9 research outputs found
Ultrastructural changes of the human enteric nervous system and interstitial cells of Cajal in diverticular disease.
Background. In spite of numerous advances
in understanding diverticular disease, its pathogenesis
remains one of the main problems to be solved. We
aimed to investigate the ultrastructural changes of the
enteric nervous system in unaffected individuals, in
asymptomatic patients with diverticulosis and in patients
with diverticular disease.
Methods. Transmission electron microscopy was
used to analyse samples of the myenteric, outer
submucosal and inner submucosal plexuses from
patients without diverticula (n=9), asymptomatic patients
with diverticulosis (n=7) and in patients with
complicated diverticular disease (n=9). We described the
structure of ganglia, interstitial cells of Cajal and enteric
nerves, as well as their relationship with each other. The
distribution and size of nerve processes were analysed
quantitatively.
Results. In complicated diverticular disease, neurons
exhibited larger lipofuscin-like inclusions, their
membranous organelles had larger cisterns and the
nucleus showed deeper indentations. Nerve remodeling
occurred in every plexus, characterised by an increased
percentage of swollen and fine neurites. Interstitial cells
of Cajal had looser contacts with the surrounding cells
and showed cytoplasmic depletion and proliferation of
the rough endoplasmic reticulum. In asymptomatic
patients with diverticulosis, alterations of enteric nerves
and ICC were less pronounced.
Conclusions. In conclusion, the present findings
suggest that most ultrastructural changes of the enteric
nervous system occur in complicated diverticular
disease. The changes are compatible with damage to the
enteric nervous system and reactive remodeling of
enteric ganglia, nerves and interstitial cells of Cajal.
Disrupted architecture of enteric plexuses might explain
clinical and pathophysiological changes associated with
diverticular diseas
Early structural alterations of intrinsic cardiac ganglionated plexus in spontaneously hypertensive rats
Persistent arterial hypertension leads to
structural and functional remodeling of the heart
resulting in myocardial ischemia, fibrosis, hypertrophy,
and eventually heart failure. Previous studies have
shown that individual neurons composing the
intracardiac ganglia are hypertrophied in the failing
human, dog, and rat hearts, indicating that this process
involves changes in cardiac innervation. However,
despite a wealth of data on changes in intrinsic cardiac
ganglionated plexus (GP) in late-stage disease models,
little is known about the effects of hypertension on
cardiac innervation during the early onset of heart failure
development. Thus, we examined the impact of early
hypertension on the structural organization of the
intrinsic cardiac ganglionated plexus in juvenile (8-9
weeks) and adult (12-18 weeks) spontaneously
hypertensive (SH) and age-matched Wistar-Kyoto
(WKY) rats. GP was studied using a combination of
immunofluorescence confocal microscopy and
transmission electron microscopy in whole-mount
preparations and tissue sections. Here, we report
intrinsic cardiac GP of SH rats to display multiple
structural alterations: (i) a decrease in the intracardiac
neuronal number, (ii) a marked reduction in axonal
diameters and their proportion within intracardiac
nerves, (iii) an increased density of myocardial nerve
fibers, and (iv) neuropathic abnormalities in cardiac glial
cells. These findings represent early neurological
changes of the intrinsic ganglionated plexus of the heart
introduced by early-onset arterial hypertension in young
adult SH rats
Innervation of the rabbit cardiac ventricles
The rabbit is widely used in experimental cardiac physiology, but the neuroanatomy of the rabbit heart remains insufficiently examined. This study aimed to ascertain the architecture of the intrinsic nerve plexus in the walls and septum of rabbit cardiac ventricles. In 51 rabbit hearts, a combined approach involving: (i) histochemical acetylcholinesterase staining of intrinsic neural structures in total cardiac ventricles; (ii) immunofluorescent labelling of intrinsic nerves, nerve fibres (NFs) and neuronal somata (NS); and (iii) transmission electron microscopy of intrinsic ventricular nerves and NFs was used. Mediastinal nerves access the ventral and lateral surfaces of both ventricles at a restricted site between the root of the ascending aorta and the pulmonary trunk. The dorsal surface of both ventricles is supplied by several epicardial nerves extending from the left dorsal ganglionated nerve subplexus on the dorsal left atrium. Ventral accessing nerves are thicker and more numerous than dorsal nerves. Intrinsic ventricular NS are rare on the conus arteriosus and the root of the pulmonary trunk. The number of ventricular NS ranged from 11 to 220 per heart. Four chemical phenotypes of NS within ventricular ganglia were identified, i.e. ganglionic cells positive for choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), and biphenotypic, i.e. positive for both ChAT/nNOS and for ChAT/tyrosine hydroxylase. Clusters of small intensely fluorescent cells are distributed within or close to ganglia on the root of the pulmonary trunk, but not on the conus arteriosus. The largest and most numerous intrinsic nerves proceed within the epicardium. Scarce nerves were found near myocardial blood vessels, but the myocardium contained only a scarce meshwork of NFs. In the endocardium, large numbers of thin nerves and NFs proceed along the bundle of His and both its branches up to the apex of the ventricles. The endocardial meshwork of fine NFs was approximately eight times denser than the myocardial meshwork. Adrenergic NFs predominate considerably in all layers of the ventricular walls and septum, whereas NFs of other neurochemical phenotypes were in the minority and their amount differed between the epicardium, myocardium and endocardium. The densities of NFs positive for nNOS and ChAT were similar in the epicardium and endocardium, but NFs positive for nNOS in the myocardium were eight times more abundant than NFs positive for ChAT. Potentially sensory NFs positive for both calcitonin gene‐related peptide and substance P were sparse in the myocardial layer, but numerous in epicardial nerves and particularly abundant within the endocardium. Electron microscopic observations demonstrate that intrinsic ventricular nerves have a distinctive morphology, which may be attributed to remodelling of the peripheral nerves after their access into the ventricular wall. In conclusion, the rabbit ventricles display complex structural organization of intrinsic ventricular nerves, NFs and ganglionic cells. The results provide a basic anatomical background for further functional analysis of the intrinsic nervous system in the cardiac ventricles
GLP1R attenuates sympathetic response to high glucose via carotid body inhibition
Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation. METHODS: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo. RESULTS: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose. CONCLUSIONS: We show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition