Effects of glucagon on glycogenolysis and gluconeogenesis are region-specific in periportal and perivenous hepatocytes

BACKGROUND: Survival of post-myocardial infarction patients is related inversely to their levels of very-low-frequency (0.003 to 0.03 Hz) RR-interval variability. The physiological basis for such oscillations is unclear. In our study, we used blocking drugs to evaluate potential contributions of sympathetic and vagal mechanisms and the renin-angiotensin-aldosterone system to very-low-frequency RR-interval variability in 10 young healthy subjects. METHODS AND RESULTS: We recorded RR intervals and arterial pressures during three separate sessions, with the patient in supine and 40 degree upright tilt positions, during 20-minute frequency (0.25 Hz) and tidal volume-controlled breathing after intravenous injections: saline (control), atenolol (0.2 mg/kg, beta-adrenergic blockade), atropine sulfate (0.04 mg/kg, parasympathetic blockade), atenolol and atropine (complete autonomic blockade), and enalaprilat (0.02 mg/kg, ACE blockade). We integrated fast Fourier transform RR-interval spectral power at very low (0.003 to 0.03 Hz), low (0.05 to 0. 15 Hz), and respiratory (0.2 to 0.3 Hz) frequencies. Beta-adrenergic blockade had no significant effect on very-low- or low-frequency RR-interval power but increased respiratory frequency power 2-fold. ACE blockade had no significant effect on low or respiratory frequency RR-interval power but modestly (approximately 21%) increased very-low-frequency power in the supine (but not upright tilt) position (P<0.05). The most profound effects were exerted by parasympathetic blockade: Atropine, given alone or with atenolol, abolished nearly all RR-interval variability and decreased very-low-frequency variability by 92%. CONCLUSIONS: Although very-low-frequency heart period rhythms are influenced by the renin-angiotensin-aldosterone system, as low and respiratory frequency RR-interval rhythms, they depend primarily on the presence of parasympathetic outflow. Therefore the prognostic value of very-low-frequency heart period oscillations may derive from the fundamental importance of parasympathetic mechanisms in cardiovascular health.     

Autonomic control of cardiovascular performance and whole body O2 delivery and utilization in swine during treadmill exercise

OBJECTIVE: The present study determined the role of the autonomic nervous system (ANS) in the regulation of systemic and pulmonary circulation and of O2 delivery and utilization in swine at rest and during graded treadmill exercise. METHODS: Instrumented swine (n = 12) were subjected to treadmill exercise (1-5 km/h) under control conditions and in the presence of single and combined beta-adrenergic, alpha-adrenergic and muscarinic (M) receptor blockade. RESULTS: Exercise produced a four-fold increase in body O2 consumption, due to a doubling of both cardiac output and the arterio-mixed-venous O2 content difference. The latter resulted from an increase in O2 extraction, from 45 +/- 1% at rest to 74 +/- 1% at 5 km/h, as the O2 carrying capacity [haemoglobin concentration (Hb)] increased by only approximately 10%. The increase in cardiac output resulted from a doubling of the heart rate and a small (< 10%) increase in stroke volume. The mean aortic pressure (MAP) was unchanged, implying a 50% decrease in systemic vascular resistance (P < or = 0.05). In contrast, exercise had no significant effect on pulmonary vascular resistance. The sympathetic division of the ANS controlled O2 delivery via beta-adrenoceptors (heart rate and contractility) and Hb concentration via alpha-adrenoceptor-mediated splenic contraction. In addition, the sympathetic division modulated systemic vascular tone via alpha- and beta-adrenoceptors, but also exerted a vasodilator influence on the pulmonary circulation via beta-adrenoceptors. The parasympathetic division controlled O2 delivery in part directly (heart rate) and in part indirectly via inhibition of beta-adrenoceptor activity (heart rate and contractility), even during heavy exercise. In addition, the parasympathetic division exerted a direct vasodilator influence on the pulmonary, but not on the systemic, circulation. CONCLUSIONS: Thus, in swine, in a manner similar to that in humans, both the sympathetic and parasympathetic division of the ANS contribute to cardiovascular homeostasis during exercise up to levels of high intensity.     

Autonomic nervous activity at episodes of myocardial ischemia in patients with coronary artery disease by heart rate power spectral analysis

Heart rate power spectral analysis in 44 patients with coronary artery disease was obtained from 24-hour dynamic electrocardiogram. 195 episodes of transient myocardial ischemia that was defined as horizontal or down sloping depression of the ST segment of > or = 0.1 mV and lasted for > or = 2 minutes were studied. The area of low frequency components (LF, 0.02-0.10 Hz) representing predominontly sympathetic tone with some contribution from the parasympathetic tone and that of high frequency components (HF, 0.15-0.40 Hz) representing mainly parasympathetic tone and the value of LF/HF on 4 minute heart rate power spectral graph at the deepest depression of ST segment were compared with that before the episode of myocardial ischemia. The area of HF of fast rate myocardial ischemia occurring in night reduces significantly (P < 0.001), the value of LF/HF increases markedly (P < 0.05) and the area of LF increases slightly. The results suggest that there is a change of autonomic nervous activity during the episode of fast rate myocardial ischemia in night, parasympathetic nervous tone decreases markedly, there may be secondary increase of sympathetic nervous activity.     

Hemorrhage exerts different effects on variabilities of heart rate and blood pressure in dogs

The aim of the present study was to evaluate the effects of hemorrhage on heart rate variability (HRV) and blood pressure variability (BPV) as indicators of autonomic nervous system (ANS) and hypovolemia. We induced hemorrhagic hypovolemia in 7 dogs by removing blood in graded stages (0%, 10%, 20%, 30%, 40% of the estimated blood volume; EBV). HR was unchanged during hemorrhage, while mean BP decreased significantly after 30% EBV hemorrhage. Low frequency component (LF: 0.04-0.15 Hz) of HRV significantly increased after 20% EBV hemorrhage but high frequency component (HF: 0.15-0.4 Hz) of HRV was not altered. LF of BPV increased significantly stepwise after 20% EBV hemorrhage and HF of BPV increased significantly after 30% EBV hemorrhage, showing that both LF and HF of BPV might indicate the degree of hypovolemia. During hemorrhage LF of HRV and BPV increased and HF of HRV was unchanged, indicating the shift of the autonomic balance toward sympathetic dominance. An excellent quantitative correlation between LF of BPV and the degree of hypovolemia was demonstrated during graded hemorrhage, while LF of HRV plateaued at its maximum value at 20% EBV hemorrhage. In conclusion, our study suggests that the spectral analysis of HRV and BPV during graded hemorrhage shows different characteristics in the quantitative evaluation of ANS and hypovolemia.     

Autonomic effects on noise recorded during signal-averaged electrocardiography

The purpose of this study was to assess the effects of autonomic stimulation and blockade on noise levels and to compare the noise measurements in the ST and TP segments of the signal-averaged ECG. Five-minute electrocardiographic data were recorded in 14 normal volunteers (8 males and 6 females; mean age 28.5 +/- 5.0 years) on two separate days (day 1-baseline, epinephrine infusion, isoproterenol infusion, beta-blockade, and combined adrenergic and parasympathetic blockade; day 2-baseline, phenylephrine infusion, parasympathetic blockade, and during phenylephrine infusion following atropine). Signal averaging was done off-line on 100 beats and noise was measured in both the ST and TP segments as the standard deviation of voltage in the segment of interest. For all conditions tested, the mean noise level measured in the ST segment (0.46 +/- 0.16 microV) was significantly less than that measured in the TP segment (0.52 +/- 0.24 microV; P = 0.0003), but there was good correlation between the noise measured in the ST and the TP segment (R2 = 0.62, P < 0.0001). Noise increased with isoproterenol infusion and decreased following adrenergic blockade. In addition, day 2 baseline noise was less than baseline noise on day 1. Finally, neither parasympathetic stimulation or blockade nor alpha-adrenergic stimulation significantly affected signal-averaged electrocardiography (SAECG) noise levels. Thus, the data support the notion that enhanced sympathetic tone increases noise levels and beta-adrenergic blockade may decrease noise levels, likely due to effects from muscle sympathetic nerve activity. These findings are important since the target population for the SAECG are patients with myocardial infarction and congestive heart failure, conditions associated with increased sympathetic tone, which may in turn impact on the reproducibility or technical aspects of the SAECG. In addition, because noise in the ST and TP segments are highly correlated and the noise measured in the ST segment is less than that in the TP segment, uniform adoption of noise measurement in the ST segment seems most appropriate.     

Heart rate and blood pressure variability in obese normotensive subjects

OBJECTIVE: To assess autonomic modulation of cardiovascular activity in massively obese subjects. DESIGN: Cross-sectional clinical study. SUBJECTS: 43 age-matched normotensive subjects: 15 moderately obese (body mass index (BMI) < 40); 14 massively obese (BMI > 40) and 14 nonobese controls (BMI < 26). MEASUREMENTS: Using power spectral analysis, heart rate and arterial pressure variability were determined at rest and after sympathetic stress (tilt). Two spectral components were analysed: a low-frequency (LF) component at around 0.1 Hz, predominantly reflecting sympathetic modulation and a high-frequency (HF) component at around 0.26 Hz, reflecting parasympathetic modulation. RESULTS: Spectral data for heart rate showed that the massively obese subjects had lower LF [mean +/- s.e.m.] normalized units (NUs) at rest (35.1 +/- 0.9) and after tilt (56.1 +/- 2.1), than the moderately obese subjects (LF NUs at rest 53.9 +/- 4.2, P < 0.001; LF NUs tilt: 66.8 +/- 5.6, P < 0.001) and nonobese control subjects (LF NUs at rest, 56.6 +/- 3.0, P < 0.001); (LF NUs tilt: 81.7 +/- 1.7, P < 0.001). Data for systolic arterial pressure variability measured at rest exhibited the inverse pattern, the massively obese group having higher mean LF values (LF mm Hg2 rest: 15.0 +/- 1.4; LF mm Hg2 tilt: 15.7 +/- 1.5) than the moderately obese group (LF mm Hg2 rest 3.2 +/- 0.7, P < 0.001; LF mm Hg2 tilt: 7.2 +/- 2.0, P < 0.001) and than the nonobese control subjects (LF mm Hg2 rest 3.5 +/- 0.5, LF mm Hg2 tilt 8.5 +/- 0.8, P < 0.001). Regression detected a significant association between BMI and LF of systolic pressure (beta = 0.364; P = 0.0007), In LF of heart rate (beta = -5.555; P = 0.00001) and very low frequency (VLF) of diastolic pressure (beta = -3.305; P = 0.0020). CONCLUSION: Obesity seems to increase sympathetic modulation of arterial pressure, but diminishes modulation of heart rate. Because our obese subjects had high plasma noradrenaline levels, their low LF power of heart rate could reflect diminished adrenoceptor responsiveness.     

Autosomal dominant hypertension and brachydactyly in a Turkish kindred resembles essential hypertension

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

A controlled evaluation of a lifts and transfer educational program for nurses

The role of the parasympathetic autonomic nervous system (ANS) in digoxin intoxication was investigated in atropine pretreated conscious rabbits. Both the electrocardiographic registration and the histologic analysis indicated possible prevention of lethal arrhythmias by atropine pretreatment. The hearts of animals pretreated with atropine appeared less damaged, since they presented only a light cytoplasmic vacuolization. It was evident that the administration of digoxin without atropine pretreatment provoked dramatic signs of digitalis intoxication followed by animal death. Myocardia of these rabbits were highly damaged. On the other hand, our experimental data indicated that the abolishment of the vagal tone by atropine blockade caused only signs (i.e. inversion of the T wave) due to myocardial ischemia, to which the light cytoplasmic vacuolation could be correlated. Myocardial ischemia could be caused by constriction of coronary blood vessels, which could be consequential to both the prevalent activity of the orthosympathetic ANS, following parasympathetic blockade, and direct digoxin effects on vascular fibrecells, which both produce vasoconstriction. Therefore, it is reasonable to assume that the parasympathetic ANS plays a major role in digitalis intoxication in rabbits.     

Parasympathetic activity is a major modulator of the circadian variability of heart rate in healthy subjects and in patients with coronary artery disease or diabetes mellitus

Autonomic heart rate control was assessed by power spectral analysis of heart rate variability in 24-hour ambulatory electrocardiographic recordings from 23 healthy subjects, 14 patients with coronary artery disease without cardiac dysfunction, and 14 patients with diabetes mellitus. The log value of the ratio of the low-frequency component (LF = 0.04 to 0.15 Hz) to the high-frequency component (HF = 0.15 to 0.5 Hz) and logHF were employed as indexes of sympathetic and parasympathetic activity, respectively. Diurnal and nocturnal logLF, logHF, and log(LF/HF) values were calculated for heart rates of 60, 70, and 80 beats/min. Intergroup differences among these three variables were not significant at any heart rate. Although a heart rate-related decrease in logHF was generally observed, the relationship between log(LF/HF) and heart rate was not consistent. The correlation between diurnal and nocturnal logHF values was significant at all three heart rates (r = 0.63, 0.87, and 0.59), whereas the diurnal log(LF/HF) was correlated with the nocturnal value only at 70 beats/min (r = 0.77). These results suggest that the heart rate during normal daily activities is a reliable indicator of parasympathetic tone, if not sympathetic tone, in healthy subjects and patients with coronary artery disease or diabetes mellitus.     

Solitary plasmacytoma of the lung with light chain extracellular deposits: a case report and review of the literature

We studied a possible correlation between autonomic cardiac activity and the level of the red blood cell acetylcholinesterase (AChE) in patients with probable Alzheimer disease (AD). The influence of cholinesterase inhibitor treatment on this autonomic activity was evaluated. Twelve patients satisfying the NINCDS-ADRDA criteria of probable AD and 10 healthy controls were studied. Autonomic cardiac activity was evaluated by means of power spectral analysis (PSA) of heart rate variability (HRV) using an autoregressive algorithm on 250 consecutive electrocardiographic R-R intervals. All patients received oral eptastigmine, a new cholinesterase inhibitor, for 1 month. Before treatment, a simultaneous recording of the electrocardiographic and respiratory activities was performed at rest and subsequently during head-up tilt test at 700. Recording was repeated on the last day of treatment. The level of AChE activity during each recording was also evaluated. Spectrum power was calculated in three main frequency bands: high frequency (HF), 0.15-0.4 Hz; low frequency (LF), 0.04-0.15 Hz; very low frequency (VLF), <0.04 Hz. In addition, we calculated the total spectrum power (TSP) and the LF/HF ratio. The TSP and the absolute value of each spectral component were significantly lower in AD patients than in controls. In contrast with controls, AD patients did not show any significant change before treatment in either the LF and HF components or in the LF/HF ratio during the tilt test. However, the modification in the LF component, induced by tilting, showed a significant correlation with the level of AChE activity (p < 0.03). During the tilt test, the treatment caused changes in LF and HF components and in the LF/HF ratio similar to those observed in controls. These results suggest that the presence of autonomic cardiac dysfunction in AD patients might be due to a cholinergic deficit in the peripheral autonomic nervous system. Some aspects of this autonomic dysfunction can be normalized by cholinesterase inhibitor treatment.     

Clinical and laboratory indices that enhance the diagnosis of postural tachycardia syndrome

OBJECTIVE: To identify clinical and laboratory indices that improve the diagnosis of the postural tachycardia syndrome (POTS). DESIGN: We assessed associations of orthostatic intolerance by using multivariate regression analysis. MATERIAL AND METHODS: We evaluated autonomic symptoms and autonomic function in 30 patients with POTS, 30 patients with mild orthostatic intolerance, and 19 age- and gender-matched control subjects. Indices of parasympathetic and sympathetic functions were analyzed on the basis of (1) autonomic function tests (head-up tilt), (2) oscillations at respiratory and nonrespiratory frequencies (0.01 to 0.09 Hz) in R-R interval and blood pressure (Wigner distribution), and (3) deterministic component (rescaled range analysis). RESULTS: The four clinical and laboratory indices that independently supported the diagnosis of POTS are as follows: (1) orthostatic heart rate during the first minute of head-up tilt, (2) autonomic deficit (adrenergic autonomic score), (3) loss of spectral powers in R-R interval during head-up tilt at the fifth minute, and (4) severity of orthostatic dizziness, fatigue, palpitations, and shortness of breath. CONCLUSION: Enhancing the sensitivity and specificity of the diagnosis of POTS should be possible by using these four indices. A hyperadrenergic state and distal neuropathy, affecting adrenergic sympathetic cardiovagal fibers, seem to be involved in the pathophysiology of POTS. Certain features suggest brain-stem dysregulation.     

Power spectral analysis of heart rate variation in diabetic patients with neuropathic foot ulceration

OBJECTIVE: To evaluate the relationship between diabetic autonomic neuropathy and diabetic neuropathic foot ulceration, we used power spectral analysis (PSA) of heart rate variation, which provides the accurate simultaneous quantification of parasympathetic and sympathetic activities, to assess autonomic function in diabetic patients. RESEARCH DESIGN AND METHODS: We studied 55 NIDDM patients including 10 diabetic patients without neuropathy, 23 diabetic patients with neuropathy and no history of foot ulceration, and 22 diabetic patients with neuropathic foot ulceration. We performed PSA of 100 R-R intervals at rest and analyzed the results by fast Fourier transformation. RESULTS: The low frequency (LF) power, which reflects sympathetic activity, and the high frequency (HF) power, which reflects parasympathetic (vagal) activity, were inversely correlated with the duration of diabetes and the fasting plasma glucose (FPG) levels. By multiple regression analysis, the FPG remained with significant influence on both LF and HF powers. The LF and HF powers were positively correlated with motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) in the upper and lower limbs and the coefficient of variation of R-R intervals. The LF and HF powers were significantly reduced in patients with neuropathy and patients with foot ulceration compared with patients without neuropathy. Although the median MCV and SCV were similar between diabetic patients with neuropathy and patients with foot ulceration, both the LF and HF powers were significantly decreased in patients with foot ulceration compared with patients with neuropathy. There was no difference in the value of the LF:HF ratio, an index of sympathovagal balance, among three subgroups. We observed a positive correlation between LF and HF power in all subjects; however, the LF and HF powers were not correlated in the subgroups of patients with foot ulceration. CONCLUSIONS: These results showed that diabetic patients with neuropathic foot ulceration have a greater impairment in spectral indexes of autonomic activity obtained by PSA than patients with neuropathy and no history of foot ulceration, whereas no difference was present in nerve conduction velocities.     

Twenty-four hour time and frequency domain variability of systolic blood pressure and heart rate in an experimental model of arterial hypertension plus obesity]

Modifications of heart rate (HR) and systolic blood pressure (SBP) variabilities (V) have been reported in the human syndrome arterial hypertension plus insulin-resistance. The aim of this study was to characterize the 24 h SBPV and HRV in both time and frequency domains during weight increase in dogs fed ad libitum with a high fat diet. Implantable transmitter units for measurement of blood pressure and heart rate were surgically implanted in five beagle male dogs. BP and HR were continuously recorded using telemetric measurements during 24 hours, before and after 6 and 9 weeks of hypercaloric diet in quiet animals submitted to a 12h light-dark cycle. To study nychtemeral cycle of SBP and HR, two periods were chosen: day (from 6.00 h to 19.00 h) and night (from 23.00 h to 6.00 h). Spontaneous baroreflex efficiency was measured using the sequence method. Spectral variability of HR and SBP was analyzed using a fast Fourier transformation on 512 consecutive values and normalized units of low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands were calculated. The energy of total spectrum (from 0.004 to 1 Hz) was also studied. Body weight (12.4 +/- 0.9 vs 14.9 +/- 0.9 kg, p < 0.05). SBP (132 +/- 1 vs 147 +/- 1 mmHg, p < 0.05) significantly increased after 9 weeks of hypercaloric diet. A nycthemeral HR rhythm was present at baseline (day: 79 +/- 1 vs night: 71 +/- 1 bpm) but not after 9 weeks (day: 91 +/- 4 bpm ; night: 86 +/- 2 bpm). Concomitantly, the efficiency of spontaneous baroreflex decreased at 6 weeks (36 +/- 1 vs 42 +/- 2 mmHg/ms, p < 0.05). A significant decrease in HF energy of HRV was found after 6 but not after 9 weeks. LF energy of SBPV was increased at 6 but not at 9 weeks (table). [table: see text] In conclusion, this study shows that an hyperlipidic and hypercaloric diet induces transient variations in autonomic nervous system activity which could be the physiopathological link between obesity, insulin-resistance and arterial hypertension.     

N(N)-nicotinic blockade as an acute human model of autonomic failure

Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.     

Subject''s perceptions of the crew interaction dynamics under prolonged isolation

BACKGROUND: Short-term variability of RR interval and blood pressure occurs predominantly at low frequency (LF; approximately 0.1 Hz) and high frequency (approximately 0.25 Hz). The arterial baroreflex is thought to be the predominant determinant of the LF component of RR variability. Patients with severe congestive heart failure (CHF) have an attenuated or absent LF oscillation in RR variability. The left ventricular assist device (LVAD) offers a unique possibility for analysis of spectral oscillations in RR interval independent of any effects of blood pressure that influence these oscillations via the baroreflex. METHODS AND RESULTS: We performed spectral analysis of RR, blood pressure, and respiration in 2 patients with CHF before and after LVAD implantation. LF components of the RR-interval and blood pressure variability were absent in both CHF patients before LVAD implantation. After LVAD implantation, spectral analysis of the RR interval showed restoration of a clear and predominant LF oscillation in the native hearts of both patients, with no such oscillation evident in the blood pressure profile. CONCLUSIONS: During total circulatory support with the LVAD, the LF oscillation in RR interval of the native heart, absent in CHF, is restored. This LF oscillation in RR interval occurs in the absence of LF oscillations in blood pressure and thus is unlikely to be explained by baroreflex mechanisms. Hence, the absence of LF oscillation in the RR interval in CHF is functional and is reversible by LVAD circulation. The presence of a predominant LF oscillation in RR interval independent of any oscillation in blood pressure suggests that the LF oscillation is a fundamental property of central autonomic outflow.     

Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice

Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS-/- mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after beta-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after beta-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 microgram/kg i.p.). At baseline, nNOS-/- mice had higher mean HR (711+/-8 vs. 650+/-8 bpm, P = 0.0004) and lower HR variance (424+/-70 vs. 1,112+/-174 bpm2, P = 0.001) compared with WT mice. In nNOS-/- mice, atropine administration led to a much smaller change in mean HR (-2+/-9 vs. 49+/-5 bpm, P = 0.0008) and in HR variance (64+/-24 vs. -903+/-295 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After beta-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS-/- mice before PTX administration was similar to that in WT mice. However, PTX-treated nNOS-/- mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex-mediated cardioinhibition unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse.     

Low and high frequency electroacupuncture at Hoku elicits a distinct mechanism to activate sympathetic nervous system in anesthetized rats

To address the effect of electroacupuncture (Ea) on autonomic nerve activity, the responses of rhythmic micturition contraction (RMC), urine excretion (UE), blood pressure (BP), renal sympathetic nerve activity (RNA) and pelvic parasympathetic nerve activity (PNA) to Ea were investigated in urethane-anesthetized rats. The acupoint Hoku (Li-4) was tested with two different stimulation frequencies (2 Hz and 20 Hz). Elongation of the RMC cycle and an increase in UE associated with the elevation of BP and RNA was elicited during Ea at Hoku. However, the pressor response induced by low frequency Ea (LFEa) was different from that by high frequency Ea (HFEa), i.e. a tonic effect was elicited by LFEa, while a phasic one was induced by HFEa. These results imply that: (1) Ea at Hoku may selectively activate the sympathetic, but not the parasympathetic nervous system, (2) Ea at Hoku with a different stimulation frequency may elicit a distinct mechanism to activate the sympathetic nervous system and (3) Ea at Hoku may ameliorate the hyperactive bladder in clinical therapy.     

Autonomic nervous function of the patients with neurally mediated syncope

Although diagnosis of neurally mediated syncope (NMS) using head-up tilt (HUT) test has been established, the exact mechanism of NMS has not yet been elucidated. We evaluated beta and alpha-adrenergic function in NMS patients by pharmacological autonomic function test. The alpha-adrenergic sensitivity of NMS patients was significantly lower than that of control subjects. The patients who need low dose isoproterenol for provocation of syncope showed higher beta-adrenergic sensitivity than patients who developed syncope without isoproterenol. Thus, pharmacological autonomic function test was useful for evaluation of NMS patients.     

Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans

BACKGROUND: Spectral analysis of RR interval and systolic arterial pressure variabilities may provide indirect markers of the balance between sympathetic and vagal cardiovascular control. METHODS AND RESULTS: We examined the relationship between power spectral measurements of variabilities in RR interval, systolic arterial pressure, and muscle sympathetic nerve activity (MSNA) obtained by microneurography over a range of blood pressures. In eight healthy human volunteers, MSNA, RR interval, intra-arterial pressure, and respiration were measured during blood pressure reductions induced by nitroprusside and during blood pressure increases induced by phenylephrine. Both low-frequency (LF; 0.10 +/- 0.01 Hz) and high-frequency (HF; 0.23 +/- 0.01 Hz) components were detected in MSNA variability. Increasing levels of MSNA were associated with a shift of the spectral power toward its LF component. Decreasing levels of MSNA were associated with a shift of MSNA spectral power toward the HF component. Over the range of pressure changes, the LF component of MSNA variability was positively and tightly correlated with LF components of RR interval (in normalized units; P < 10(-6)) and of systolic arterial pressure variability (both in millimeters of mercury squared and normalized units; P < 5 x 10(-5) and P < 5 x 10(-6), respectively). The HF component of MSNA variability was positively and tightly correlated with the HF component (in normalized units) of RR-interval variability (P < 3 x 10(-4)) and of systolic arterial pressure variability (P < .01). CONCLUSIONS: During sympathetic activation in normal humans, there is a predominance in the LF oscillation of blood pressure, RR interval, and sympathetic nerve activity. During sympathetic inhibition, the HF component of cardiovascular variability predominates. This relationship is best seen when power spectral components are normalized for total power. Synchronous changes in the LF and HF rhythms of both RR interval and MSNA during different levels of sympathetic drive are suggestive of common central mechanisms governing both parasympathetic and sympathetic cardiovascular modulation.     

Expression of Pit-1 mRNA and activin/inhibin subunits in clinically nonfunctioning pituitary adenomas. In situ hybridization and immunohistochemical analysis

Autonomic nervous activity is involved in the onset of paroxysmal atrial fibrillation, but it is not clear how the sympathetic and parasympathetic nervous systems interact before the onset of atrial fibrillation. Twelve lone atrial fibrillation patients and 10 healthy volunteers were studied using 24-hour Holter electrocardiography monitoring. A total of 17 episodes were analyzed. Autonomic nervous activity was assessed based on the high frequency power (HF) spectrum (HF represents parasympathetic nervous activity) and the ratio to the low frequency power (LF) spectrum (L/H represents sympathetic nervous activity) of heart rate variability during sinus rhythm, and the 24-hour averaged autonomic indices were compared between atrial fibrillation patients and healthy volunteers. Comparative data were obtained 30, 20, 10, and 2 min before the onset of atrial fibrillation for each episode. There were no significant differences in the HF and L/H ratio between the patients and healthy volunteers. There were no significant differences in the HF values before the onset of paroxysmal atrial fibrillation, but the L/H ratio before the onset of atrial fibrillation at 30, 20 and 10 min was 1.03 +/- 0.42, 0.95 +/- 0.50, and 1.32 +/- 0.46, respectively, and just before the episode was 1.73 +/- 0.73, so the Spearman's rank correlation coefficient was 0.43. Basal autonomic nervous activity in patients with paroxysmal atrial fibrillation showed no changes compared with healthy volunteers. Sympathetic nervous activity increased progressively from about 30 min before the onset of atrial fibrillation, but parasympathetic nervous activity showed no significant changes. Therefore, a transient augmentation of sympathetic tone may be important in the onset of atrial fibrillation.