Sympathetic nerve-derived ATP regulates renal medullary vasa recta diameter via pericyte cells: a role for regulating medullary blood flow?

Pericyte cells are now known to be a novel locus of blood flow control, being able to regulate capillary diameter via their unique morphology and expression of contractile proteins. We have previously shown that exogenous ATP causes constriction of vasa recta via renal pericytes, acting at a variety of membrane bound P2 receptors on descending vasa recta (DVR), and therefore may be able to regulate medullary blood flow (MBF). Regulation of MBF is essential for appropriate urine concentration and providing essential oxygen and nutrients to this region of high, and variable, metabolic demand. Various sources of endogenous ATP have been proposed, including from epithelial, endothelial, and red blood cells in response to stimuli such as mechanical stimulation, local acidosis, hypoxia, and exposure to various hormones. Extensive sympathetic innervation of the nephron has previously been shown, however the innervation reported has focused around the proximal and distal tubules, and ascending loop of Henle. We hypothesize that sympathetic nerves are an additional source of ATP acting at renal pericytes and therefore regulate MBF. Using a rat live kidney slice model in combination with video imaging and confocal microscopy techniques we firstly show sympathetic nerves in close proximity to vasa recta pericytes in both the outer and inner medulla. Secondly, we demonstrate pharmacological stimulation of sympathetic nerves in situ (by tyramine) evokes pericyte-mediated vasoconstriction of vasa recta capillaries; inhibited by the application of the P2 receptor antagonist suramin. Lastly, tyramine-evoked vasoconstriction of vasa recta by pericytes is significantly less than ATP-evoked vasoconstriction. Sympathetic innervation may provide an additional level of functional regulation in the renal medulla that is highly localized. It now needs to be determined under which physiological/pathophysiological circumstances that sympathetic innervation of renal pericytes is important

Angiotensinergic innervation of rat and human mesenteric resistant blood vessels

In contrast to the current believe that angiotensin II (Ang II) only interacts with the sympathetic nervous system (SNS) as a circulating hormone, we document here the existence of an endogenous renin-angiotensin system (RAS) in the sympathetic coeliac ganglion and the angiotensinergic innervation with mesenteric resistant blood vessels. Our findings indicate that Ang II is synthesized inside the neurons of sympathetic coeliac ganglion and may act as an endogenous neurotransmitter locally on the mesenteric resistant blood vessels

Preganglionic innervation of the pancreas islet cells in the rat

The position and number of preganglionic somata innervating the insulin-secreting β-cells of the endocrine pancreas were investigated in Wistar rats. This question was approached by comparing the innervation of the pancreas of normal rats with the innervation of the pancreas in alloxan-induced diabetic animals. The presumption was made that alloxan treatment destroys the β-cells of the islet of Langerhans and results in a selective degeneration of the β-cells innervation. Cell bodies of preganglionic fibers innervating the pancreas were identified by retrograde transport of horseradish peroxidase following pancreas injections. It was found that 25% of the cells innervating the pancreas in the left dorsal vagal motor nucleus, 50% of the cells in the ambiguus nucleus and 50% of the cells innervating the pancreas, that originate in segments C3-C4 of the spinal cord, fail to become labeled after alloxan treatment. The position and distribution of these cell groups are described in detail and are assumed to be involved in preganglionic β-cell innervation. A second cell population in the ventral horn and intermediolateral column of the segments T3-L2 of the cord also was labeled in normal rats and was not affected by the alloxan treatment. These thoracic cell groups are thus considered as sympathetic preganglionic somata that maintain direct connections to the pancreas. Additional preliminary information is presented dealing with the general aspects of sympathetic and parasympathetic organization of the pancreas innervation.

SHP-2 deletion in postmigratory neural crest cells results in impaired cardiac sympathetic innervation

Autonomic innervation is an essential component of cardiovascular regulation that is first established from the neural crest (NC) lineage in utero and continues developing postnatally. Although in vitro studies have indicated that SH2-containing protein tyrosine phosphatase 2 (SHP-2) is a signaling factor critical for regulating sympathetic neuron differentiation, this has yet to be shown in the complex in vivo environment of cardiac autonomic innervation. Targeting SHP-2 within postmigratory NC lineages resulted in a fully penetrant mouse model of diminished sympathetic cardiac innervation and concomitant bradycardia. Immunohistochemistry of the sympathetic nerve marker tyrosine hydroxylase revealed a progressive loss of adrenergic ganglionic neurons and reduction of cardiac sympathetic axon density in Shp2 cKOs. Molecularly, Shp2 cKOs exhibit lineage-specific suppression of activated phospo-ERK1/2 signaling but not of other downstream targets of SHP-2 such as pAKT. Genetic restoration of the phosphorylated-extracellular signal-regulated kinase (pERK) deficiency via lineage-specific expression of constitutively active MEK1 was sufficient to rescue the sympathetic innervation deficit and its physiological consequences. These data indicate that SHP-2 signaling specifically through pERK in postmigratory NC lineages is essential for development and maintenance of sympathetic cardiac innervation postnatally

Investigation into cardiac sympathetic innervation during the commencement of haemodialysis in patients with chronic kidney disease

Background: Patients with chronic kidney disease (CKD) who undergo chronic haemodialysis (HD) show altered sympathetic tone, which is related to a higher cardiovascular mortality. The purpose of this study was to investigate the effect of transition from pre-HD to HD on cardiac sympathetic innervation. Methods: Eighteen patients aged 58 ± 18 years (mean ± standard deviation [SD]), 13 males and five females, with stage 5 CKD and nine healthy control subjects aged 52 ± 17 (mean ± SD), three males and six females, were included in this prospective study between May 2010 and December 2013. All patients underwent 123I-labelled meta-iodobenzylguanidine (123I-MIBG) scintigraphy for cardiac sympathetic innervation and electrocardiographically gated adenosine stress and rest 99mTc-labelled tetrofosmin single-photon emission computed tomography for myocardial perfusion imaging prior to (pre-HD) and 6 months after the start of HD. Results of 123I-MIBG scans in patients were compared to controls. Impaired cardiac sympathetic innervation was defined as late heart-to-mediastinum ratio (HMR) < 2.0. Results: Mean late HMR was lower in patients during HD (2.3) than in controls (2.9) (p = 0.035); however, in patients it did not differ between pre-HD and after the start of HD. During HD, two patients showed new sympathetic innervation abnormalities, and in three patients innervation abnormalities seemed to coincide with myocardial perfusion abnormalities. Conclusions: CKD patients show cardiac sympathetic innervation abnormalities, which do not seem to progress during the maintenance HD. The relationship between sympathetic innervation abnormalities and myocardial perfusion abnormalities in HD patients needs further exploration

Pathogenesis of sudden death following water immersion (immersion syndrome)

Sympathetic activity under cold stress is investigated. Predominantly vagal cardio-depressive reflexes are discussed besides currently known mechanisms of sudden death after water immersion. Pronounced circulatory centralization in diving animals as well as following exposure in cold water indicates additional sympathetic activity. In cold water baths of 15 C, measurements indicate an increase in plasma catecholamine levels by more than 300 percent. This may lead to cardiac arrhythmias by the following mechanisms: cold water essentially induces sinus bradycardia; brady-and tachycardiarrhythmias may supervene as secondary complications; sinusbradycardia may be enhanced by sympathetic hypertonus. Furthermore, ectopic dysrhythmias are liable to be induced by the strictly sympathetic innervation of the ventricle. Myocardial ischemia following a rise in peripheral blood pressure constitutes another arrhythmogenic factor. Some of these reactions are enhanced by alcohol intoxication

Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation

Background Nerve growth factor (NGF) is the prototypical target-derived neurotrophic factor required for sympathetic neuron survival and for the growth and ramification of sympathetic axons within most but not all sympathetic targets. This implies the operation of additional target-derived factors for regulating terminal sympathetic axon growth and branching. Results Here report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGFβ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG. Conclusions These findings show that GDF5 is a novel target-derived factor that promotes sympathetic axon growth and branching and makes a distinctive regional contribution to the establishment of sympathetic innervation, but unlike NGF, plays no role in regulating sympathetic neuron survival