmHg for a control period of 30 min. In three of five experimental groups PP was then increased to 175 mmHg. In two of the groups the renal nerves were stimulated at 2 (P-175_2Hz) or 5 Hz (P-175_5Hz) for 60 min. The remaining group served as a control (P-175_c). In two groups IK pressure was maintained at 90 mmHg with 5Hz nerve stimulation (P-90_5Hz) or without nerve stimulation (P-90_c). MAP of the assay rat decreased by 22 and 27% (P < 0.001) in the P-175_c and P175_2Hz groups, respectively during the 60 min period of nerve stimulation, but remained stable in P-175_5Hz. Renal blood flow increased in the IK when PP was increased in P-175_c, but did not change significantly in P-175_2Hz or P-175_5Hz. Blood pressure remained constant in the assay rat when the IK was perfused at 90 mmHg. The renal excretory functions of the IK decreased in a frequency dependent manner by 2 and 5 Hz renal nerve stimulation compared with P-175_c. We conclude that 5 Hz renal nerve stimulation inhibits the pressure dependent release of humoral depressor substances from an IK perfused at 175 mmHg, whereas this is not seen when stimulating at 2 Hz. It is suggested that the release of antihypertensive substances from the renal medulla requires an increased renomedullary blood flow.     

The inflammatory consequences of psychologic stress: relationship to insulin resistance, obesity, atherosclerosis and diabetes mellitus, type II

Inflammation is frequently present in the visceral fat and vasculature in certain patients with cardiovascular disease (CVD) and/or adult onset Diabetes Mellitus Type II (NIDDM). An hypothesis is presented which argues that repeated acute or chronic psychologically stressful states may cause this inflammatory process. The mediators are the major stress hormones norepinephrine (NE) and epinephrine (E) and cortisol together with components of the renin-angiotensin system (RAS), the proinflammatory cytokines (PIC), as well as free fatty acids (ffa), the latter as a result of lipolysis of neutral fat. NE/E commence this process by activation of NF(kappa)B in macrophages, visceral fat, and endothelial cells which induces the production of toll-like receptors which, when engaged, produce a cascade of inflammatory reactions comprising the acute phase response (APR) of the innate immune system (IIS). The inflammatory process is most marked in the visceral fat depot as well as the vasculature, and is involved in the metabolic events which culminate in the insulin resistance/metabolic syndromes (IRS/MS), the components of which precede and comprise the major risk factors for CVD and NIDDM. The visceral fat has both the proclivity and capacity to undergo inflammation. It contains a rich blood and nerve supply as well as proinflammatory molecules such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), leptin, and resistin, the adipocytokines, and acute phase proteins (APP) which are activated from adipocytes and/or macrophages by sympathetic signaling. The inflammation is linked to fat accumulation. Cortisol, IL-6, angiotensin II (angio II), the enzyme 11(beta) hydroxysteroid dehydrogenase-1 and positive energy balance, the latter due to increased appetite induced by the major stress hormones, are factors which promote fat accumulation and are linked to obesity. There is also the capacity of the host to limit fat expansion. Sympathetic signaling induces TNF which stimulates the production of IL-6 and leptin from adipocytes; these molecules promote lipolysis and ffa fluxes from adipocytes. Moreover, catecholamines and certain PIC inhibit lipoprotein lipase, a fat synthesizing enzyme. The brain also participates in the regulation of fat cell mass; it is informed of fat depot mass by molecules such as leptin and ffa. Leptin stimulates corticotrophin releasing hormone in the brain which stimulates the SNS and HPA axes, i.e. the stress response. Also, ffa through portal signaling from the liver evoke a similar stress response which, like the response to psychologic stress, evokes an innate immune response (IIR), tending to limit fat expansion, which culminates in inflammatory cascades, the IRS-MS, obesity and disease if prolonged. Thus, the brain also has the capacity to limit fat expansion. A competition apparently exists between fat expansion and fat loss. In "western" cultures, with excessive food ingestion, obesity frequently results. The linkage of inflammation to fat metabolism is apparent since weight loss diminishes the concentration of inflammatory mediators. The linkage of stress to inflammation is all the more apparent since the efferent pathways from the brain in response to fat signals, which results in inflammation to decrease and limit fat cell mass, is the same as the response to psychologic stress, which strengthens the hypothesis presented herein.     

The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features

As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality. Considerable heterogeneity in the clinical presentation of major depression across the life cycle may reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late-onset depression). The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated. New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations. This review highlights the major features of late-life depression, with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological, inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non-pharmacological and novel treatments for depression are discussed. Ultimately, future research must aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced health outcomes via the implementation of early intervention paradigms.