Platelet cNOS activity is reduced in patients with IDDM and NIDDM

Several studies in vitro and in vivo suggest that the nitric oxide (NO) production is impaired in diabetes mellitus. Reduced levels of NO could contribute to vascular alteration facilitating platelet-vascular wall interaction, adhesion of monocytes to endothelium, vascular smooth muscle proliferation and by decreasing endothelium-dependent vasodilation. In this study we evaluated the activity of the constitutive nitric oxide synthase (cNOS) in platelets of patients with insulin-dependent diabetes mellitus (IDDM) and with non-insulin-dependent diabetes mellitus (NIDDM). When compared to that of normal subjects, cNOS activity is significantly lower in patients with IDDM and with NIDDM (1.57 +/- 0.25 vs. 0.66 +/- 0.10 fmol/min/10(9) PLTs and 1.57 +/- 0.25 vs. 0.67 +/- 0.08, respectively; p<0.005). These data demonstrate that the platelet cNOS activity is decreased in diabetes mellitus.     

Muscle sympathetic nerve activity during cold pressor test in patients with cerebrovascular accidents

BACKGROUND AND PURPOSE: Autonomic dysfunction is frequently present in patients with cerebrovascular accidents (CVA). However, the pathophysiological mechanisms of these disorders are not clear. The purpose of the study was to assess the effects of CVA on the autonomic nervous system. METHODS: In eight male patients with a history of CVA with damage of the cortical or subcortical structures, we measured the cold pressor response during recording of muscle sympathetic nerve activity (MSNA) from the peroneal nerve on the hemiplegic side. We also studied 10 age-matched male control subjects. Tests were performed before, during, and after immersion of the nonhemiplegic hand in ice water for a period of 3 minutes in each phase. We also recorded changes in heart rate (HR), arterial blood pressure, skin temperature of the middle finger, and perception of pain using the Borg's score. RESULTS: During the control period, the mean burst count of MSNA in CVA (57.2 +/- 3.9 beats/100 HR) was higher than in control subjects (36.3 +/- 3.2 beats/100 HR) (P<.05). Total MSNA (the mean burst amplitude per minute times burst rate) increased significantly in CVA and control during the immersion period by 79.9 +/- 18.4% and 133.1 +/- 25.6%, respectively. The percent change in total MSNA in CVA was attenuated during immersion compared with control subjects. The HR and skin temperature responses as well as the Borg's score were similar in both groups during control, hand immersion, and recovery periods. CONCLUSIONS: The present results suggest that increased MSNA in CVA may be due to damage of cortical or subcortical structures or stroke-related changes in other areas or nonspecific changes that cause continuous increase in basal MSNA.     

Respiratory quotient is inversely associated with muscle sympathetic nerve activity

The relative amounts of the macronutrients oxidized by an individual are reflected in the respiratory quotient (RQ), which varies inversely with lipid oxidation. A high RQ, indicating a relatively low lipid oxidation, and a low activity of the sympathetic nervous system have both been identified as risk factors for body weight gain. The stimulatory effect of norepinephrine on lipid oxidation suggests that low lipid oxidation may contribute to the relationship between low sympathetic nervous activity and body weight gain. The purpose of the present study was to determine whether low basal muscle sympathetic nerve activity (MSNA), a direct measure of sympathetic nervous outflow, is independently associated with low lipid oxidation. Intraneural recordings of basal MSNA were performed in 39 healthy, nondiabetic males, 19 Caucasians (mean +/-SD, 33 +/- 9 yr, 91 +/- 23 kg, and 28 +/- 11% body fat) and 20 Pima Indians (30 +/- 5 yr, 94 +/- 25 kg, and 35 +/- 8% fat) immediately after measurement of 24-h RQ in a respiratory chamber. Basal MSNA, energy balance, and age were independent determinants of 24-h RQ, together explaining 45% of its variability. Accordingly, 24-h RQ adjusted for energy balance and age was inversely related to MSNA (r = -0.41; P = 0.01). Race, percent body fat, and fasting plasma insulin were not independent determinants of 24-h RQ. Although MSNA explained only a limited part of the variability in 24-h RQ, the results support the hypothesis that an effect on lipid oxidation contributes to the demonstrated relationship between low activity of the sympathetic nervous system and body weight gain.     

Baroreflex control of muscle sympathetic nerve activity is attenuated in the elderly

To determine whether the baroreflex control of sympathetic nerve activity is attenuated in the elderly, muscle sympathetic nerve activity (MSNA) from the tibial nerve was monitored using microneurography, and heart rate and blood pressure were recorded during the depressor (phase II) or pressor (phase IV) period to Valsalva's maneuver in 10 younger subjects and 7 aged subjects. The baroreflex slope for heart rate showed attenuation in the aged subjects during the pressor phase but not during the depressor phase, the baroreflex slope for MSNA was also attenuated in the aged subjects during the pressor and tended to be attenuated during the depressor phases. These data suggest impaired baroreflex function for both heart rate and sympathetic nerve activity in the elderly.     

Is autonomic neuropathy a risk factor for severe hypoglycaemia? The EURODIAB IDDM Complications Study

The hypothesis that diabetic patients with autonomic neuropathy are at increased risk of severe hypoglycaemia was examined in an epidemiological study of over 3000 IDDM patients in Europe (EURODIAB IDDM Complications Study). Autonomic function was assessed by two standard cardiovascular tests: change in heart rate and systolic blood pressure on standing. Severe hypoglycaemia was defined as an attack serious enough to require the help of another person. Compared to patients (68%) reporting no attacks in the last year, those reporting one or more attacks were older (34.0 +/- 10.7 vs 32.1 +/- 9.9 years, mean +/- SD, p < 0.0001), had had diabetes for a longer period (16.6 +/- 9.5 vs 13.8 +/- 9.1 years, p < 0.0001), had better glycaemic control (HbA1c 6.4 +/- 1.8 vs 6.9 +/- 1.9%, p < 0.0001) and were more likely (p = 0.002) to have abnormal responses to both autonomic tests (13.0 vs 7.7%). A single abnormal autonomic response was not associated with an increased risk of severe hypoglycaemia. The odds ratio for severe hypoglycaemia in people with abnormal responses to both autonomic tests, compared to those with normal responses, was 1.7 (95% confidence interval 1.3, 2.2) after controlling for age, duration of diabetes, glycaemic control and study centre. In conclusion, a combined autonomic deficit in heart rate and blood pressure responses to standing is associated with only a modest increase in the risk of severe spontaneous hypoglycaemia. Although the increase in risk is not large, severe hypoglycaemia was a frequently reported event in this study. IDDM patients with deficient autonomic responses who strive for tight glycaemic control may therefore be at particular risk of severe hypoglycaemia.     

The rhythmicity of sympathetic nerve activity

This review focuses on that most engaging feature of the sympathetic nervous system, its rhythmicity. In particular examining the nature of sympathetic nerve activity (SNA), its characteristics, the frequencies of these rhythms and possible mechanisms responsible for their generation. Sympathetic activity can be thought of as a complex output of the central nervous system providing subtle control over end organ function. This control is exerted in a number of frequency bands including rhythms related to the cardiac and respiratory cycles, 10 Hz, and between 0.2 and 0.4 Hz. The generation and control over the occurrence of each of these rhythms is likely to be quite separate. Although afferent feedback from sources such as baroreceptors can explain some of the rhythmical properties in each case there is good evidence for inherent generation of aspects of these rhythms. A variety of brainstem cell groups are thought to be involved in their generation with the rostral ventrolateral medulla, although unlikely to be solely responsible for tone generation, an important regulator of overall activity. SNA also varies in the number of nerves recruited to fire in each synchronized discharge. Little is known about this control other than it appears to be quite separate from the control over the timing of discharges. Spinal cord mechanisms are possibly involved. SNA frequencies above 0.7 Hz do not appear to directly induce oscillations in innervated vasculature, however, are likely to contribute to setting the level of vasconstrictive tone. Slower frequencies appear to directly cause oscillations in blood flow.     

Epidural midazolam attenuates renal sympathetic nerve activity in rabbits

The effects of epidural midazolam on heart rate (HR), mean arterial pressure (MAP) and the renal sympathetic nerve activity (RSNA) were examined. Under alpha-choloralose anesthesia, 31 male Japanese-white rabbits received epidural catheterization and surgical procedures for measurement of the renal sympathetic nerve activity. Epidural low (0.05%) and high (0.5%) concentrations of midazolam did not affect HR, but significantly decreased MAP and RSNA-spikes (the spike count of RSNA). Intravenous flumazenil significantly increased MAP and RSNA-spikes. These findings suggest that the decrease in RSNA-spikes induced by epidural midazolam is derived from the benzodiazepine receptor. Intramuscular midazolam (0.5%) did not affect HR, but decreased MAP and RSNA-spikes significantly. In the spinal cord dissected rabbits, epidural midazolam (0.5%) did not affect HR and MAP, but significantly attenuated RSNA-spikes. In conclusion, epidural midazolam attenuated RSNA through the benzodiazepine receptors of both the spinal and supraspinal nervous system.     

Reflex control of cardiac sympathetic nerve activity in anesthetized rats

Reflex control of sympathetic outflow to the heart was evaluated by recording the efferent discharges of the interior cardiac sympathetic nerves in anesthetized rats. The reflex responses of inferior cardiac sympathetic nerve activity (ICNA) to arterial baroreceptor loading by phenylephrine and to arterial/atrial baroreceptor unloading by hemorrhagic hypotension were compared with those of renal sympathetic nerve activity (RNA) and adrenal sympathetic nerve activity (ANA). The reflex decrease in ICNA to the phenylephrine-induced graded increase in arterial blood pressure was smaller than that of RNA or ANA. Thus ICNA is less sensitive to arterial baroreceptor stimulation. Hemorrhage produced a volume-dependent decrease in ICNA. The response was significantly smaller than that in RNA and was directionally opposite to that in ANA. Cervical vagotomy but not sinoaortic denervation abolished the hemorrhage-induced ICNA response, suggesting an important role of vagal pathways. These findings demonstrate that the reflex responses of sympathetic outflow to the heart were quantitively and qualitatively different from those to the kidney and the adrenal gland, indicating the regional control of sympathetic nerve activity in the regulation of cardiovascular functions.     

Microalbuminuria in IDDM is associated with increased expression of monocyte procoagulant activity

Insulin-like growth factor II (IGF-II) plays a key role in mammalian growth, influencing foetal cell division and differentiation and possibly metabolic regulation. The mature 67 amino acid peptide shares sequence homology with both insulin and IGF-I. The liver is the main endocrine source of IGFs, but autocrine/paracrine activity is found in most tissues. The type 1 receptor mediates most of the biological effects of IGF-I and IGF-II; the type 2 receptor is involved with IGF-II degradation. Binding proteins may both localise IGFs to the receptors and regulate their activities. The IGF2 gene is maternally imprinted in mouse and human. Relaxation of IGF2 imprinting occurs in the Beckwith-Wiedemann syndrome of somatic overgrowth, sporadic Wilms' tumour and a number of other cancers. In the general adult population, the IGF2-INS gene cluster may also influence body weight, in which case IGF-II function could become a target for therapeutic intervention in obesity.     

Plasma noradrenaline correlates to sympathetic muscle nerve activity in normotensive man

Recordings of multiunit sympathetic activity were made in muscle branches of the peroneal nerve in 22 healthy subjects at rest in recumbent position. Nerve activity was quantitated in terms of burst incidence (number of pulse synchronous sympathetic bursts per 100 heart beats or per min). In a separate session, 4-45 months later, blood was drawn from an antecubital vein for noradrenaline analysis. Both sympathetic activity and plasma concentrations of noradrenaline varied widely between subjects and both parameters increased with age. There was a significant positive correlation between a subject's level of sympathetic activity and his plasma concentration of noradrenaline. It is suggested that overflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma levels of noradrenaline at rest.     

Evaluation by microneurography of muscle sympathetic nerve activity in myelopathic patients

The purpose of this study was to observe the functional condition of the muscle sympathetic nerve activity (MSNA) in nine patients with mild myelopathy for which surgery was indicated [mean score 14/17 by Japanese Orthopaedic Association (JOA) cervical myelopathy and 7/11 for thoracic myelopathy]. The MSNA was obtained from the tibial nerve at the popliteal fossa by microneurography. The resting activities and the responses during handgripping were analyzed and compared with those of a control group of nine healthy volunteers and patients with disorders unrelated to myelopathy. The MSNA with the subjects supine was recorded first at rest for 5 min. (rest period), next during exertion of 20% of the maximum voluntary handgripping power for 5 min. (handgripping period), and last at rest for 5 min. (recovery period). The number of MSNA bursts per min. (burst rate) in the group with myelopathy was more than that in the control group (p < 0.05) in all three periods. The response by MSNA to handgripping in the group with myelopathy was higher than that in the control group at the start of handgripping (p < 0.01), and tended to be higher even 5 min. after handgripping ended. The results appeared to demonstrate that MSNA of patients with mild myelopathy for which surgery is indicated is increased in the lower extremities.     

Physical training and baroreceptor control of sympathetic nerve activity in humans

In nine sedentary subjects (16.5 +/- 0.4 years, mean +/- SEM) we measured blood pressure (Finapres device), heart rate (electrocardiogram), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) at rest and during intravenous infusion of phenylephrine and nitroprusside. These measurements were performed before and after 10 weeks of endurance training (2 h/d, 5 d/wk) that increased maximum oxygen consumption from 34.8 +/- 2.1 to 40.4 +/- 1.8 mL/kg per minute (P < .02). Basal mean blood pressure and muscle sympathetic nerve activity were lower after than before endurance training (86.5 +/- 2.6 versus 97.5 +/- 1.8 mm Hg, P < .05, and 14.0 +/- 1.8 versus 21.2 +/- 2.3 bursts per minute, P < .02), and the changes in these variables were closely related (r = .95, P < .01). Similar mean blood pressure increases induced by phenylephrine caused greater reductions in heart rate and muscle sympathetic nerve activity after than before endurance training (-8.6 +/- 0.8 versus -6.1 +/- 1.1 beats per minute, P = NS, and -78.0 +/- 4.6% versus -53.6 +/- 4.8%, P < .05). Likewise, similar mean blood pressure reductions induced by nitroprusside caused greater increases in heart rate and muscle sympathetic nerve activity after than before endurance training (18.6 +/- 3.0 versus 12.4 +/- 2.4 beats per minute, P < .05, and 128.1 +/- 26% versus 63.2 +/- 11%, P < .02). No alteration in hemodynamics, oxygen consumption, muscle sympathetic nerve activity, and baroreceptor reflex sensitivity occurred in four other age-matched sedentary subjects studied before and after a 10-week observation period without endurance training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Scintigraphic assessment of regionalized defects in myocardial sympathetic innervation and blood flow regulation in diabetic patients with autonomic neuropathy

OBJECTIVES: This study sought to evaluate whether regional sympathetic myocardial denervation in diabetes is associated with abnormal myocardial blood flow under rest and adenosine-stimulated conditions. BACKGROUND: Diabetic autonomic neuropathy (DAN) has been invoked as a cause of unexplained sudden cardiac death, potentially by altering electrical stability or impairing myocardial blood flow, or both. The effects of denervation on cardiac blood flow in diabetes are unknown. METHODS: We studied 14 diabetic subjects (7 without DAN, 7 with advanced DAN) and 13 nondiabetic control subjects without known coronary artery disease. Positron emission tomography using carbon-11 hydroxyephedrine was used to characterize left ventricular cardiac sympathetic innervation and nitrogen-13 ammonia to measure myocardial blood flow at rest and after intravenous administration of adenosine (140 microg/kg body weight per min). RESULTS: Persistent sympathetic left ventricular proximal wall innervation was observed, even in advanced neuropathy. Rest myocardial blood flow was higher in the neuropathic subjects (109 +/- 29 ml/100 g per min) than in either the nondiabetic (69 +/- 8 ml/100 g per min, p < 0.01) or the nonneuropathic diabetic subjects (79 +/- 23 ml/100 g per min, p < 0.05). During adenosine infusion, global left ventricular myocardial blood flow was significantly less in the neuropathic subjects (204 +/- 73 ml/100 g per min) than in the nonneuropathic diabetic group (324 +/- 135 ml/100 g per min, p < 0.05). Coronary flow reserve was also decreased in the neuropathic subjects, who achieved only 46% (p < 0.01) and 44% (p < 0.01) of the values measured in nondiabetic and nonneuropathic diabetic subjects, respectively. Assessment of the myocardial innervation/blood flow relation during adenosine infusion showed that myocardial blood flow in neuropathic subjects was virtually identical to that in nonneuropathic diabetic subjects in the distal denervated myocardium but was 43% (p < 0.05) lower than that in the nonneuropathic diabetic subjects in the proximal innervated segments. CONCLUSIONS: DAN is associated with altered myocardial blood flow, with regions of persistent sympathetic innervation exhibiting the greatest deficits of vasodilator reserve. Future studies are required to evaluate the etiology of these abnormalities and to evaluate the contribution of the persistent islands of innervation to sudden cardiac death complicating diabetes.     

Total cardiac denervation in diabetic autonomic neuropathy

Total loss of the autonomic regulation of heart rate is described in a 28-year-old diabetic with extensive autonomic neuropathy. The patient had an almost fixed heart rate that barely responded to any of the tests that stimulate or inhibit the autonomic nerves. Its behavior was similar to that of the transplanted heart.     

Age-related changes in sympathetic modulation of sensory nerve activity in rat skin

OBJECTIVES: Sensory nerves play an important role in mediating neurogenic inflammation and subsequent tissue healing. A decrease in sensory nerve function with increasing age has been reported to correlate with poor tissue healing. Sympathetic nerves are known to modulate sensory nerve function, and changes in this modulation could also have important implications with ageing. The aims of this study were to examine the effect of different frequency electrical stimulation (ES) on the microvascular responses obtained to sensory nerve activation in young, aged and capsaicin-pretreated rats and modulation of these responses by sympathetic efferents. METHODS: Using laser Doppler flowmetry, vascular responses to antidromic ES of the sciatic nerve were monitored in the base of vacuum-induced blisters in the hind footpad. The non-selective alpha-adrenoceptor antagonist phentolamine (3 mg/kg, i.v.) was administered 20 min prior to ES. RESULTS: At high frequency ES (20V, 2ms, 15Hz for 1 min), the vascular response in old rats was significantly reduced (46 percent decrease, p < 0.05) compared to young control. At low frequency ES (20 V, 2 ms, 5 Hz for 1 min) however, older rats produced similar vascular responses to the young. Capsaicin-pretreated rats showed significantly reduced vascular responses to both high and low frequency ES, regardless of age. Pretreatment with phentolamine significantly increased the microvascular response in young rats at high (87 percent) and low (36 percent) frequency ES. In contrast, phentolamine significantly increased the ES-induced response in old rats at high frequency only (147 percent increase). CONCLUSIONS: The results suggest that the aged sensory nerve responds preferentially to low frequency ES and that sympathetic efferents exert an inhibitory modulatory effect on the vascular response evoked by sensory nerve stimulation. There are age-related changes in sympathetic modulation of sensory nerve-mediated responses which is dependent on stimulation frequency.     

Attenuation of regional differentiation of sympathetic nerve activity during sleep in humans

The purpose of the present study was to clarify how the regional differentiation of sympathetic nerve activity (SNA) is modified during natural sleep in humans. In humans, muscle and skin sympathetic nerve activities (MSNA, SSNA) have been reported to discharge independently according to a regional differentiation of SNA during wakefulness. However, in natural sleep, MSNA and SSNA have been documented to synchronize during sleep stage 2 (Rechtschaffen and Kales). In the present study, we measured MSNA and SSNA simultaneously using a double recording technique of microneurography in eight healthy volunteers during natural sleep, and analyzed how MSNA and SSNA can be synchronized. We found that the synchronicity of MSNA and SSNA was accelerated in correlation with the deepening of the non-rapid eye movement (nonREM) sleep stages. We also documented that the burst properties of MSNA different from those of SSNA in wakefulness become similar to those of SSNA in the sleep stage, and MSNA synchronizes with SSNA. The synchronicity of MSNA and SSNA is presumably caused by a reduced effect of central inhibitory baroreflex pathways on MSNA during nonREM sleep. The present findings suggest that the regional differentiation of sympathetic nerve activity is attenuated with the deepening of nonREM sleep stages.     

24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients

A retrospective review was performed to determine "crankshaft" prevalence in 86 immature patients who underwent posterior spinal fusion for idiopathic scoliosis. Tanner stage, chronologic age, bone age, and epiphyseal status were used as maturity indicators. Overall, 62 (72%) patients progressed < or = 10 degrees, 18 (21%) patients progressed 11-15 degrees, and six (7%) patients progressed > or = 16 degrees in the coronal plane. Tanner I patients with open triradiate cartilage had the highest rate of crankshaft occurrence; nine (75%) of 12 patients progressed >10 degrees (p < 0.05). Fifty-two percent of Tanner I, 26% of Tanner II, 11% of Tanner III, and no Tanner IV patients progressed >10 degrees (p < 0.05). Cobb angle increases of >10 degrees degrees occurred in 54% of patients with open triradiate cartilage (p < 0.05) and in 48% of patients with open capital femoral epiphyses (p < 0.05). Anterior and posterior spinal fusion should be considered in prepubertal (Tanner I) patients with open triradiate cartilage.     

Impact of systemic depulsation on tissue perfusion and sympathetic nerve activity

BACKGROUND: We postulated that pathophysiologic processes under nonpulsatile circulation are related to the behavior of the sympathetic nerve activity that regulates tissue perfusion. METHODS: Pulsatile and nonpulsatile pumps were installed in parallel in the left heart bypass circuit of anesthetized goats (n = 9) so that pulsatile circulation could be converted to nonpulsatile circulation instantly. At 5 minutes before and after systemic depulsation, we measured hemodynamic indices, renal nerve activity, and regional blood flow of the brain, heart, and renal cortex. RESULTS: Renal nerve activity was significantly elevated after systemic depulsation (15.6 +/- 9.3 versus 19.4 +/- 9.8 microV), when mean aortic pressure remained almost constant. The renal cortical flow was significantly reduced after depulsation (3.61 +/- 1.23 versus 2.93 +/- 1.19 mL.min-1.g-1), whereas no significant difference was found in the regional blood flow of the brain or the heart. CONCLUSIONS: The significant reduction of renal cortical blood flow after systemic depulsation is associated with a significant increase in renal nerve activity. Our results suggest that increased renal nerve activity plays an important role in the reduction of renal function after systemic depulsation.     

Effects of amlodipine and nifedipine retard on autonomic nerve activity in hypertensive patients

1. The effects of 1,4-dihydropyridine calcium antagonists with different biological half-lives, amlodipine and nifedipine retard on 24 h blood pressure (BP), heart rate (HR) and autonomic nerve activity in patients with essential hypertension were compared. 2. Twenty patients (six men and 14 women; mean (+/- SEM) age 63 +/- 2 years) with essential hypertension were enrolled in the present study. Their ambulatory BP and electrocardiograms were monitored for 24 h at intervals of 30 min with a portable recorder after a 4 week drug-free period, after a 4 week treatment period with amlodipine (2.5 or 5 mg once daily) and after a 4 week treatment period with nifedipine retard (10 or 20 mg twice daily). The order of the three periods was randomized. Autonomic nerve activity was evaluated by power spectral analysis of HR variability, using the high frequency (HF) component as an index of parasympathetic activity and the ratio of the low frequency (LF) to the HF component as an index of sympathovagal balance. 3. Amlodipine and nifedipine retard significantly lowered the 24 h BP to a similar extent (amlodipine: -12.7 +/- 2.6/-5.6 +/- 1.4 mmHg, P < 0.01/P < 0.01; nifedipine retard: -15.1 +/- 2.1/-6.9 +/- 1.5 mmHg, P < 0.01/P < 0.01). Amlodipine did not change the 24 h average HR, while nifedipine retard significantly increased it (+3.3 +/- 1.2 b.p.m., P < 0.05). Amlodipine also did not change the HF component or the ratio of the LF to the HF component. However, nifedipine retard significantly decreased the HF component (P < 0.01) and increased the ratio of the LF to the HF component (P < 0.05). 4. These results suggest that nifedipine retard caused a decrease in parasympathetic activity and an increase in sympathetic activity with reflex tachycardia in these patients with essential hypertension, while amlodipine did not produce such effects on the autonomic nervous system.