Sympathetic single axonal discharge after spinal cord injury in humans: activity at rest and after bladder stimulation.

STUDY DESIGN: Clinical experimental mechanistic study. OBJECTIVES: (1) To determine in three spinal cord-injured patients whether individual muscle sympathetic nerve fibres below the level of the spinal lesion display spontaneous activity. (2) To determine in these patients if individual sympathetic vasoconstrictor fibres show a prolonged discharge following a bladder stimulus. SETTING: University hospital in Gothenburg, Sweden. METHODS: Microneurographic recordings of action potentials from individual muscle nerve sympathetic fibres in a peroneal nerve. Recordings of skin blood flow and electrodermal responses in a foot. RESULTS: In all patients, there was sparse ongoing spontaneous impulse traffic in individual sympathetic fibres. Brisk mechanical pressure over the urinary bladder evoked a varying number of action potentials in individual fibres, but the activity was brief and did not continue after the end of the evoked multiunit burst. CONCLUSION: Prolonged discharges in individual sympathetic fibres are unlikely to contribute to a long duration of blood pressure increases induced by brief bladder stimuli.

Fenofibrate-associated changes in renal function and relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) experience.

AIMS/HYPOTHESIS: Fenofibrate has been noted to cause an elevation in serum creatinine in some individuals. Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes. METHODS: A fenofibrate-associated creatinine increase (FACI) was defined as an increase in serum creatinine of at least 20% from baseline to month 4 in participants assigned to fenofibrate. Baseline patient characteristics, and baseline and 4-month drug, clinical, laboratory characteristics and study outcomes were examined by FACI status. RESULTS: Of the sample, 48% of those randomised to receive fenofibrate had at least a 20% increase in serum creatinine within 4 months. In multivariable analysis, participants who were older, male, used an ACE inhibitor at baseline, used a thiazolidinedione (TZD) at 4 months post-randomisation, had baseline CVD, and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI. Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months. No differences in study outcomes were seen by FACI criteria. CONCLUSIONS/INTERPRETATION: Several characteristics predict a rapid rise in serum creatinine upon starting fenofibrate. Participants who met the criteria for FACI also had a greater change in triacylglycerol levels. In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated, no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI. TRIAL REGISTRATION: ClincalTrials.gov: NCT00000620. FUNDING: The ACCORD Trial was supported by grants (N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA-Y1-HC-9035 and IAA-Y1-HC-1010) from the National Heart, Lung, and Blood Institute; by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute; by the Centers for Disease Control and Prevention; by General Clinical Research Centers and by the Clinical and Translational Science Awards. Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca Pharmaceuticals LP, Bayer HealthCare LLC, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, sanofi-aventis US and Takeda Pharmaceuticals provided study medications, equipment or supplies.

Muscle sympathetic response to arousal predicts neurovascular reactivity during mental stress.

Mental stress often begins with a sudden sensory (or internal) stimulus causing a brief arousal reaction, and is followed by a more long lasting stress phase. Both arousal and stress regularly induce blood pressure (BP) increases whereas effects on muscle sympathetic nerve activity (MSNA) are variable. Here we have compared responses of MSNA and BP during arousal induced by an electrical skin stimulus and mental stress evoked by a 3 min paced auditory serial arithmetic test (PASAT) in 30 healthy males aged 33 ± 10 years. In addition, recordings were made of ECG, respiratory movements, electrodermal activity and perceived stress. We also monitored corresponding effects of a cold test (CT: 2 min immersion of a hand in ice water). The arousal stimulus evoked significant inhibition of one or two MSNA bursts in 16 subjects, who were classified as responders; the remaining 14 subjects were non-responders. During mental stress responders showed a significant decrease of MSNA and a lesser BP increase compared to non-responders. In non-responders MSNA was unchanged or increased. Perceived stress was higher in non-responders (P = 0.056), but other measures were similar in the two groups. In non-responders mental stress and the cold test induced increases of BP that lasted throughout the subsequent rest period. During the cold test MSNA and BP increased equally in responders and non-responders. In the whole group of subjects, there was a significant correlation (r = 0.80, P < 0.001) between MSNA responses induced by arousal and by mental stress but not between responses evoked by arousal and the cold test (r < 0.1, P > 0.6). Additionally arousal-induced MSNA change was positively correlated with blood pressure changes during MS (systolic BP: r = 0.48; P < 0.01; diastolic BP: r = 0.42; P < 0.05) but not with blood pressure changes during CT. We conclude that in males the MSNA response to arousal predicts the MSNA and BP responses to mental stress.

Autonomic innervation in multiple system atrophy and pure autonomic failure.

BACKGROUND: Pure autonomic failure (PAF) and multiple system atrophy (MSA) are both characterised by chronic dysautonomia although presenting different disability and prognosis. Skin autonomic function evaluation by indirect tests has revealed conflicting results in these disorders. Here, the authors report the first direct analysis of skin sympathetic fibres including structure and function in PAF and MSA to ascertain different underlying autonomic lesion sites which may help differentiate between the two conditions. METHODS: The authors studied eight patients with probable MSA (mean age 60±5 years) and nine patients fulfilling diagnostic criteria for PAF (64±8 years). They underwent head-up tilt test (HUTT), extensive microneurographic search for muscle and skin sympathetic nerve activities from peroneal nerve and punch skin biopsies from finger, thigh and leg to evaluate cholinergic and adrenergic autonomic dermal annexes innervation graded by a semiquantitative score presenting a high level of reliability. RESULTS: MSA and PAF patients presented a comparable neurogenic orthostatic hypotension during HUTT and high failure rate of microneurographic trials to record sympathetic nerve activity, suggesting a similar extent of chronic dysautonomia. In contrast, they presented different skin autonomic innervation in the immunofluorescence analysis. MSA patients showed a generally preserved skin autonomic innervation with a significantly higher score than PAF patients showing a marked postganglionic sympathetic denervation. In MSA patients with a long disease duration, morphological abnormalities and/or a slightly decreased autonomic score could be found in the leg reflecting a mild postganglionic involvement. CONCLUSION: Autonomic innervation study of skin annexes is a reliable method which may help differentiate MSA from PAF.

Tactile direction discrimination and vibration detection in diabetic neuropathy.

OBJECTIVE: To evaluate the clinical usefulness of quantitative testing of tactile direction discrimination (TDD) in patients with diabetic neuropathy. MATERIALS AND METHODS: TDD and vibration detection were examined on the dorsum of the feet in 43 patients with type 1 diabetes mellitus and clinical signs and symptoms indicating mild neuropathy, and abnormal results for neurography, temperature detection, or heart rate variability. Test-retest examination of TDD was performed in nine of the patients. RESULTS: Twenty-six of the patients had abnormal TDD (sensitivity 0.60) and 20 had abnormal vibration detection (sensitivity 0.46). Ten of the patients had abnormal TDD and normal vibration detection. Four of the patients had abnormal vibration detection and normal TDD. Test-retest examination of TDD showed a high degree of reproducibility (r = 0.87). CONCLUSION: TDD seems more useful than vibration detection in examination of diabetic neuropathy.

EEG theta rhythm in infants and preschool children.

OBJECTIVE: To study behavioral correlates of theta oscillations in infants and preschool children. METHODS: EEG was recorded during baseline (visual attention) and two test conditions--exploration of toys and attention to 'social' stimulation. Age specific frequency boundaries of theta and mu rhythms were assessed using narrow bin analysis of EEG spectra. RESULTS: Theta spectral power increased whereas mu power decreased under test conditions in both age groups. In preschoolers theta rhythm increased predominantly over anterior regions during exploratory behavior and over posterior regions during attention to social stimulation. Theta frequency range changed with age from 3.6 to 5.6 Hz in infants to 4-8 Hz in children, and mu range from 6.4-8.4 Hz to 8.4-10.4 Hz. CONCLUSIONS: In early life, theta oscillations are strongly related to behavioral states with substantial attentional and emotional load. The scalp distribution of theta spectral power depends on age and behavioral condition and may reflect engagement of different brain networks in control of behavior. SIGNIFICANCE: The findings contribute to the scanty knowledge about the developmental course of theta rhythm. Data on behavioral correlates of theta rhythm in early life may improve our understanding of cognitive and mental processes in healthy and neuropsychiatrically diseased children.

Deprivation and repletion of androgen in vivo modifies triacylglycerol synthesis by rat hepatocytes.

Given the same quantity of fatty acid, livers from male rats esterify less fatty acid and secrete less triacylglycerol in very-low-density lipoprotein than do livers from female animals. To elucidate the role of testosterone in maintenance of this male pattern, conversion of [1-14C]oleic acid into triacylglycerol was assessed in vitro by rat hepatocytes (male) following gonadectomy and replacement with testosterone. Following castration, incorporation of fatty acid into triacylglycerol was increased. In contrast, esterification of exogenous fatty acid into phospholipid, cholesteryl esters, and diacylglycerol was unchanged. Treatment with testosterone (75 micrograms/day) reduced incorporation of exogenous fatty acid into triacylglycerol. Higher doses of testosterone (200 or 100 micrograms/day) modified the effect, such that inhibition was observed only at low oleate (0.5 mM) concentrations. At higher substrate concentrations (1.0-2.0 mM) the inhibitory effect was no longer observed. Further, a similar dose-dependent effect of testosterone was observed following in vivo treatment of castrate females with testosterone. These data support the concept of a regulatory role of testosterone in hepatic triacylglycerol synthesis. These findings also demonstrate a biphasic effect of testosterone, an effect that is dependent not only upon the dose of testosterone administered, but also on the concentration of fatty acid to which the hepatocyte is exposed in vitro.

Sympathetic neural burst amplitude distribution: A more specific indicator of sympathoexcitation in human heart failure.

BACKGROUND: Human muscle sympathetic nerve activity (MSNA) is usually measured as the number of pulse-synchronous bursts in multiunit mean voltage recordings. We recently suggested burst amplitude distribution as a more sensitive indicator of altered MSNA in congestive heart failure (CHF). Here, we test whether this distribution can discriminate between different conditions with increased MSNA burst frequency and whether it reflects single vasoconstrictor fiber firing intensity. METHODS AND RESULTS: We analyzed resting multiunit MSNA in 36 CHF patients (24 with mild to moderate CHF, 12 with severe CHF investigated before and after heart transplantation), 14 patients with pituitary deficiency, 25 matched healthy control subjects, and an additional 56 healthy men with a wider age range (21 to 71 years). Pituitary deficiency was associated with increased MSNA burst frequency (60 versus 37 bursts/min in control subjects), equivalent to that in mild to moderate CHF (61 bursts/min). However, burst amplitude distribution in hypopituitary patients (median burst amplitude, 37%) did not deviate from matched control subjects (36%), whereas amplitudes increased with disease severity in CHF (43% in mild to moderate, 52% in severe) and normalized after transplantation (36%). In the larger healthy group, MSNA burst frequency increased with age, and burst amplitude distribution remained unaffected. In 8 CHF patients, single-unit firing frequency showed a close positive relationship to multiunit burst amplitude distribution (r=0.82, P:<0.01) but none to burst frequency (r=0.39, P:=0.3). CONCLUSIONS: Muscle vasoconstrictor fiber activity is better reflected by multiunit MSNA burst amplitude distribution than by burst frequency, at least in CHF. This distribution can discriminate between conditions with increased burst frequency.

Firing properties of single muscle vasoconstrictor neurons in the sympathoexcitation associated with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) in humans is associated with a marked sympathoexcitation, including an augmented muscle sympathetic nerve activity (MSNA) in intraneural multiunit recordings. In the present study, single-unit recording was used to evaluate whether the firing properties of individual muscle vasoconstrictor neurons can reveal underlying mechanisms for this increase in MSNA. METHODS AND RESULTS: Eight patients with CHF (NYHA class II to IV; left ventricular ejection fraction, 29+/-5%, mean+/-SEM) were studied. In standard multiunit recordings, MSNA burst incidence (bursts/100 heartbeats) ranged from 65% to 100% (88+/-5%). Using selective tungsten microelectrodes, we made recordings from 16 single muscle vasoconstrictor axons. Mean unit firing probability (ie, the percentage of cardiac intervals in which a single axon fired) was 54.5+/-5.2% (range, 21 to 89%), and mean firing frequency was 0.98+/-0.22 Hz (0.14 to 3.86 Hz), both of which were higher than seen previously in healthy subjects (P<0.001). Although single neurons occasionally generated multiple spikes per sympathetic burst, such multiple firing was rare and was not different from that seen in healthy subjects. CONCLUSIONS: An increased firing frequency of individual vasoconstrictor neurons is one mechanism for the increased number of multiunit MSNA bursts at rest in CHF. The neurons discharge in more diastoles than in healthy subjects (ie, firing probability is increased), but the likelihood of discharging >1 impulse per sympathetic burst is not increased. Despite the intense multiunit activity at rest, the firing characteristics of individual vasoconstrictor axons indicate a remaining capacity for transient increases of MSNA in CHF.

The subcutaneous lipolytic response to regional neural stimulation is reduced in obese women.

Disturbed fat tissue metabolism with a reduction of the lipolytic rate could be an important pathogenetic factor in obesity. Lipolysis of the subcutaneous tissue of the thigh is partly under neural control and can be increased by intraneural stimulation of the lateral cutaneous femoral nerve in lean women. In the present study, we tested whether the lipolytic response to intraneural stimulation is altered in vivo in obese subjects. Seven obese women were examined and the results were compared with those of seven age-matched lean women. After an overnight fast, the lateral cutaneous femoral nerve was intraneurally stimulated for 10 min, and the local subcutaneous lipolytic response to this procedure was evaluated with microdialytic measurements of interstitial glycerol concentrations in the receptive field of the stimulated nerve fascicle. To exclude unspecific effects of stimulation, lipolysis was also controlled in a corresponding area of the contralateral leg. Intraneural stimulation produced no significant change in subcutaneous lipolysis in obese women (25.7 +/- 9.7%, NS). This finding is in sharp contrast with the marked regional lipolytic response in lean women in which the same stimulation procedure enhanced the regional interstitial glycerol levels by 72 +/- 17% (P < 0.05) compared with the unstimulated corresponding area of the contralateral leg. These in vivo results suggest that human obesity is characterized by a profound unresponsiveness of the subcutaneous adipose tissue to neurally stimulated lipolysis. This could be an important factor in the development and treatment of obesity.

Mitral valve prolapse in women with oral contraceptive-related cerebrovascular insufficiency. Associated persistent hypercoagulable state.

We examined a group of former oral contraceptive (OC) users, who had experienced cerebrovascular insufficiency, for the presence of hypercoagulable states. We found hypercoagulability in this group in the form of decreased plasma antithrombin III activity, increased platelet coagulant activity, and elevated plasma beta-thromboglobulin level. Certain characteristics (cigarette smoking, vascular headache, hyperlipidemia, and mitral valve prolapse) were encountered with increased frequency among former OC users who had experienced cerebrovascular insufficiency. The association of mitral valve prolapse with OC-related cerebrovascular insufficiency was particularly striking. We propose that preexisting hypercoagulable states, such as may exist in a subset of individuals with mitral valve prolapse, will magnify the risk of OC-related cerebrovascular morbidity.

Emerging noninvasive biochemical measures to predict cardiovascular risk.

New predictors of cardiovascular events are needed to improve the accuracy of risk stratification. Such predictors should be easily measurable in the population and potentially modifiable. This review reports on new biomarkers that are closely linked to the pathogenic mechanisms underlying the progression of the atherosclerotic plaque leading to rupture and thrombosis that ultimately precipitate acute clinical events, such as stroke and myocardial infarction. These risk factors have been associated with subclinical or clinical cardiovascular disease in large populations and include markers of lipoprotein and lipid metabolism, vitamin B12 metabolism, fibrinolysis, coagulation, inflammation, infection, endothelial dysfunction, the angiotensin system, and oxidative stress. For other key processes of atherosclerosis and cardiac disease, such as apoptosis or programmed cell death, there are currently no markers that can be measured noninvasively. Atherosclerosis is a multifactorial condition and possibly only a subset of factors are the main determinants of disease in a given patient. A better definition of the cardiovascular risk profile will help to better target primary and secondary prevention. Further epidemiological studies are needed to characterize the actual predictive and clinical value of these new emerging cardiovascular biomarkers.

In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver.

We have previously demonstrated in hepatocyte suspensions prepared after in vivo GH deprivation [hypophysectomy (hypox)] that rates of esterification of [1-14C]oleic acid into triglyceride (TG) and phospholipid (PL) were diminished, and that these esterification rates were correspondingly restored by repletion with recombinant GH. The current studies were designed to determine if GH exerts a similar effect on the secretion of very low density lipoprotein (VLDL), the primary plasma carrier of TG. We assessed rates of secretion of VLDL lipid and apoprotein by perfused livers prepared from cortisol/T3-replaced hypox female rats in the presence and absence of recombinant human (h) GH infusion. We also determined rates of synthesis and secretion of VLDL TG from infused [1-14C]oleic acid. After hypox, rates of secretion of VLDL lipid (TG, PL, and cholesterol) and apoprotein (total) were significantly decreased. In addition, VLDL secreted under these conditions was depleted of PL, relative to the other lipid components. Secretion of newly synthesized VLDL TG from [1-14C]oleic acid was also decreased; however, neither intracellular accumulation of labeled TG nor absolute tissue levels of TG were significantly changed. Conversely, GH treatment of hypox rats effectively restored rates of secretion of VLDL TG, PL, cholesterol (C) and apoprotein to control levels. These findings support the putative role of GH in regulating VLDL secretion in vivo by demonstrating that alterations in plasma GH are accompanied by changes in VLDL secretion. The findings further suggest that GH may regulate VLDL secretion by altering the amount of PL and/or apoprotein available for formation of the VLDL particle.

Stimulation of in vitro triglyceride synthesis in the rat hepatocyte by growth hormone treatment in vivo.

Hepatic fatty acid metabolism in the rat is sexually differentiated. Rates of esterification by the liver of fatty acid into triglyceride and other esterification products (phospholipid, diglyceride, cholesteryl esters) are higher in the female than in the male. There is evidence to suggest that GH feminizes other hepatic systems that exhibit sexual dimorphism, including hepatic steroid metabolism, PRL receptors, and estrogen binding. To investigate the role of GH in maintenance of the high rates of fatty acid esterification observed in the female, we assessed rates of [1-14C]oleic acid utilization by hepatocytes prepared from hypophysectomized (hypox) cortisol/T3-replaced female rats with an without continuous in vivo infusion of human (h) GH (5 micrograms/h). In addition, we assessed the effect of in vivo hGH treatment (5 micrograms/h) on [1-14C]oleic acid utilization in the normal male rat. Hypophysectomy was accompanied by a reduction in incorporation of [1-14C]oleic acid into products of esterification (triglyceride, phospholipid, diglyceride) and oxidation (CO2, ketone bodies). Continuous infusion of hGH (5 micrograms/h; 14 days) restored rates of fatty acid esterification in the hypox-cortisol/T3-replaced female rat, with the exception of cholesteryl esters. hGH infusion partially restored rates of fatty acid oxidation in the hypox cortisol/T3-replaced female rat. Treatment of the adult male rat with continuous infusion of hGH (5 micrograms/h; 7 days) resulted in increased rates of incorporation of [1-14C] oleic acid into triglyceride. In contrast, incorporation of oleic acid into phospholipid, diglyceride, and cholesteryl esters was unaltered. These results suggest that GH may be an important regulator of hepatic fatty acid metabolism.

Postmenopausal estrogen administration suppresses muscle sympathetic nerve activity.

The activity of the sympathetic nervous system shows gender-specific differences with lower sympathoneural activity to the muscle vascular bed in women compared with men, with this difference vanishing after menopause. The present study tested the hypothesis that estrogen exerts regulatory influence on the autonomic nervous system in postmenopausal women. Eleven healthy postmenopausal women (age, 58.5 +/- 1.0 yr; mean +/- SEM) were studied in a randomized double-blind crossover protocol with transdermal administration of 100 microgram/day estradiol (E(2)) or placebo (P) for 2 days. Muscle sympathetic activity (MSA), blood pressure, and heart rate were recorded at rest and during sympathoexcitatory maneuvers (apnea, cold pressor test). E(2) administration significantly increased serum E(2) to physiological levels (E(2), 469.5 +/- 51.5; P, 34.8 +/- 2.2 pmol/L; P < 0.05) and significantly lowered MSA (E(2), 30.1 +/- 3.0 vs. P 37.7 +/- 3.1 bursts/min; P < 0.05). At the same time, blood pressure and heart rate were not affected. MSA was significantly enhanced during apnea and the cold pressure test, and this physiological response to the maneuvers was not changed after estrogen supplementation. In conclusion, elevation of low postmenopausal estrogen levels to physiological premenopausal levels by transdermal E(2) administration supresses MSA. This effect is most likely the consequence of a direct E(2) effect on central nervous autonomic centers, which could explain the gender-specific differences in sympathetic outflow to the muscle vascular bed. The sympathoinhibitory estrogen effects could be important for beneficial cardiovascular effects of estrogen replacement therapy in postmenopausal women.

Sympathetic nerve activity and insulin in obese normotensive and hypertensive men.

The relationship between resting levels of muscle sympathetic nerve activity (MSA) and blood pressure is a matter of controversy. Body weight has recently been identified as an independent determinant of muscle sympathetic discharge, which may have influenced previous studies focused on MSA and mechanisms of hypertension. In the present study, we measured resting MSA and plasma insulin levels in 18 obese (body mass index, 32 +/- 4 kg/m2) (mean +/- SD), middle-aged (52 +/- 6 years), hypertensive (155 +/- 11/97 +/- 8 mm Hg) subjects and 16 age- and body mass index-matched normotensive control subjects. In the postabsorptive state, resting MSA was similar in the hypertensive and normotensive groups (43 +/- 4 versus 39 +/- 3 bursts per minute, 69 +/- 5 versus 64 +/- 5 bursts per 100 heart beats, P = NS) (mean +/- SEM) and did not correlate with either systolic or diastolic blood pressure. Weak but significant positive correlations were found between resting MSA and both fasting insulin levels (P < .05) and body mass index (P = .05) in hypertensive but not normotensive subjects. There was a strong positive correlation between fasting insulin and body mass index in both normotensive subjects and the entire study group (P < .005). Fasting insulin and body mass index correlated with diastolic blood pressure (P < .05) in the entire study group. In conclusion, a relationship between fasting insulin, body mass index, and blood pressure was confirmed, whereas only a weak correlation was found between MSA and fasting insulin in hypertensive but not normotensive subjects. The fact that MSA was similar in the two groups argues strongly against augmented MSA being important for the maintenance of hypertension, at least in middle-aged, obese men.

Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women.

Twenty obese women aged 45-65 years with borderline hypertension were allocated randomly to either a group with an energy-restricted diet or to a control group. Body weight, blood pressure, urinary sodium, and urinary excretion of norepinephrine and plasma volume were recorded. Resting muscle sympathetic nerve activity was measured in the peroneal nerve by tungsten microelectrodes and expressed as bursts per minute. These measurements were repeated after 3 days of semistarvation and after a body weight reduction of 7% while each patient's weight was in a steady state. After 3 days of semistarvation, only body weight was reduced, whereas after the long-term energy intake restriction, there were reductions of body weight (79.9 +/- 3.4 versus 74.1 +/- 3.4 kg; p less than 0.001), diastolic blood pressure (93 +/- 3 versus 86 +/- 4 mm Hg; p = 0.01), and muscle sympathetic nerve activity (49 +/- 2 versus 42 +/- 3 bursts/min; p less than 0.05). Other variables were unchanged. There were no changes in body weight, blood pressure, or muscle sympathetic nerve activity in the control group. We conclude that body weight decrease in obesity results in a reduction of blood pressure that is at least partially caused by a reduction of sympathetic vasoconstrictor activity.

Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency.

Perturbations in the sympathetic nervous system may be anticipated in adults with hypopituitarism and untreated GH deficiency, because the syndrome is associated with both peripheral and central factors known to modulate sympathetic traffic. The higher prevalence of hypertension and increased cardiovascular morbidity/mortality reported in GH-deficient patients may suggest increased activity of the sympathetic nervous system. We recorded muscle sympathetic nerve activity (MSNA) in 10 hypopituitary adults with adequate hormonal replacement therapy except GH and in 10 healthy controls matched for age, gender, and body mass index to test whether hormonal aberrations in hypopituitarism and untreated GH deficiency are associated with an increase in sympathetic nerve traffic. Blood samples for insulin-like growth factor I, free T4, and TSH were taken after an overnight fast, followed by an oral glucose tolerance test. Direct intraneural recordings of MSNA were performed with a tungsten microelectrode from the peroneal nerve. The hypopituitary subjects had markedly increased MSNA (54 +/- 4 bursts/min vs. 34 +/- 4 in controls; P < 0.002), which was not related to abdominal obesity or altered glucose metabolism. When assessed for the whole study group, MSNA was inversely correlated to serum insulin-like growth factor I (r = -0.59; P < 0.006) and TSH (r = -0.46; P < 0.04). MSNA was positively correlated to diastolic blood pressure (r = 0.80; P < 0.0005) in patients, but not in controls. The intense sympathetic discharge is suggested to be of central origin and may be an important underlying mechanism for the secondary hypertension and increased cardiovascular morbidity/mortality in this patient group.

Regulation and counterregulation of lipolysis in vivo: different roles of sympathetic activation and insulin.

To obtain further information on the regulation of lipolysis in vivo, the effect of increasing sympathetic nerve activity via lower body negative pressure (LBNP, -20 mm Hg) was studied in 11 healthy human subjects. Subcutaneous and muscle microdialysis as well as blood flow measurements were performed in the postabsorptive state and during an euglycemic hyperinsulinemic clamp. LBNP for 30 min in the postabsorptive phase resulted in an approximately 50% increase (P < 0.005) in the interstitial-arterial concentration difference for glycerol in adipose tissue, whereas no such effect was registered in muscle. Blood flow in adipose tissue and the forearm remained unaltered. During euglycemic hyperinsulinemic conditions (p-insulin 645 +/- 62 pmol/liter), both interstitial adipose tissue and arterial concentrations of glycerol were reduced. LBNP resulted in an increase in interstitial-arterial concentration difference in glycerol similar to that seen in the postabsorptive state (approximately 50%, P < 0.05). Muscle glycerol was not changed by either insulin or LBNP. Glucose infusion rate during the clamp was significantly decreased during LBNP (7.82 +/- 0.88 vs. 8.67 +/- 1.1 ml/kg.min, P < 0.05). We conclude that the sympathetic nervous activation by LBNP results in an increased lipolysis rate in adipose tissue both in the postabsorptive phase and during insulin infusion. On the other hand, muscle glycerol output was not affected by either LBNP or insulin. The data suggest that 1) lipolysis is regulated differently in muscle and adipose tissue, 2) postabsorptive lipolysis is mainly regulated by insulin, and 3) sympathetic nervous activation effectively inhibits the antilipolytic action of insulin by inducing insulin resistance.

Diclofenac evaluated in a human experimental model of central pain.

The putative central analgesic activity of diclofenac was investigated in a human experimental pain model using intraneural electrical stimulation in the median nerve. Since pain is induced proximal to the peripheral nociceptors, the model can be used to test central analgesic properties of i.a. pharmacological interventions performed during series of repeated stimulations. A single intravenous dose of 50 mg diclofenac or saline was administered during an ongoing series of painful intraneural stimulations in a double-blind cross-over study in 10 healthy volunteers. Neither diclofenac nor saline caused any significant change in the level of pain experienced during stimulation. Thus, no central analgesic effect of diclofenac could be demonstrated in this model. The stability of individual visual analogue scale (VAS) scores throughout the experimental sessions, also after administration of the potent peripheral analgesic agent diclofenac, underlines the validity of intraneural stimulation as a central pain model in humans.