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Cardiovascular, metabolic, and hormonal responses to noradrenaline in diabetic patients with autonomic neuropathy.

Denervation hypersensitivity is a well-known phenomenon in patients with autonomic failure. In diabetic autonomic neuropathy hypersensitivity to beta-adrenergic stimulation has been demonstrated. We infused noradrenaline, mainly an alpha-adrenoceptor agonist, in three escalating doses (0.5, 2.5, and 5 micrograms min-1) in three age and sex matched groups of eight subjects: healthy volunteers, diabetic patients with and without autonomic neuropathy. During steady state in each infusion period we measured heart rate, blood pressure, cardiac output, hepato-splanchnic blood flow, vascular resistance, glucose kinetics, metabolites (beta-hydroxybuturate, glycerol, and lactate), and glucoregulatory hormones (noradrenaline, adrenaline, growth hormone, pancreatic polypeptide, cortisol, and insulin). Systolic and mean blood pressure increased in all groups but diabetic patients with autonomic neuropathy showed a significantly higher increase (p < 0.01) than the other two groups, with a lower threshold for increase in blood pressure. Cardiac output, hepato-splanchnic blood flow, vascular resistance, and heart rate did not change in any of the groups. The incremental increase in glucose and beta-hydroxybuturate was higher in patients with autonomic neuropathy. Otherwise, only minor changes were seen in hormonal and metabolic parameters. The cardiovascular hypersensitivity seen in diabetic autonomic neuropathy was mainly explained by increased peripheral vascular resistance, which increased significantly (p < 0.05) more in these patients. In conclusion, diabetic patients with autonomic neuropathy show denervation hypersensitivity to alpha-adrenergic stimulation by noradrenaline, especially as regards cardiovascular effects.

3-Hydroxybutyric Acid↗

Trigeminal antidromic vasodilatation and plasma extravasation in the rat: effects of sensory, autonomic and motor denervation.

The cutaneous vasodilatation and plasma extravasation observed following antidromic stimulation of trigeminal sensory branches in the rat are reduced by atropine. The atropine-sensitive component does not originate from the seventh cranial nerve (facial nerve) or from the mental nerve, because after chronic section of these nerves an atropine-sensitive component persists. The cholinergic component of the plasma extravasation is abolished by chronic bilateral extirpation of the superior cervical ganglia but this is not the case for the vasodilatation. Our data suggest that trigeminal sensory fibres are not the only fibres involved in these vascular responses seen in the lower lip of the rat after electrical stimulation of the mental nerve.

Animals↗

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.

Adult↗

Autonomic nervous system and arrhythmias: studies in the transplanted denervated human heart.

The function of the cardiac autonomic nervous system (ANS) was evaluated by comparison of normal subjects with cardiac transplant recipients. By use of standard intracardiac His bundle recording techniques, the following conclusions regarding basic cardiac electrophysiology were drawn: (1) the sinus node functions normally at rest despite autonomic denervation; (2) the AV node does not show the expected decrease in functional refractory period with increased heart rate in the denervated state, and (3) the adrenergic receptor of the cardiac conduction system does not depend upon autonomic innervation to function normally. Electrophysiologic studies of digitalis demonstrated: (1) in therapeutic doses, the AV nodal blocking effect of digitalis is autonomically mediated; (2) sinus node slowing by digitalis also requires an intact autonomic innervation. Arrhythmia analysis in 47 transplant patients revealed an increased incidence of ventricular arrhythmias in autonomic cardiac denervation. In addition, sudden death in the ischemic denervated heart does occur, weakening the concept of a primary role of the cardiac ANS in this phenomenon.

Arrhythmias, Cardiac↗

Cardiovascular and catecholamine changes induced by supine exercise and upright posture in vasovagal syncope. Comparisons with normal subjects and subjects with sympathetic denervation.

The haemodynamic and catecholamine responses to supine leg exercise were studied in vasovagal syncope (n = 10), pure autonomic failure (n = 10) and in control (n = 10) subjects. With exercise, blood pressure increased in controls; with a smaller rise in vasovagal syncope, and a substantial fall in pure autonomic failure. Heart rate increased similarly in controls and vasovagal syncope, but less in pure autonomic failure. The increase in cardiac index was less in controls and pure autonomic failure than vasovagal syncope; the fall in systemic vascular resistance was greatest in pure autonomic failure, but also fell more in vasovagal syncope than controls. Plasma noradrenaline levels increased in controls; with a smaller rise in vasovagal syncope and no increase in pure autonomic failure. Plasma adrenaline levels increased in vasovagal syncope only. The blood pressure responses to standing before and after exercise were similar in controls and vasovagal syncope, with no postural blood pressure fall; in pure autonomic failure there was a greater postural blood pressure fall post exercise. In conclusion, with supine exercise, blood pressure rose in controls and vasovagal syncope, and fell in pure autonomic failure. Systemic vascular resistance fell more in vasovagal syncope and pure autonomic failure, than controls. Noradrenaline responses differed and adrenaline rose in vasovagal syncope only. Standing post exercise did not induce syncope in vasovagal syncope, but increased postural hypotension in pure autonomic failure. There are clear differences in response to exercise in vasovagal syncope and pure autonomic failure. The differences between vasovagal syncope and control subjects suggest an underlying abnormality which may predispose to vasodepression in subjects with vasovagal syncope.

Adult↗

Social and motivational functioning is not critically dependent on feedback of autonomic responses: neuropsychological evidence from patients with pure autonomic failure.

Social, emotional and motivational behaviours are associated with production of automatic bodily responses. Re-representation in the brain through feedback of autonomic and skeletomuscular arousal is proposed to underlie "feeling states". These influence emotional judgments and bias motivational decision-making and guide social interactions. Consistent with this hypothesis, dissocial behaviour and deficits on emotional and motivation tasks are associated with blunted bodily responses in patients with orbitofrontal brain lesions or developmental psychopathy. To determine the critical dependence of social and emotional behaviours on bodily responses mediated by the autonomic nervous system, we examined patients with pure autonomic failure (PAF), a peripheral denervation of autonomic neurons with onset in middle age. Compared to healthy subjects, PAF patients were unimpaired on tests of motivational decision-making (Iowa Gambling Task), recognition of emotional facial expressions, Theory of Mind Tasks and tests of social cognition. Only on a test of emotional attribution, which is perhaps more sensitive to subjective feeling states, did PAF patients score worse than the comparison group, though there was no evidence that this deficit was specific to a discrete emotion and requires further validation. These findings suggest that emotional and social functioning is not critically tied to on-going experience of autonomic arousal state, Acquisition of autonomic failure late in life may protect against maladaptive social behaviour through established behavioural responses that may be associated with central "as if" representations.

Aged↗

Changes in renal blood flow in response to sympathomimetics in the rat transplanted and denervated kidney.

BACKGROUND: Renal denervation and re-innervation may affect vascular responses to sympathomimetics, which may play a role in the maintainance of renal blood flow (RBF) following renal transplantation. The purpose of the present study was to elucidate pharmacological alteration of the renal sympathetic response following kidney transplantation. Using the rat kidney transplantation model, we focused on responses to various sympathomimetics in order to investigate the effects of sympathetic denervation and functional remodulation mechanisms in the transplanted kidney. METHODS: Male isogenic rats underwent unilateral kidney denervation or kidney transplantation accompanied by unilateral native nephrectomy. Renal blood flow was evaluated using a laser Doppler flow meter following bolus injection of 50 microg/kg dopamine and continuous infusion of 60 microg/min phenylephrine (PE) at 0, 30, 60, 90 and 240 days after transplantation as well as at 30 days after denervation. RESULTS: Bolus injection of dopamine (50 microg/kg) induced an initial reduction in RBF (that of alpha-adrenoceptors) followed by a long-lasting increase in RBF (that of beta-adrenoceptors) in the native kidney. In grafted or denervated kidneys, the dopamine-induced decrease in RBF mediated by alpha-adrenoceptors was markedly enhanced while the increase in RBF mediated by an action of dopamine on beta-adrenoceptors was blunted. The effects of the post-transplant period on vascular responses to dopamine were significant, but not completely synchronized with the native kidney, even at 240 days. Continuous infusion of PE (60 microg/min) produced a gradual increase in RBF in the native kidney, whereas a sudden reduction (i.e. breakthrough in autoregulation) was observed in the denervated and transplanted kidney. CONCLUSIONS: The responses to sympathomimetics in the grafted kidney were shifted towards flow reduction (i.e. enhanced vasoconstriction via stimulation of alpha-adrenoceptors and blunted vasodilatation via stimulation of beta-adrenoceptors. This functional impairment was recovered in a time-dependent manner. In addition, the hemodynamic autoregulation system in the kidney deteriorated following transplantation or denervation.

Animals↗

Regeneration of the hepatic nerves following surgical denervation of the liver in dogs.

This study was conducted to examine the regeneration process of hepatic nerves following surgical hepatic denervation in dogs. A denervation model was surgically created by removing all visible nerves around the hepatoduodenal ligament along with the peri-hepatic tissues. The hepatic nerves were examined on the hepatic specimens taken at 1 week, 1 month and 3 months post-denervation by means of immunohistochemical staining, and also electron microscopy. At 1 week post-denervation, the extrinsic hepatic nerves were observed not to have regenerated. However, at 1 month post-denervation, GAP-43-positive nerves were identified and regenerating axons were shown to be present on electron microscopic observation. The immunoreactivity for anti-GAP-43 antibody was not shown any longer at 3 months post-denervation, and the regenerated nerve axons were shown to be similar to those at pre-denervation on ultrastructural study. Results of the present study suggested that regeneration of the extrinsic hepatic nerves began to appear about 1 month after the hepatic denervation, and was completed by 3 months post-denervation.

Animals↗

[An animal model of surgical, external cardiac denervation. Studies of the autonomic control of heart rate].

A great role is played in clinical practice by monitoring of vegetative functions, such as heart and respiratory rates. Mean values, rhythms, and interaction of both control variables in the form of respiratory sinus arrhythmia may provide plenty of information, primarily when computerised, and may enable conclusions to be drawn as to neuro-circulatory tonus. The model described in this paper has been devised for the purpose of producing information on types of changes in neurovegetative control in response to functional systemic effects from pharmaceuticals or from substantial, locally delimited lesions of nerve structures. External cardiac denervation is applied for stepwise discontinuation of sympathetic, parasympathetic, spinal, and medullary control systems up to the stage of cerebral death, resulting in cardiac "automatism". Data may thus be derived on the Bainbridge reflex, and correlations may be established with in vitro experiments on chronotropic control of the heart. The results presented in this paper may be of relevance to situations in intensive medical care or to cases with lesions to the central nervous system up to irreversible loss of brain function, when heart rate data recorded from monitoring of the central nervous system or of vegetative functions must be interpreted in all their variability with high reliability and accuracy for differential diagnosis and prognostication.

Animals↗

Cardiac denervation and cardiovascular reactivity to psychological stress.

OBJECTIVE: This study investigated the mechanisms responsible for increases in heart rate and blood pressure during psychological stress, which are incompletely understood. Since cardiac transplant patients have denervated hearts, they provide a unique model for isolating central versus peripheral influences on the cardiovascular response to stress. METHODS: The authors compared the responses to two laboratory stressors of 20 ambulatory heart transplant recipients and two groups of normal subjects, one whose ages were matched to the ages of the transplant patients (mean = 46 years) and one whose ages were matched to the ages of the heart donors (mean = 27 years). The three groups of subjects performed mental arithmetic and reaction time tasks. RESULTS: Heart rate increase during the mental arithmetic task was significantly attenuated in the transplant recipients. During stress, stroke volume increased in the transplant recipients but decreased in both groups of comparison subjects. The difference in age between the heart recipients and donors did not account for the difference in reactivity between the heart transplant patients and the normal subjects. CONCLUSIONS: Direct neural stimulation of the heart is more important than peripherally circulating factors in producing tachycardia during psychological stress. Cardiac but not vascular responses to psychological stress are altered by cardiac denervation.

Adult↗

Influence of cerebrovascular sympathetic, parasympathetic, and sensory nerves on autoregulation and spontaneous vasomotion.

The effect of removal of cerebrovascular sympathetic, parasympathetic or sensory nerve on brain cortical blood flow and spontaneous vasomotion during changes in systemic blood pressure was studied by laser-Doppler flowmetry in anaesthetized rats. Selective section of sympathetic fibres along the internal carotid artery markedly affected the ability to autoregulate, as measured in microvessels of the middle cerebral arterial territory. Removal of the parasympathetic nerves tended to reduce the ability to autoregulate, whereas no significant influence was found after sensory denervation. Following the denervations, spontaneous vasomotion was not significantly affected in frequency or amplitude.

Adrenergic Fibers↗

Immediate effects of hepatic denervation on hepatic hemodynamics in dogs.

This study was conducted to examine the immediate effects of hepatic surgical denervation on the hepatic blood flow in anesthetized dogs. A surgical denervation model was created by removing all visible nerves around the portal vein, the hepatic artery and the bile duct along with the peri-hepatic tissues. The hepatic hemodynamics were measured pre and postoperatively in the hepatic denervation group (n = 6) and control group (n = 6). The portal venous blood flow and the hepatic tissue blood flow showed no significant differences between the two groups throughout the experiment. The hepatic arterial blood flow at 120 min after denervation (220 +/- 46 ml/min) had significantly higher than that (114 +/- 14 ml/min) in the control group (p < 0.05). These results indicate that hepatic denervation is implicated in the hepatic arterial blood flow, and the hepatic nerves play an important role in the regulation of the hepatic arterial blood flow.

Animals↗

Diabetic heart disease--current problems and their management.

Diabetic heart disease (DHD) is one of the most important contemporary management problems confronting the entire diabetic management team. DHD is multifactorial and multifaceted. The three major problems are: coronary artery disease (CAD), autonomic cardiac denervation and a specific heart muscle disease in diabetes (diabetic cardiomyopathy). Various other ancillary problems include obesity, hypertension, lipid aberrations and rheological alterations etc. CAD and diabetes mellitus (DM) have a greater association; the disease is more severe, sets in early and has many atypical features including painless, silent onset, delayed arrival at intensive coronary care unit, increased incidence of pump failure and arrhythmias and high case fatality rate. Autonomic cardiac denervation is an important and a common companion of diabetic peripheral neuropathy and has serious repercussions in DHD. Simple, sensitive screening tests may identify such a group so as to exercise caution in management. Various clinical (non-invasive, invasive and autopsy) and experimental studies provide evidence for the existence of a specific diabetic heart muscle disease comprising of small vessel disease and metabolic aberrations. Recent advances in literature and our own experience are reviewed. The practical management aspects of each facet, such as maintenance of high index of suspicion, early diagnosis and referral, close monitoring, role of rigid blood glucose control and specific role of each member of the diabetic team is outlined. The possible preventative strategies are discussed.

Autonomic Nervous System Diseases↗

Cytochrome oxidase staining in the major pelvic ganglion of the male rat.

Cytochrome oxidase staining was used as a marker of metabolic activity in neural elements in the rat major pelvic ganglion. Many neurons in the ventral pole of the ganglion have little cytochrome oxidase activity, while neurons in other locations show gradations in staining intensity. Punctate staining around principal neurons may represent preganglionic terminals, since it was greatly reduced after denervation of the ganglion. Image analysis was used to compare neuronal size to staining intensity. There was a negative correlation between cell size and staining intensity; the largest neurons were only lightly stained for cytochrome oxidase, while the medium and the small neurons showed a full range of metabolic activity. To study metabolic activity of an identified neuronal population, the seminal vesicles were injected with a retrograde tracer. The largest seminal vesicles neurons (1500 to 3200 microns2) had low enzyme activity, whereas the majority of neurons to this organ were smaller with gradations in staining. These results are indicative of the metabolic activity of the autonomic innervation to various pelvic tissues. Cytochrome oxidase histochemistry should prove valuable in assessing the demands placed on autonomic ganglia in differing functional and dysfunctional states.

Animals↗

Peptidergic innervation of the rat cornea.

Corneal nerves regulate corneal epithelial integrity, proliferation, and wound healing. The mechanisms by which the nerves mediate their effects remain poorly understood; however, the release of biologically active neuropeptides has been hypothesized. The purpose of the current investigation was to determine the relative densities, distribution patterns, and origins of rat corneal nerves containing each of eight different neuropeptides, calcitonin gene-related peptide (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), methionine-enkephalin (M-ENK), vasoactive intestinal polypeptide (VIP), somatostatin (SOM), and cholecystokinin (CCK). In the first set of experiments, immunohistochemical demonstrations of the above neuropeptides were performed on free-floating corneal sections cut tangential to the corneal surface. The results showed that six of the peptides, CGRP, SP, GAL, NPY, M-ENK, and VIP were present in rat corneal nerves. The innervation patterns of corneal nerves containing each of these six peptides were then documented by mapping all fibers in serial sections from select corneal quadrants onto a series of line drawings by using a drawing tube. In the second set of experiments, the origins of the corneal peptidergic nerve fibers were determined by selective ocular denervations. Unilateral combined sensory and sympathetic ocular denervations or unilateral sympathetic ocular denervations were performed in adult rats by transecting the ophthalmomaxillary nerve and/or removing the superior cervical ganglion. After 5-7 days, each of the ipsilateral corneas was sectioned and processed immunohistochemically for the presence of one of the six peptides found in experiment one, and the fibers that survived the ocular denervations were plotted onto line drawings. Ocular denervations revealed that corneal peptidergic nerves have sensory (CGRP, SP, and GAL), sympathetic (NPY), and parasympathetic (GAL, NPY, M-ENK, and VIP) origins. The results of this investigation have shown that the peptidergic innervation of the rat cornea is more extensive and complex than previously reported. This is the first investigation to show the presence of GAL in the rat cornea, and the first to demonstrate the presence of NPY-, VIP-, and M-ENK-IR nerve fibers in the cornea of any species.

Animals↗

Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy.

OBJECTIVE: The calcineurin pathway has been involved in the development of cardiac hypertrophy, yet it remains unknown whether calcineurin activity can be regulated in myocardium independently from hypertrophy and cardiac load. METHODS: To test that hypothesis, we measured calcineurin activity in a rat model of infrarenal aortic constriction (IR), which affects neurohormonal pathways without increasing cardiac afterload. RESULTS: In this model, there was no change in arterial pressure over the 4-week experimental period, and the left ventricle/body weight ratio did not increase. At 2 weeks after IR, calcineurin activity was increased 1.8-fold (P<0.05) and remained elevated at 4 weeks (1.7-fold, P<0.05). Similarly, the cardiac activity of calcium calmodulin kinase II (CaMKII) was increased significantly after IR, which confirms a regulation of Ca(2+)-dependent enzymes in this model. In cardiac myocytes, the increased activity of calcineurin was accompanied by a significant decrease in L-type Ca(2+) channel activity (I(Ca)) and contraction velocity (-dL/dt). Cardiac denervation prevented the activation of calcineurin after IR, which demonstrates that a neurohormonal mechanism is responsible for the changes in enzymatic activity. In addition, cardiac denervation suppressed the effects of IR on I(Ca) and -dL/dt, which shows that calcineurin activation is related to altered contractility. However, action potential duration, the densities of inward rectifier K(+) currents (I(K1)), and outward K(+) currents (I(to) and I(K)) were not altered in IR myocytes. CONCLUSIONS: Calcineurin can be activated in the heart through a neural stimulus, which induces alterations in Ca(2+) currents and contractility. These effects occur in the absence of myocyte hypertrophy, electrophysiological changes in action potential, and K(+) channel currents.

Animals↗