Role of the amygdaloid cholecystokinin (CCK)/gastrin-2 receptors and terminal networks in the modulation of anxiety in the rat. Effects of CCK-4 and CCK-8S on anxiety-like behaviour and [3H]GABA release.

The amygdala plays a key role in fear and anxiety. The intercalated islands are clusters of glutamate-responsive GABAergic neurons rich in cholecystokinin (CCK)-2 receptors which control the trafficking of nerve impulses from the cerebral cortex to the central nucleus of amygdala. In this study, the nature of the CCK-glutamate-GABA interactions within the rat rostral amygdala, and their relevance for anxiety, were studied. CCK/gastrin-like immunoreactive nerve terminals were found to be mainly restricted to the paracapsular intercalated islands and the rostrolateral part of the main intercalated island. Behaviourally, the bilateral microinjection of CCK-4 (0.043-4.3 pmol/side) or CCK-8S (4.3 pmol/side) into the rostrolateral amygdala reduced the open-arm exploration in the elevated plus-maze without affecting locomotion. In contrast, neither CCK-4 nor CCK-8S (0.043-4.3 pmol/side) had any effects in the shock-probe burying test as compared with their saline-treated controls. Biochemically, CCK-4 (0.3 and 1.5 microm), unlike CCK-8S, enhanced significantly the K(+)-stimulated release of [(3)H]GABA from amygdala slices. These effects were fully prevented by prior superfusion of the slices with either the selective CCK-2 receptor antagonist CR2945 (3 microm), or 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX), 10 microm, a glutamatergic (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist. It is suggested that CCK modulates glutamate-GABA mechanisms by acting on CCK-2 receptors via volume transmission occurring at the level of the basolateral amygdaloid nucleus and/or by synaptic or perisynaptic volume transmission in the region of the rostrolateral main and paracapsular intercalated islands, resulting in subsequent disinhibition of the central amygdaloid nucleus and anxiety or panic-like behaviour.

The nerve supply of the lumbar intervertebral disc.

The anatomical studies, basic to our understanding of lumbar spine innervation through the sinu-vertebral nerves, are reviewed. Research in the 1980s suggested that pain sensation was conducted in part via the sympathetic system. These sensory pathways have now been clarified using sophisticated experimental and histochemical techniques confirming a dual pattern. One route enters the adjacent dorsal root segmentally, whereas the other supply is non-segmental ascending through the paravertebral sympathetic chain with re-entry through the thoracolumbar white rami communicantes. Sensory nerve endings in the degenerative lumbar disc penetrate deep into the disrupted nucleus pulposus, insensitive in the normal lumbar spine. Complex as well as free nerve endings would appear to contribute to pain transmission. The nature and mechanism of discogenic pain is still speculative but there is growing evidence to support a 'visceral pain' hypothesis, unique in the muscloskeletal system. This mechanism is open to 'peripheral sensitisation' and possibly 'central sensitisation' as a potential cause of chronic back pain.

Relationship between plasma norepinephrine at peak exercise and 123I-MIBG imaging of the heart and lower limbs in heart failure.

BACKGROUND: Past studies suggested that plasma norepinephrine during exercise originates in sympathetic nerve endings and that the main origin differs among pathophysiological conditions. AIMS: This study investigated the most important site of sympathetic terminals as an origin of plasma norepinephrine during exercise in patients with heart failure using (123)I- metaiodobenzylguanidine (MIBG) scintigraphy. METHODS AND RESULTS: Twenty patients with organic heart disease underwent exercise testing and (123)I-MIBG scintigraphy. Systemic (123)I-MIBG uptake was measured 4 hours after (123)I-MIBG injection, and the heart-to-brain (H/B) and lower limb-to-brain ratios (L/B) were calculated. Plasma norepinephrine concentration was measured at rest and at peak exercise. Subjects were divided into two groups: those with preserved left ventricular ejection fraction (LVEF> or =45%, n=8) and those with reduced LVEF (<45%, n=12). Plasma norepinephrine at rest did not correlate with H/B or L/B. In the preserved LVEF group, plasma norepinephrine at peak exercise was correlated with H/B (r=0.722), but not with L/B. In the reduced LVEF group, the norepinephrine response to peak exercise correlated with L/B (r=0.642), but not with H/B. CONCLUSION: The present findings suggest that norepinephrine concentration is regulated by sympathetic terminal function of working muscles in patients with impaired LVEF and by that of the heart in patients with preserved LVEF.

Fistula in ano surgery has no impact on pudendal nerve terminal motor latency.

BACKGROUND: Anal fistula surgery is recognized as a major risk factor for anal incontinence. This incontinence is mainly due to surgical sphincter lesions, although a neurogenic mechanism through damage to the pudendal nerve is not excluded. The objective of our study was to evaluate the influence of anal surgery on the anal terminal motor latency of the pudendal nerve (PNTML). MATERIALS AND METHODS: The PNTML values were measured pre- and postoperatively, respectively, in 33 patients (28 men, 5 women) treated for anal suppuration and 34 patients (21 men, 13 women) undergoing pedicular hemorrhoidectomy using the Milligan and Morgan technique. RESULTS: The average age was 49.6 years in the hemorrhoid group and 45 years in the fistula group (p=0.19). There was no difference in the sex ratio between the two groups (p=0.06). In the anal fistula group, the preoperative mean PNTML was 2.42 (+/-0.46) ms on the infected side and 2.40 (+/-0.42) ms on the healthy side, with a significant difference from the control group's preoperative ipsilateral latencies: 2.73 (+/-0.60) ms (p=0.02, p=0.01). The variations in the postoperative PNTML of the fistula group, both on the healthy side (DeltaPNTML=0.06+/-0.42 ms) and on the diseased side (DeltaPNTML=0.03+/-0.40 ms), are comparable with those of the hemorrhoid group (DeltaPNTML=0.01+/-0.48 ms; p=0.63, p=0.84). CONCLUSION: The nervous conduction of the pudendal nerves does not seem to be altered by the presence of an infectious process in the ischiorectal fossa nor by the surgical procedure. However, a more refined electrophysiological study would seem to be necessary to assess the repercussions on the perineal innervation.

[Neuroanatomic basis for discogenic pain]. / Neuroanatomische Grundlagen des diskogenen Schmerzes.

AIMS: The aim of this study is to give a short overview about the innervation of the intervertebral disc and the nerve connections between the somatosensible and autonomous nervous systems in the paravertebral region. METHODS: A short review of the clinical and experimental literature including gross-anatomical, histochemical and immunohistochemical studies as well as functional studies after application of tracer substances has been made. We also present our own experimental immunohistochemical and molecular biological investigations on paravertebral muscle biopsies of a patient with post-discotomy syndrome. RESULTS: The annulus fibrosus of the intervertebral disc is innervated by myelinated nerve fibres. Neuronal markers for pain-leading fibres were found to be positive in the dorsal region of the annulus, and especially in the posterior longitudinal ligament. Nerve ingrowth into the diseased intervertebral disc was found in chronic back pain. The main innervation of the intervertebral disc is formed by the sinuvertebral nerves. The sinuvertebral nerves are recurrent branches of the ventral rami that re-enter the intervertebral foramina to be distributed within the vertebral canal. They are mixed polysegmental nerves and nerve plexuses, each being formed by a somatic root from a ventral ramus and an autonomic root from a grey ramus communicans. The number of nerve bundles was reduced by resection of sympathetic trunks. The expression of neuronal markers in the sarcolemma of the paravertebral muscles is reduced after discotomy. CONCLUSIONS: The neuroanatomical basis of discogenic pain can be summarised as follows: 1. The intervertebral disc receives an extensive innervation, especially the annulus fibrosus. 2. Nerve extension was found into the nucleus pulposus of the degenerated disc. 3. The sinuvertebral nerve plexuses facilitate a polysegmental signal and pain spreading. 4. The innervation of the intervertebral disc is very high connected with the paravertebral muscles. 5. A local denervation of the paravertebral muscles was found in post-discotomy syndrome.

Treatment of end-neuromas, neuromas-in-continuity and scarred nerves of the digits by proximal relocation.

This paper reports the results of treatment by proximal relocation of 104 painful nerves in 57 digits in 48 patients. These included 86 digital nerves and 18 terminal branches of the superficial radial nerve and the dorsal branch of the ulnar nerve. Eighty-three were end-neuromas and 14 were neuromas-in-continuity, of which nine followed nerve repair and five occurred following a closed crush injury. Seven were painful as a result of tethering in scarred tissue. Eighty nerves (77%) required a single relocation and 24 (23%) required more than one operation. Ninety-eight per cent of nerve relocations achieved complete pain relief at the primary site. One patient had mild pain on pressure at the primary site after relocation of two nerves from this site. Over 90% of the nerves had no spontaneous pain, pain on movement or hypersensitivity of the overlying skin at the final site of relocation. However, the incidence of mild or no pain on direct pressure at the site of nerve relocation was lower at 83% as relocated nerves, although traumatized less often at the sites chosen for relocation, can still be painful on direct pressure.

Morphometric characterization of the neuromuscular junction of rodents intoxicated with 2,4-dithiobiuret: evidence that nerve terminal recycling processes contribute to muscle weakness.

2,4-Dithiobiuret (DTB) causes ascending motor weakness when given chronically to rodents. In muscles of animals with DTB-induced weakness, quantal release of acetylcholine (ACh) is impaired. We examined in detail the structural changes that occurred at neuromuscular junctions and their associated Schwann cells of extensor digitorum longus (EDL) muscles of male rats treated with DTB to the onset of muscle weakness, 5-8 days. Our objective was to assess the involvement of the Schwann cells and to determine the most likely primary targets of DTB. At the onset of muscle weakness, nerve terminals exhibited some enlarged regions, but did not sprout. Terminal Schwann cells became flatter and expanded to cover most of the endplate. The extent of invasion of the synaptic cleft by Schwann cell processes was not significantly different from controls; extension of Schwann cell sprouts away from the junction was not seen. Thus, the morphology of the Schwann cells, although clearly affected by DTB, does not suggest that they contribute directly to the physiological defects of DTB-treated terminals. Abnormal tubulovesicular structures or tangles of neurofilaments were clustered in the centers of about 25% of treated terminals. Fewer synaptic vesicles occupied the region opposite the postsynaptic folds. Vesicle volumes were variable and included some very large vesicles, corresponding with the variable MEPP amplitudes reported previously for terminals of DTB-treated rodents. The postsynaptic area stained by rhodamine-labeled alpha-bungarotoxin expanded with terminal swelling, apparently by unpleating of the postsynaptic folds. No loss of ACh receptors or spread of ACh receptors beyond terminal boundaries was detected. Morphometric data are consistent with the conclusion that DTB affects, either directly or indirectly, vesicular release of ACh and the subsequent vesicular recycling process.

Nerve fibres are required to evoke a contact sensitivity response in mice.

Previous work has indicated that the dermis and epidermis of skin contains abundant nerve fibres closely associated with Langerhans' cells. We have investigated whether these nerve endings are necessary for inducing and evoking a contact sensitivity (CS) response. Topical application of a general or a peptide (calcitonin gene-related peptide and substance P)-specific neurotoxin was employed to destroy the nerve fibres at skin sites subsequently used to induce or evoke the CS response. Elimination of nerve fibres abolished both induction and effector stages of the specific CS response. Denervation did not destroy the local Langerhans' cells, which were observed in increased numbers, or prevent them from migrating to lymph nodes. The local CS response was also abolished by systemic deletion of capsaicin-sensitive nerve fibres, suggesting that the loss of response was not non-specific but associated with the loss of specific nerve fibres. The results indicate that peptidergic nerve fibres are required to elicit a CS response and may be vital to the normal function of the immune system.

Capsaicin treatment inhibits osteopenia and heat hyperalgesia induced by chronic constriction injury to the sciatic nerve in rats.

Chronic constriction injury (CCI) to the rat sciatic nerve results in osteopenia in the affected hind limb. One possible mechanism for this osteopenia is neurogenic inflammation, in which neuropeptides, represented by substance P (SP), are involved. We attempted to determine whether capsaicin treatment, which can deplete SP from nerve terminals, is effective in inhibiting osteopenia induced by CCI. Capsaicin (total dose, 125 mg/kg) or the vehicle alone was given intraperitoneally to adult rats 2 days before (Experiment 1) and 7 days after (Experiment 2) CCI surgery. Paw withdrawal latency (PWL) was measured prior to and every week for 5 weeks after surgery. Bone mineral density (BMD) and the number of osteoclasts in tibial bones were determined 5 weeks after surgery. In rats treated with the vehicle, BMD on the CCI side was decreased significantly, while the number of osteoclasts was significantly increased in both experiments. Capsaicin treatment either before or 1 week after surgery inhibited the decreases in BMD as well as the increase in the number of osteoclasts on the CCI side. PWL for the CCI side in the vehicle group was significantly shorter than for the sham side in both experiments. However, capsaicin treatment before surgery resolved heat hyperalgesia in Experiment 1, while in Experiment 2, even though heat hyperalgesia developed on the CCI side, it was resolved by capsaicin treatment. The results of the present study show that capsaicin inhibits the development of osteopenia as well as heat hyperalgesia induced by CCI. They also support our hypothesis that neurogenic SP release is involved in the pathogenesis of bony changes induced by CCI.

Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn.

Abnormal or excessive activity related to pain and injury in early life may alter normal synaptic development and lead to changes in somatosensory processing. The aim of the current study was to define the critical factors that determine long-term plasticity in spinal cord afferent terminals following neonatal inflammation. Hindpaw inflammation was produced in neonatal rat pups with 5 or 25 microl 2% carrageenan, and 5 or 25 microl complete Freund's adjuvant (CFA). All groups displayed a clear inflammatory response that recovered in 2 weeks in all but the 25 microl CFA group, who had persistent chronic inflammation confirmed by histological examination of the paw at 8 weeks. The 25 microl CFA group was also the only group that displayed a significant expansion of the sciatic and saphenous nerve terminal field in lamina II of the dorsal horn at 8 weeks, using wheat-germ agglutinin-horse radish peroxidase transganglionic labelling. This effect was not accompanied by changes in dorsal root ganglion (DRG) cell number, expression of activating transcription factor 3 (ATF3), or alterations in calcitonin gene related peptide (CGRP) or isolectin B4 binding; and was not mimicked by partial nerve damage. No long-term change in mechanical or thermal behavioural sensory thresholds was seen in any group. Lower dose CFA caused an acute, reversible expansion of terminal fields in lamina II in neonatal animals, while CFA did not produce this effect in adults. The duration and effect of neonatal inflammation is therefore dependent on the type and volume of inflammatory agent used. The expansion of afferent terminals in lamina II following neonatal CFA inflammation is maintained into adulthood if the inflammation is also maintained, as seen following 25 microl CFA. This effect is not seen in adult animals, emphasising the plasticity of the nervous system early in development.

Effects of anterior lumbar spinal fusion on the distribution of nerve endings and mechanoreceptors in the rabbit facet joint: quantitative histological analysis.

The purpose of this study was to investigate the density and distribution of neural endings in rabbit lumbar facet joints after anterior spinal fusion and to evaluate the effects of intervertebral immobilization. An extraperitoneal approach was applied, and L5/6 was fixed with a plate and screws. Bilateral L4/5, L5/6, and L6/7 facet joint capsules were harvested from the rabbits 4, 8, and 16 weeks postoperatively. Capsular tissues were processed using a modified gold chloride staining method, and the specimens were sliced into 15-micro m sections. All sections were analyzed microscopically, and neural ending numbers per unit volume were calculated. Three types of neural ending were identified in each specimen: Pacinian corpuscles, Ruffini corpuscles, and free nerve endings. In the L5/6 fusion segment there was a significant decrease in the number of Pacinian corpuscles at 4 weeks and of Ruffini corpuscles at 4, 8, and 16 weeks after the fusion compared with the control; and in the L4/5 upper adjacent segment there was a significant increase in the number of free nerve endings. The number of Ruffini endings for the L6/7 lower adjacent segment was significantly lower more than 8 weeks after the fusion. These results suggest that immobilization of the intervertebral segment causes a reduction in the number of mechanoreceptors in the facet joint capsules because of the reduction in mechanical stimulation. Moreover, in the upper adjacent facet joint there may be neural sprouting caused by nociceptive stimulation.

Acute limb ischemia does not facilitate but inhibits norepinephrine release from muscle sympathetic nerve endings in anesthetized rabbit.

Although myocardial ischemia is associated with regional cardiac sympathetic nerve deterioration, it remains unknown whether acute hindlimb ischemia impairs muscle sympathetic nerve function. In the study presented here we implanted dialysis probes in the adductor muscle of anesthetized rabbits and measured dialysate norepinephrine levels as an index of muscle sympathetic nerve activity. Acute hindlimb ischemia was induced by injection of microspheres and occlusion of the common iliac artery. Dialysate norepinephrine levels decreased from 19.3 +/- 3.5 pg/ml at control to 9.4 +/- 3.7 pg/ml at 30 min of ischemia and further to 1.7 +/- 0.2 pg/ml at 75 min of ischemia. During acute hindlimb ischemia, baroreflex (bilateral carotid occlusion) and high potassium level-induced norepinephrine response was inhibited, but tyramine-induced norepinephrine response was preserved. In conclusion, acute hindlimb ischemia caused decreases in dialysate norepinephrine levels. This reduction may be mediated by an impairment of axonal conduction and/or of norepinephrine releasing function at skeletal muscle sympathetic nerve endings.

Loss and sprouting of nitric oxide synthase neurons in the human epileptic hippocampus.

PURPOSE: Nitric oxide (NO) has been implicated in a variety of functions, including the control of synaptic plasticity and sensory signaling. Current evidence suggests that this unconventional neurotransmitter mediates N-methyl-d-aspartate (NMDA) receptor-linked excitotoxicity. This study describes the expression of neuronal NO synthase (nNOS) immunoreactivity (IR) in hippocampi from patients with temporal lobe epilepsy (TLE). METHODS: Hippocampi from patients with clinical symptoms, neuroimaging, and EEG typical of hippocampal sclerosis (HS; n = 22) were compared with those from patients with neocortical temporal lesions (NONHS; n = 4) and autopsy (AUT; n = 18) patients for total cells, and nNOS-IR neuron and puncta densities. RESULTS: Compared with AUT, HS hippocampi had significantly less nNOS-IR neuron densities in the fascia dentata (FD); hilus, and CA4, CA3, CA2, and CA1 subfields. HS hippocampi had significantly greater nNOS-IR puncta densities in the FD, as compared with AUT and NONHS. CONCLUSIONS: Our results show that hippocampi from TLE patients exhibit a loss of nNOS-IR neurons and an abnormal FD innervation. The release of NO can influence the dynamics of ionic channels and neurotransmitter release, thus affecting neuronal membrane potential. Because the NOergic transmission does not obey the topographic constraints imposed on conventional transmitters, target cells can be stimulated even in regions with severe deafferentation. The plastic changes described here may contribute to abnormal hippocampal excitability.

Effects of moderate hypothermia on in situ cardiac sympathetic nerve endings.

Although hypothermia is known to alter neuronal control of circulation, it has been uncertain whether clinically used hypothermia (moderate hypothermia) affects in situ cardiac sympathetic nerve endings. We examined the effects of moderate hypothermia on cardiac sympathetic nerve ending function in anesthetized cats. By use of a cardiac dialysis technique, we implanted dialysis probes in the midwall of the left ventricle and monitored dialysate norepinephrine (NE) levels as an index of NE output from cardiac sympathetic nerve endings. Hypothermia (27.0+/-0.5 degrees C) induced decreases in dialysate NE levels. Dialysate NE levels did not return to the control level at normothermia after rewarming. Dialysate NE response to inferior vena cava occlusion was attenuated at hypothermia but restored at normothermia after rewarming. Dialysate NE response to high K(+) (100 mM) was attenuated at hypothermia and was not restored at normothermia after rewarming. Hypothermia induced increases in dialysate dihydroxyphenylglycol (DHPG) levels. There were no differences in desipramine (neuronal NE uptake blocker, 10 microM) induced increment in dialysate NE level among control, hypothermia, and normothermia after rewarming. However, hypothermia induced an increase in DHPG/NE ratio. These data suggest that hypothermia impairs vesicle NE mobilization rather than membrane NE uptake. We conclude that moderate hypothermia suppresses exocytotic NE release via central mediated reflex and regional depolarization.

Functional immunohistochemistry of neuropeptides and nitric oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental migraine model.

The supratentorial cerebral dura of the albino rat is equipped with a rich sensory innervation both in the connective tissue and around blood vessels, which includes nociceptive axons and their terminals; these display intense calcitonin gene-related peptide (CGRP) immunoreactivity. Stereotactic electrical stimulation of the trigeminal (Gasserian) ganglion, regarded as an experimental migraine model, caused marked increase and disintegration of club-like perivascular CGRP-immunopositive nerve endings in the dura mater and induced an apparent increase in the lengths of CGRP-immunoreactive axons. Intravenous administration of sumatriptan or eletriptan, prior to electrical stimulation, prevented disintegration of perivascular terminals and induced accumulation of CGRP in terminal and preterminal portions of peripheral sensory axons. Consequently, immunopositive terminals and varicosities increased in size; accumulation of axoplasmic organelles resulted in the "hollow" appearence of numerous varicosities. Since triptans exert their anti-migraine effect by virtue of agonist action on 5-HT(1D/B) receptors, we suggest that these drugs prevent the release of CGRP from perivascular nerve terminals in the dura mater by an action at 5-HT(1D/B) receptors. Nitroglycerine (NitroPOHL), given subcutaneously to rats, induces increased beading of nitric oxide synthase (NOS)-immunoreactive nerve fibers in the supratentorial cerebral dura mater, and an apparent increase in the number of NOS-immunoreactive nerve fibers in the dural areas supplied by the anterior and middle meningeal arteries, and the sinus sagittalis superior. Structural alterations of nitroxidergic axons innervating blood vessels of the dura mater support the idea that nitric oxide (NO) is involved in the induction of headache, a well-known side effect of coronary dilator agents.

Exteroceptive suppression periods and pericranial muscle tenderness in chronic tension-type headache: effects of psychopathology, chronicity and disability.

We examined pericranial muscle tenderness and abnormalities in the second exteroceptive suppression period (ES2) of the temporalis muscle in chronic tension-type headache (CTTH; n = 245) utilizing a blind design and methods to standardize the elicitation and scoring of these variables. No ES2 variable differed significantly between CTTH sufferers and controls (all tests, P>0.05). We found no evidence that CTTH sufferers with daily or near daily headaches, a mood or an anxiety disorder, or high levels of disability exhibit abnormal ES2 responses (all tests, P>0.05). CTTH sufferers were significantly more likely than controls to exhibit pervasive tenderness in pericranial muscles examined with standardized (500 g force) manual palpation (P<0.005). Female CTTH sufferers exhibited higher levels of pericranial muscle tenderness than male CTTH sufferers at the same level of headache activity (P<0.0001). Elevated pericranial muscle tenderness was associated with a comorbid anxiety disorder. These findings provide further evidence of pericranial hyperalgesia in CTTH and suggest this phenomenon deserves further study. Basic research that better elucidates the biological significance of the ES2 response and the factors that influence ES2 assessments appears necessary before this measure can be of use in clinical research.

ACE inhibition improves cardiac NE uptake and attenuates sympathetic nerve terminal abnormalities in heart failure.

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial beta-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial beta-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced beta-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial beta-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.

Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure.

The integrative mechanisms of autonomic dysfunction in congestive heart failure (CHF) remain poorly understood. We sought to study cardiac retention of [11C]hydroxyephedrine (HED), a specific tracer for sympathetic presynaptic innervation, and its functional correlates in CHF. Thirty patients with mild to moderate heart failure underwent resting cardiac HED positron emission tomography imaging, spectrum analysis testing of systolic pressure and heart rate variability in the resting supine and 70 degrees head-up tilt positions, and testing of baroreflex sensitivity. Compared with control subjects, global myocardial HED retention index was reduced by 30% (p <0.01) in patients with CHF. The HED retention index did not correlate significantly with heart rate variability. However, it correlated with baroreflex sensitivity at rest (r = 0.43, p = 0.05) and with systolic pressure low-frequency (0.03 to 0.15 Hz) variability at head-up tilt (r = 0.76, p <0.01), as well as with low-frequency systolic pressure variability response from baseline to tilt (r = 0.75, p <0.01). We conclude that cardiac HED retention is reduced in patients with CHF. This correlates with blunted vascular sympathetic effector responses during posture-induced reflex activation and baroreflex control of heart rate, suggesting an interdependence between cardiac presynaptic innervation abnormalities and neural mechanisms important to blood pressure maintenance in CHF.