Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses.

Incidentally discovered adrenal masses are common and mostly benign and non-functioning adenomas. However, evolving evidence suggests that a notable proportion of these adrenal adenomas may demonstrate mild autonomous cortisol secretion (MACS), which has been associated with an increased risk for hypertension, hyperglycemia, obesity, dyslipidemia, vertebral fractures, adverse cardiovascular events, and mortality. Therefore, it is advised that all patients with an incidentally discovered adrenal mass be tested for MACS. When there is convincing evidence for MACS, surgical adrenalectomy has been associated with an improvement in certain metabolic parameters and a reduction in vertebral fractures; however, conclusive evidence demonstrating decreased cardiovascular outcomes or mortality are not yet available. Future studies with adequate randomization and follow-up to assess adverse clinical endpoints are needed to determine the optimal management and follow-up of patients with MACS.

Phosphorylated Alpha-Synuclein Within Cutaneous Autonomic Nerves of Patients With Parkinson's Disease: The Implications of Sample Thickness on Results.

The detection of cutaneous phosphorylated alpha-synuclein (P-syn) in patients with Parkinson's disease (PD) has ranged from 30% to 100% across different studies. We hypothesize that part of the variability in P-syn detection is due to methodological differences using sections of different tissue thickness. Three skin biopsies were obtained from 29 individuals with PD and 21 controls. Tissues were cut into 10-, 20-, and 50-µm-thick sections and double-stained with protein gene product (PGP) 9.5 and P-syn. We quantified the deposition of P-syn with and without PGP 9.5 in sweat glands, pilomotor muscle, and blood vessels using confocal digital images of autonomic structures. Overall, the P-syn-positive rates with PGP 9.5 colocalization in subjects with PD were 100% using 50 µm sections, 90% using 20 µm sections, and 73% using 10 µm sections with 100% specificity. (No P-syn was detected within control subjects.) Without PGP 9.5, colocalization of the P-syn-positive rates was 100% for all samples, but specificity dropped below 70%. In this study, double-immunostained 50 µm skin biopsy tissue sections are superior to 20 and 10 µm tissue sections at detecting P-syn in subjects with PD. The increased sensitivity is likely secondary to a combination of greater volume of tissue analyzed and improved visualization of nerve fiber architecture.

Nerves in cancer.

The contribution of nerves to the pathogenesis of malignancies has emerged as an important component of the tumour microenvironment. Recent studies have shown that peripheral nerves (sympathetic, parasympathetic and sensory) interact with tumour and stromal cells to promote the initiation and progression of a variety of solid and haematological malignancies. Furthermore, new evidence suggests that cancers may reactivate nerve-dependent developmental and regenerative processes to promote their growth and survival. Here we review emerging concepts and discuss the therapeutic implications of manipulating nerves and neural signalling for the prevention and treatment of cancer.

Elimination of microglia in mouse spinal cord alters the retrograde CNS plasticity observed following peripheral axon injury.

Following the transection of peripherally located sympathetic preganglionic axons of the cervical sympathetic trunk (CST), transient retrograde neuronal and glial responses occur in the intermediolateral cell column (IML) of the spinal cord, the location of the parent neuronal cell bodies. The role of microglia in this central response to peripheral axon injury was examined in mice fed the PLX5622 diet containing colony-stimulating factor-1 receptor (CSF-1R) inhibitor for 28 days, which eliminated approximately 90% of spinal cord microglia. Microglia elimination did not impact baseline neurotransmitter expression in the IML neurons, and the typical neuronal plasticity observed following CST transection was unaffected. Oligodendrocyte precursor cells (OPCs) were significantly increased at one week post injury in the IML of mice fed the control diet, with no change in mature oligodendrocytes (OLs). Following microglia elimination, the baseline population of OPCs in the IML was increased, suggesting increased OPC proliferation. Injury in the microglia depleted mice resulted in no additional increase in OPCs. Though baseline astrocyte activation and GFAP protein expression were unaffected, microglia elimination led to increased activation and GFAP protein post injury when compared with mice fed the control diet. These results reveal that microglia regulate the baseline OPC population in the uninjured spinal cord and that activated microglia influence the activities of OL lineage cells as well as astrocytes. The regulatory roles of microglia observed in this study likely contribute to the long term survival of the IML neurons observed following the distal axon injury.

Proteomic Analysis of Pelvic Autonomic Nerve in Nerve-sparing Radical Hysterectomy for Cervical Carcinoma.

BACKGROUND/AIM: This study was designed to identify candidate proteins which can be used for visualization of pelvic autonomic nerve during nerve-sparing surgery. MATERIALS AND METHODS: Both soft tissue and vesical branch of the inferior hypogastric nerve from five women were collected during surgery. These 10 tissue specimens were analysed using liquid chromatography-mass spectrometry (LC-MS) and Human Protein Atlas (HPA) for protein expression. The existence of nerve fibres was confirmed using haematoxylin and eosin (H&E) and anti-S-100 staining. RESULTS: A total of 413 proteins were detected. There were three proteins (isoform 1 of fibronectin, protein S100-A8 and A9) which implied a relation with pelvic autonomic nerve. In nerve tissue from one case, the existence of nerve fibre was not confirmed. CONCLUSION: Further large studies are expected to present more nerve-specific candidate proteins which can be used for the easy and safe identification of autonomic nerves.

Cutaneous somatic and autonomic nerve TDP-43 deposition in amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the involvement of the sensory and autonomic nervous system in amyotrophic lateral sclerosis (ALS) and to determine whether TDP-43/pTDP-43 deposits in skin nerve fibers signify a valuable biomarker for ALS. METHODS: Eighteen patients with ALS and 18 age- and sex-matched control subjects underwent physical examinations, in addition to donating skin biopsies from the distal leg. The density of epidermal, Meissner's corpuscle (MC), sudomotor, and pilomotor nerve fibers were measured. Confocal microscopy was used to determine the cutaneous somatic and autonomic nerve fiber density and TDP-43/pTDP-43 deposition. RESULTS: Intraepidermal nerve fiber density (IENFD) was reduced in individuals with ALS (P < 0.001). MC density (MCD) (P = 0.001), sweat gland nerve fiber density (SGNFD) (P < 0.001), and pilomotor nerve fiber density (PNFD) (P < 0.001) were all reduced in ALS patients. The SGNFD correlated with the small-fiber neuropathy Symptoms Inventory Questionnaire (SFN-SIQ), VAS and age. The SFN-SIQ was higher in ALS with sensory symptoms than without sensory symptoms (P = 0.000). Furthermore, the SFN-SIQ was higher in ALS with autonomic symptoms than without autonomic symptoms (P = 0.002). SFN-SIQ was higher in ALS patients that were pTDP-43 positive than pTDP-43 negative (P = 0.04), respectively. CONCLUSIONS: We established in the peripheral nervous system that higher SFN-SIQ and VAS was involved in ALS, indicating the loss of SGNF. The deposition of TDP-43/pTDP-43 in ALS nerve fibers may indicate an important role in the underlying pathogenesis of ALS. This observation might be used as a potential biomarker for diagnosing ALS.

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic.

Striated Perineal Muscles: Location of Somatic and Autonomic Neurons Projecting to the Male Pig Ischiocavernous Muscle. Neurochemical Features of the Sympathetic Subset.

The location, number and size of the central and peripheral neurons innervating the ischiocavernous muscle (ICM) were studied in male pigs by means of Fast Blue (FB) retrograde neuronal tracing. Moreover the immunohistochemical properties of the sympathetic ganglia were investigated combining the double immunolabeling method. After injection of FB into the left ICM, a mean number of 245.3 ± 134.9 labeled neurons were found in the ipsilateral ventral horn of the S1-S3 segments of the spinal cord (SC), 129.7 ± 45.5 in the L6-S3 ipsilateral and S2-S3 contralateral spinal ganglia (SGs), 2279.3 ± 622.1 in the ipsilateral L2-S2 and contralateral L5-S2 sympathetic trunk ganglia (STGs), 541.7 ± 158 in the bilateral caudal mesenteric ganglia (CMGs), and 78.3 ± 35.8 in the microganglia of the pelvic plexus (PGs). The mean area of the ICM projecting neurons was 1217 ± 69.7 µm2 in the SC, 2737.5 ± 176.5 µm2 in the SGs, 982.8 ± 36.8 µm2 in the STGs, 865.9 ± 39.14 µm2 in the CMGs and 426.2 ± 24.72 µm2 in the PGs. The FB positive neurons of autonomic ganglia contained Dopamine ß hydroxylase, vesicular acetylcholine transporter, neuronal nitric oxyde sinthase, calcitonine gene related peptide, leu-enkephaline, neuropeptide Y, substance P, vasoactive intestinal polypeptide, and somatostatine often colocalized with tyrosine hydroxylase. The particular localization of the motor somatic nucleus, the abundant autonomic innervation and the qualitatively different content of ICM projecting sympathetic neurons suggest a complex regulation of this striated muscle involved in involuntary functions, such as the erection, ejaculation, micturition and defecation. Anat Rec, 301:837-848, 2018. © 2017 Wiley Periodicals, Inc.

A new potential biomarker for dementia with Lewy bodies: Skin nerve α-synuclein deposits.

OBJECTIVE: To investigate whether (1) phosphorylated α-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB. METHODS: We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of α-synuclein. RESULTS: No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions. CONCLUSIONS: (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia.

Plasticity in Uterine Innervation: State of the Art.

Early studies often claimed that autonomic nerves were unimportant for uterine function, since denervation of the uterus had little effects on reproductive success. In 1979, Thorbert wrote, "It seems unlikely that Nature has equipped the uterus with a complex innervation merely as a structural ornament. Our ignorance in this area may be rather due to defects in methods of study". Investigations carried out over the last four decades proved that Thorbert's words were correct, because it is now clear that autonomic and sensory nerves regulate many critical uterine functions. However, the most remarkable aspect of uterine innervation is its capacity to change in response to physiological fluctuations in levels of sex hormones, as those accompanying pregnancy, the sex cycle and puberty. The present review provides an overview about how sex hormones influence uterine innervation. Data are presented about how this physiological plasticity is mimicked by exogenous administration of sex hormones, particularly estrogen. We will review recent developments illustrating the complex multifactorial mechanisms regulating uterine neural plasticity and the nature of molecular signals involved. Finally, we will go through recent findings pointing to the relevance of uterine innervation in gynecological diseases leading to pain and infertility.

Neurochemical features of the autonomic neurons projecting to the cremaster muscle of the boar.

The cremaster muscle (CM) is a striated muscle showing some unusual features for ordinary striated muscles, in fact it receives, besides somatic innervation, a conspicuous autonomic sympathetic innervation. The autonomic neurons associated with the CM of 4 male intact pigs were typified combining the retrograde nontrans-synaptic fluorescent tracer Fast Blue (FB) and double labeling immunohistochemical methods. We collected the L4 sympathetic trunk ganglion (STG), that our preliminary studies proved to contain the highest number (575.5 ± 152.93; mean ± S.E.M., n = 4) of FB+ sympathetic neurons projecting to CM. About half of the CM projecting neurons of this ganglion were catecholaminergic and showed the colocalization of Tyrosine Hydroxylase (TH) with Neuropeptide Y (NPY), Leu-Enkephaline (LENK), Vasoactive Intestinal Polypeptide (VIP), Calcitonine Gene Related Peptide (CGRP), Substance P (SP), neuronal Nitric Oxyde Sinthase (n-NOS), and Vesicular Acetylcholine Transporter (VAChT). The noncatecholaminergic neurons were immunoreactive for all the other markers tested, even if in small percentages. The conspicuous and heterogeneous contribution of the sympathetic autonomic neurons to the muscle innervation is consistent with the hypothesis of a possible origin of the CM fibers by transdifferentiation of the smooth muscle-like gubernaculum mesenchyma into striated myotubes, suggesting that the cremaster myogenesis is independent from that of the abdominal muscles.

Sex and estrogen affect the distribution of urocortin-1 immunoreactivity in brainstem autonomic nuclei of the rat.

Urocortin-1 (UCN-1), a neuropeptide closely related to the hypothalamic hormone corticotropin-releasing factor, has been associated with stress, feeding behaviors, cardiovascular control, and to exhibit functional gender differences. This study was done to investigate whether estrogen (E; 17ß-estradiol) treatment (9 weeks) altered UCN-1 immunoreactivity in brainstem autonomic nuclei in female Wistar rats. Experiments were done in age matched adult males (controls), females (intact), and ovariectomized (OVX) only and OVX+E (30pg/ml plasma) treated females. All animals received intracerebroventricular injections of colchicine and were then perfused transcardially with Zamboni's fixative. Coronal brainstem sections (40µm) were cut and processed immunohistochemically for UCN-1. In males, moderate UCN-1 fiber labeling was found in the nucleus of the solitary tract (NTS) and throughout the rostral ventral lateral medulla (RVLM). Additionally, a few UCN-1 immunoreactive neurons were observed in hypoglossal nucleus (XII), facial nucleus (FN) and nucleus ambiguus (Amb). In intact females and OVX+E females, fewer UCN-1 labeled fibers were found within NTS compared to males. In contrast, the RVLM was more densely innervated in the female cases. Furthermore, in both intact and OVX+E females UCN-1 labeled neurons were found not only within Amb, FN and XII, but also within NTS, RVLM and nucleus raphé pallidus (RP). In OVX only animals, moderate to dense UCN-1 fiber labeling was observed in the NTS complex and throughout RVLM compared to males and the other female groups. However, in contrast to all other groups, UCN-1 labeled neurons were found in greater number within Amb, FN, NTS, dorsal motor nucleus of the vagus, XII, RVLM, magnocellular reticular nucleus and RP. These data not only suggest that sex differences exist in the distribution of UCN-1 within brainstem autonomic areas, but that circulating level of E may play an important role with regards to the function of these UCN-1 neurons during stress responses.

The regulation of food intake by the gut-brain axis: implications for obesity.

Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity.

Identification of neurons that express ghrelin receptors in autonomic pathways originating from the spinal cord.

Functional studies have shown that subsets of autonomic preganglionic neurons respond to ghrelin and ghrelin mimetics and in situ hybridisation has revealed receptor gene expression in the cell bodies of some preganglionic neurons. Our present goal has been to determine which preganglionic neurons express ghrelin receptors by using mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter for the ghrelin receptor (also called growth hormone secretagogue receptor). The retrograde tracer Fast Blue was injected into target organs of reporter mice under anaesthesia to identify specific functional subsets of postganglionic sympathetic neurons. Cryo-sections were immunohistochemically stained by using anti-EGFP and antibodies to neuronal markers. EGFP was detected in nerve terminal varicosities in all sympathetic chain, prevertebral and pelvic ganglia and in the adrenal medulla. Non-varicose fibres associated with the ganglia were also immunoreactive. No postganglionic cell bodies contained EGFP. In sympathetic chain ganglia, most neurons were surrounded by EGFP-positive terminals. In the stellate ganglion, neurons with choline acetyltransferase immunoreactivity, some being sudomotor neurons, lacked surrounding ghrelin-receptor-expressing terminals, although these terminals were found around other neurons. In the superior cervical ganglion, the ghrelin receptor terminals innervated subgroups of neurons including neuropeptide Y (NPY)-immunoreactive neurons that projected to the anterior chamber of the eye. However, large NPY-negative neurons projecting to the acini of the submaxillary gland were not innervated by EGFP-positive varicosities. In the celiaco-superior mesenteric ganglion, almost all neurons were surrounded by positive terminals but the VIP-immunoreactive terminals of intestinofugal neurons were EGFP-negative. The pelvic ganglia contained groups of neurons without ghrelin receptor terminal innervation and other groups with positive terminals around them. Ghrelin receptors are therefore expressed by subgroups of preganglionic neurons, including those of vasoconstrictor pathways and of pathways controlling gut function, but are absent from some other neurons, including those innervating sweat glands and the secretomotor neurons that supply the submaxillary salivary glands.

Classical and nerve-sparing radical hysterectomy: an evaluation of the nerve trauma in cardinal ligament.

OBJECTIVES: This study evaluated histopathology and clinical outcome of autonomic nerve trauma and vessels removal within the cardinal ligament (CL) during nerve-sparing radical hysterectomy (NSRH) compared with radical hysterectomy (RH). METHODS: 25 women with FIGO stage Ib1-IIa cervical cancer underwent RH (n=13) or NSRH (n=12). Removed CLs lengths were measured. Biopsies were collected from the proximal, middle and distal segment of CLs and fixed. Different markers were used for immunohistochemisty analysis: tyrosine hydroxylase for sympathetic nerves; vasoactive intestinal polypeptide for parasympathetic nerves; CD34 for blood vessels; and D2-40 for lymphatic vessels. The volume density (Vv), a parameter of biological stereology, was used to quantitatively measure CL components, while post-operative functions, such as defecation, micturition and two-year disease free survival in RH and NSRH groups were compared. RESULTS: The nerves mainly existed in the middle and distal segments of CLs. The Vv was greater in RH compared with NSRH for both sympathetic and parasympathetic nerve markers (P<0.05), while the Vv of blood and lymphatic vessels were same in the two groups. Average time to achieve residual urine≤50ml and first defecation were shorter in NSRH than in RH (P<0.05). CONCLUSIONS: Less autonomic nerves within CL are transected in NSRH than in RH, while blood/lymphatic vessels are efficiently removed in both treatments. Compared to RH, NSRH decreases iatrogenic injury, which leads to reduced post-operative co-morbidities, with ensure the same radicality.

Afferent signaling drives oxytocinergic preautonomic neurons and mediates training-induced plasticity.

We showed previously that oxytocinergic (OTergic) projections from the hypothalamic paraventricular nucleus (PVN) to the dorsal brain stem mediate training-induced heart rate (HR) adjustments and that beneficial effects of training are blocked by sinoaortic denervation (SAD; Exp Physiol 94: 630-640; 1103-1113, 2009). We sought now to determine the combined effect of training and SAD on PVN OTergic neurons in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Rats underwent SAD or sham surgery and were trained (55% of maximal capacity) or kept sedentary for 3 mo. After hemodynamic measurements were taken at rest, rats were deeply anesthetized. Fresh brains were frozen and sliced to isolate the PVN; samples were processed for OT expression (real-time PCR) and fixed brains were processed for OT immunofluorescence. In sham rats, training improved treadmill performance and increased the gain of baroreflex control of HR. Training reduced resting HR (-8%) in both groups, with a fall in blood pressure (-10%) only in SHR rats. These changes were accompanied by marked increases in PVN OT mRNA expression (3.9- and 2.2-fold in WKY and SHR rats, respectively) and peptide density in PVN OTergic neurons (2.6-fold in both groups), with significant correlations between OT content and training-induced resting bradycardia. SAD abolished PVN OT mRNA expression and markedly reduced PVN OT density in WKY and SHR. Training had no effect on HR, PVN OT mRNA, or OT content following SAD. The chronic absence of inputs from baroreceptors and chemoreceptors uncovers the pivotal role of afferent signaling in driving both the plasticity and activity of PVN OTergic neurons, as well as the beneficial effects of training on cardiovascular control.

Immunolocalization of neurotransmitter-synthesizing enzymes and neuropeptides with associated receptors in the photophores of the hatchetfish, Argyropelecus hemigymnus Cocco, 1829.

Anatomical and functional studies of the autonomic innervation of the photophores of luminescent fishes are scarce. The present immunohistochemical study demonstrated the presence of nerve fibers in the luminous epithelium and lens epithelium of the photophores of the hatchet fish, Argyropelecus hemigymnus and identified the immunoreactive elements of this innervation. Phenylethanolanine N-methyltransferase (PNMT) and catecholamine (CA)-synthesizing enzymes were detected in nerve varicosities inside the two epithelia. Neuropeptides were localized in neuropeptide Y (NPY) and substance P (SP)- and its NK11 receptor-immunopositive nerves in the lens epithelium. Neuropeptides were also localized in non-neural cell types such as the lens cells, which displayed immunoreactivities for pituitary adenylate cyclase activating peptide (PACAP) and their receptors R-12 and 93093-3. This reflects the ability of the neuropeptide-containing nerves and lens cells to turn on and off the expression of selected messengers. It appears that the neuropeptide-containing nerves demonstrated in this study may be sensory. Furthermore, neuronal nitric oxide synthase-immunopositive axons associated with photocytes in the luminous epithelium have previously been described in this species. Whereas it is clear that the photophores receive efferent (motor) fibers of spinal sympathetic origin, the origin of the neuropeptide sensory innervation remains to be determined. The functional roles of the above neuropeptides or their effects on the bioluminescence or the chemical nature of the terminals, either sensory or postganglionic neurons innervating the photophores, are still not known.

Pancreatic neuronal melanocortin-4 receptor modulates serum insulin levels independent of leptin receptor.

The leptin-regulated melanocortin (MC) system modulates energy homeostasis and hypothalamic MC neuronal circuits regulate insulin secretion. We therefore hypothesized that MC system components were present in the pancreas. In order to determine the veracity of the hypothesis, we examined c-Fos, melanocortin-4 receptor (Mc4r), and alpha-melanocyte-stimulating hormone (α-MSH) expression levels in nondiabetic (intact leptin receptor signaling) and Zucker diabetic fatty (ZDF; leptin receptor deficiency) rats. We infused rats via the third ventricle with the α-MSH analog Nle4, D-Phe7-α-MSH (NDP-MSH), a Mc4r agonist. Subsequently, both hypothalamic and pancreatic c-Fos and Mc4r mRNAs were upregulated. Likewise, immunohistochemical analysis showed that an increased Mc4r and α-MSH expression in nerves surrounding the pancreatic vasculature and islets. Increases in c-Fos, α-MSH, and Mc4r expression were independent of leptin receptor function. Conversely, serum insulin was significantly reduced by NDP-MSH treatment, an effect which was reversed by the Mc4r specific blocker HS014. Finally, proopiomelanocortin (POMC) mRNA, the precursor of α-MSH, was detected by RT-PCR in pancreatic tissue homogenates. These findings suggest that pancreatic Mc4r and autonomic neurons participate in a communication pathway between the central MC system and pancreatic islets to regulate insulin secretion.

Carvedilol ameliorates sympathetic nerve sprouting and electrical remodeling after myocardial infarction in rats.

BACKGROUND: We hypothesized that carvedilol, a nonselective ß-blocker, can exert antiarrhythmogenic effects by inhibiting sympathetic nerve sprouting and electrical remodeling at peri-infarct zones after myocardial infarction (MI). METHODS: MI was induced by ligation of the coronary artery. The rats in the carvedilol group received 5.0mg/kg carvedilol twice a day. Eight weeks after MI, monophasic action potential duration (MAPD), effective refractory period (ERP) and the inducibility of ventricular arrhythmia at the peri-infarct zones were evaluated and compared with MI rats. After these studies, the expression of growth associated protein 43 (GAP43) and tyrosinehydroxylase (TH) at the peri-infarct zones were examined by western blot and RT-PCR analysis. RESULTS: Eight weeks after surgery, carvedilol shortened the duration of the MAPD determined as 20% (MAPD(20)) and 90% (MAPD(90)) repolarization time (33 ± 9 ms and 110 ± 18 ms vs 21 ± 6 ms and 76 ± 13 ms, both P<0.05) and ERP (76 ± 15 ms vs 62 ± 12 ms, P<0.05), respectively. Carvedilol decreased the inducibility of ventricular arrhythmia after MI (76% vs 32%, P<0.05). The expression of GAP43 and TH were suppressed by carvedilol after MI. CONCLUSION: Carvedilol exerts antiarrhythmogenic effects by ameliorating sympathetic nerve sprouting and electrical remodeling in MI rats. The effects of carvedilol on amelioration of electrical remodeling may be partly related to the inhibition of sympathetic remodeling.