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PubMed1995

Regional origins of 3-methoxy-4-hydroxyphenylglycol in plasma: effects of chronic sympathetic nervous activation and denervation, and acute reflex sympathetic stimulation.

The plasma level and urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the principal metabolite of noradrenaline in the brain, are often used as indicators of central nervous system noradrenergic activity. Using percutaneously placed catheters, we studied the regional inputs into the plasma MHPG pool in 62 healthy volunteers. Veno-arterial plasma concentration differences and regional organ blood flows were used to quantify the relative amounts of MHPG contributed by various sites into plasma. Positive veno-arterial concentration gradients were found across the forearm, cardiac and jugular vessels in the healthy subjects. By far the majority of MHPG in plasma was derived from skeletal muscle, 5.3 +/- 1.8 nmol/min, with only minimal contribution (0.9 +/- 0.2 nmol/min) from the brain. Thus, to obtain an accurate indication of central nervous system noradrenergic activity the confounding influences of regional MHPG production must be excluded. 34 patients with chronic congestive heart failure, 6 patients with pure autonomic failure and 9 recent heart transplant recipients were used to investigate the possible effects of chronic sympathetic nervous system overactivity and sympathetic underactivity and denervation on peripheral MHPG production and plasma MHPG concentration. To examine the utility of plasma MHPG determinations as an indicator of acute alterations in sympathetic nervous activity we examined the influence of a variety of laboratory stressors on the arterial level and cardiac production of MHPG. The resting arterial plasma MHPG concentration mirrored sympathetic function in the patients with cardiac failure (sympathetic activation) and pure autonomic failure (sympathetic denervation), with mean MHPG plasma concentrations being 180 and 40% of those in healthy subjects. Cardiac MHPG production was increased in heart failure patients, and near zero with the cardiac sympathetic denervation accompanying transplantation and pure autonomic failure. In contrast, acute reflex stimulation of sympathetic nervous activity was not associated with parallel changes in the arterial level or cardiac production of MHPG. Measurements of peripheral plasma MHPG levels provide an index of prevailing sympathetic nervous function in clinical models of sympathetic overactivity and denervation, but are insensitive to acute sympathetic nervous system responses.

Adrenergic Uptake Inhibitors↗

PubMed1995

Neural input and the development of adrenergic intracellular signaling: neonatal denervation evokes neither receptor upregulation nor persistent supersensitivity of adenylate cyclase.

In the adult, denervation of adrenergic target tissues leads to compensatory upregulation of receptor sites and to supersensitive responses. When 6-hydroxydopamine (6-OHDA) was given to neonatal rats, cardiac beta-receptors failed to show significant upregulation throughout the first five postnatal weeks and alpha 1-receptors were unchanged except at 35 days of age, despite 70-95% depletion of norepinephrine. The failure to upregulate could not be attributed to the high background level of receptor expression commensurate with ontogenetic increases in receptor numbers, since the same deficiency was seen in the liver, a tissue in which beta-receptors decline with development; liver alpha 1-receptors also failed to upregulate after neonatal denervation. Examination of the linkage of beta-receptors to adenylate cyclase indicated major differences from mature regulatory mechanisms, as denervation supersensitivity was completely absent (liver) or emerged only transiently several weeks after 6-OHDA treatment (heart). In the heart, there was evidence for a defect in the G-protein-dependent component of the receptor/cyclase linkage that could contribute to the delayed appearance of supersensitivity. Because the fundamental patterns of receptor ontogeny and of adenylate cyclase responsiveness are still present after neonatal denervation, it is unlikely that neural input provides the major impetus for basal development. However, adult-type regulation of receptors and responses did not emerge even after a prolonged period; thus, neural input during a critical developmental stage may be required for the cell to learn how to adjust receptor expression and the receptor/cyclase link in response to stimulation.

Adenylyl Cyclases↗

PubMed1985

Mode of reinnervation in neonatally denervated lamina of the cat's lateral geniculate nucleus.

Physiological properties of relay cells were studied in the lateral geniculate nucleus (LGN) of neonatally one-eye-removed adult cats. Most of the relay cells recorded from the denervated lamina (lamina A1) were still classifiable into either Y- or X-cells, like those recorded from the non-denervated lamina (lamina A). However, receptive field centers of both Y- and X-cells in the denervated lamina were slightly over twice as large as those of the corresponding classes in the non-denervated lamina. These data indicate that reinnervated relay cells may receive excessive convergent inputs from either Y or X type retinal axons which have grown translaminarly.

Animals↗

PubMed1985

Effect of denervation on the glycolytic metabolism of the main electric organ of Electrophorus electricus (L.).

Biochemical modifications of the glycolytic metabolism of the electric organ of Electrophorus electricus (L.) have been studied as a function of denervation. The activities of LDH, MDH and the concentrations of ATP, lactic and pyruvic acids were measured at intervals of zero, 15, 30 and 60 days following denervation. In parallel, CPK activity was also measured. All of these biochemical characteristics were substantially altered by denervation. The results obtained point to a change, after 15 days of denervation, from the normal anaerobic to an aerobic metabolism which remains after 30 days and reverts to anaerobic at 60 days.

Adenosine Triphosphate↗

PubMed1988

Denervation alters the size, number, and distribution of clusters of acetylcholine receptor-like molecules on frog cardiac ganglion neurons.

Acetylcholine receptor (AChR)-like molecules are found in clusters on the surface of parasympathetic neurons in the frog cardiac ganglion. Electron microscopy of immunoperoxidase-stained tissue reveals that in normally innervated ganglia most of these clusters are located at synaptic sites. Denervation for 2-3 weeks results in a 64% reduction in the total surface area occupied by AChR-like clusters; this change is brought about by the combined effects of a 4-fold decrease in cluster size and a 30% increase in cluster number. Denervation also changes the distribution of AChR-like clusters: clusters, normally restricted to portions of the cell surface, are more widely distributed following denervation. Denervation of amphibian skeletal muscle for a comparable period of time has no effect on the size or the number of synaptic clusters of AChRs. These results suggest that AChRs in nerve and in muscle are regulated differently by innervation.

Animals↗

PubMed2004

Cutaneous and sympathetic denervation in neonatal rats with a mutation in the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 gene.

The mutilated-foot rat (mf rat) is an autosomal recessive mutant with characteristic digit deformities in adult animals, and this phenotype mimics many aspects of human sensory neuropathy. The genetics of mf rats was recently elucidated. To understand whether the genotype is responsible for cutaneous denervation before clinically overt mutilation in adult mf rats, we investigated skin innervation in postnatal day 7 (P7) mf rats and compared the patterns with P7 wild-type rats. The mf rat carries a G-->A mutation in the gene encoding the delta subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct4). In the footpad skin of P7 mf rats, there was a >90% loss of epidermal nerves (0.7-7.9% of P7 wild-type rats) as indicated by neuronal markers including protein gene product 9.5 (PGP 9.5), growth-associated protein 43 (GAP43), calcitonin gene-related peptide (CGRP), and substance P (SP). The epidermis of hairy skin in hind feet was completely denervated in mf rats as well. Compared with an approximately 80% reduction in the size of dermal nerve fascicles and a parallel loss of nerve fibers, the nearly complete absence of epidermal innervation suggests further sensory nerve degeneration at the level of nerve terminals in the epidermis. In contrast, the loss of epidermal nerves in the abdominal skin of mf rats was less extensive than that in the footpad skin of mf rats; CGRP (+) and SP (+) fibers were moderately reduced (28.3-56.4% of levels of wild-type rats) with normal amounts of PGP 9.5 (+) and GAP43 (+) nerves. Sympathetic innervation as assessed by tyrosine hydroxylase immunoreactivity was absent from the footpad and abdominal skin of mf rats. In conclusion, there is regional skin denervation with diffuse sympathetic denervation in P7 mf rats. These results suggest that the mutation in Cct4 underlies cutaneous nerve degeneration in mf rats.

Abdomen↗

PubMed2006

Reuptake of L-DOPA-derived extracellular dopamine in the striatum with dopaminergic denervation via serotonin transporters.

The aim of our present study was to determine whether exogenous L-DOPA-derived extracellular dopamine (DA) in the denervated striatum is taken up via serotonin (5-HT) transporters. Rats with dopaminergic denervation by 6-hydroxydopamine were injected with L-DOPA 50 mg/kg (i.p.) and extracellular DA levels in the denervated striatum were measured using in vivo microdialysis technique. During the experiments, fluoxetine, a selective serotonin reuptake inhibitor, was locally perfused into the striatum through the microdialysis probe. Cumulative amounts of L-DOPA-derived extracellular DA during 300 min were increased by fluoxetine dose-dependently (10 microM and 50 microM). These results suggest that reuptake of DA via 5-HT transporters plays an important role in the clearance of L-DOPA-derived DA from the extracellular space when dopaminergic neurons are extensively denervated.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Denervated or innervated flaps for the lower lip reconstruction? Are they really different to get a good result?

OBJECTIVE: This study compares innervated and denervated flaps for the lower lip reconstruction in terms of oral sphincter function and sensation. STUDY DESIGN AND SETTING: A prospective trial. METHODS: This study was carried out on 31 patients with lower lip carcinoma. They were divided in 2 groups: 18 patients with denervated local flaps and 13 patients with innervated flaps. During the follow-up period, all patients were evaluated by electromyography tests and an assessment of the sensation on the lower lip and sphincter function was undertaken by clinical parameters. RESULTS: Compound muscle action potential (CMAP) was obtained in all patients. The amplitudes of CMAP were below normal and the values for distal motor latency (DML) were slightly longer than normal values. Interference patterns were observed on whistling in all cases. There were no differences in terms of sphincteric function in each group. CONCLUSIONS: The denervated random local flaps used for the lower lip reconstruction have no functional inferiority when compared to the innervated-pedicled local flaps. SIGNIFICANCE: This study demonstrates that denervated flaps can be employed for a functional lip reconstruction. EBM RATING: B-2b.

Adult↗

PubMed2000

Cardiac autonomic denervation in congestive heart failure: comparison of Chagas' heart disease with other dilated cardiomyopathy.

Congestive heart failure (CHF) is associated with activation of the cardiac sympathetic nerves. However, impairment of the sympathetic nerve terminals in patients with CHF has been indicated by studies showing reduction of cardiac norepinephrine uptake and stores. This investigation studies the histochemical evaluation of the sympathetic nerve terminals in CHF. The cardiac parasympathetic innervation was also studied to address the question of specificity of the presumed sympathetic denervation. Nineteen patients with CHF underwent cardiac transplantation or partial ventriculectomy, which provided the heart tissue. In 11 of them, the dilated cardiomyopathy was associated with Chagas' disease. Inflammatory process and fibrosis were studied histologically. The sympathetic and parasympathetic nerve fibers were visualized through histochemical techniques for, respectively, catecholamines and acetylcholinesterase activity. By using a computer-assisted morphometric program, the inflammation, fibrosis, and parasympathetic innervation were quantified. Moderate to severe fibrosing myocarditis characterized the hearts of the chagasic patients. In cardiomyopathies not associated with Chagas' disease, the inflammation was discrete, if present, but the amount of fibrosis was similar to that found in Chagas' cardiomyopathy. Reduction of both kinds of nerve terminals occurred in the heart of all patients. The parasympathetic denervation was proven to be more severe in chagasic cardiomyopathy. Our data on the heart innervation indicate a progressive autonomic denervation in heart failure. In Chagas' heart disease, the denervation seems to be more severe or rapid, probably because of the sustained inflammatory process.

Acetylcholinesterase↗

PubMed1990

Reafferentation of the subcortically denervated hippocampus as a model for transplant-induced functional recovery in the CNS.

Subcortical deafferentation of the hippocampal formation is known to induce profound behavioural deficits. Transplants of fetal septal or brainstem tissue are capable of restoring some aspects of normal physiological and behavioural function in subcortically deafferented (i.e. fimbria-fornix or septal lesioned) rats. Such grafts have been shown to re-establish extensive new afferent inputs to the denervated hippocampal formation. As shown for grafted cholinergic and noradrenergic neurons, the ingrowing axons form laminar innervation patterns which closely mimic those of the normal cholinergic and noradrenergic innervations. The ingrowth appears to be very precisely regulated by the denervated target: each neuron type produces distinctly different innervation patterns; the growth is inhibited by the presence of an intact innervation of the same type; and it is stimulated by additional denervating lesions. Both ultrastructually and electrophysiologically the graft-derived fibres have been seen to form extensive functional synaptic contacts. Biochemically, cholinergic septal grafts and noradrenergic locus coeruleus grafts restore transmitter synthesis and turnover in the reinnervated hippocampus. Intracerebral microdialysis has revealed that acetylcholine and noradrenaline release is restored to normal or supranormal levels in the graft-reinnervated hippocampus, and that the grafted neurons can be activated in a normal way from the host through behavioural activation induced by sensory stimulation or electrical stimulation of the lateral habenula. These results indicate that the grafted monoaminergic neurons can restore tonic regulatory neurotransmission at previously denervated synaptic sites even when they are implanted into the ectopic brain sites. Such functional reafferentation may be sufficient for at least partial restoration of function in the subcortically deafferented hippocampus.

Adrenergic Fibers↗

PubMed2000

Differential effect of interferon-gamma injection on mitogenic responses in sympathetically denervated submaxillary lymph nodes of rats.

This study aimed to assess the effect of interferon (IFN)-gamma treatment on mitogenic responses in submaxillary lymph nodes in the presence or absence of local sympathetic nerves. Adult male rats were subjected to a unilateral superior cervical ganglionectomy and to a contralateral sham-operation. Seven days later, rats received five i.p. daily injections of human IFN-gamma (10(5) U.I./kg) or saline. On the day after the last injection, rats were killed at six different times throughout a 24-h cycle and the mitogenic effect of lipopolysaccharide (LPS) and concanavalin A (Con A) was assessed in single-cell suspensions of lymph nodes. In vehicle-treated rats, proliferation responses to LPS in innervated lymph nodes did not show time-of-day variations while those in denervated lymph nodes attained a maximum at 17:00 h. Following IFN-gamma administration, a promoting effect of LPS mitotic response was detected at 01:00 h at the innervated side only. As far as the mitogenic responses to Con A, proliferation in innervated lymph nodes of vehicle-treated controls attained a maximum at 09:00 h. Such a daily variation in response to Con A was not detectable at the denervated side. IFN-gamma treatment increased significantly Con A activity by promoting a greater mitogenic response at 01:00 h. Sympathetic denervation of lymph nodes brought about a shift in the maximum in number of cells per mg of lymph node from 21:00 to 13:00 h. After IFN-gamma treatment, maxima in cell number occurred at 05:00 h at both the innervated and denervated side. The results indicate that IFN-gamma effects in rat submaxillary lymph nodes are under substantial modulation by local sympathetic nerves.

Animals↗

PubMed1998

Muscarinic receptor subtype involvement in brain cholinergic stimulation by intracerebroventricular neostigmine in sinoaortic denervated rats.

1. The present studies evaluated the participation of central muscarinic receptors in the cardiovascular effects of centrally injected neostigmine, a quaternary anticholinesterase, in conscious, sham-operated rats and in sinoaortic denervated animals. 2. The dose-dependent pressor effect of neostigmine (0.1 to 1 microg i.c.v.) was greater in sinoaortic denervated rats than in sham-operated animals, but only a dose-dependent bradycardic effect was seen in sham-operated rats. 3. Doses of 3.3 nmol (i.c.v.) of both the M1 muscarinic antagonist, pirenzepine, and the M3 muscarinic antagonist, 4-DAMP, prevented the pressor response to 1 microg of neostigmine in sham-operated rats and in sinoaortic denervated animals; however, the M2 muscarinic antagonist, AF-DX116, partially blocked this response in sham-operated rats while failing to do so in sinoaortic denervated rats. In sham rats, doses of 3.3 nmol (i.c.v.) of both pirenzepine and 4-DAMP prevented the bradycardic response to 1 microg (i.c.v.) of neostigmine, whereas AF-DX116 induced a partial blockade. 4. 4-DAMP, at the dose of 0.3 nmol (i.c.v.), but not pirenzepine at the same dose, prevented the pressor effect of neostigmine (0.1 to 1 microg i.c.v.) in both groups of rats. Both muscarinic antagonists at this dose prevented the bradycardia elicited by the anticholinesterase (0.1 to 1 microg i.c.v.), but 4-DAMP showed a greater antagonistic action on this cardiac effect than pirenzepine. In sham-operated rats, i.c.v. injection of 0.3 nmol of AF-DX116 failed to modify the cardiovascular responses to 0.3 microg of neostigmine. 5. Results suggest mainly an involvement of brain M3-subtype muscarinic receptors in the cardiovascular effect of intracerebroventricular administration of anticholinesterase neostigmine in both groups of rats.

Animals↗

PubMed2002

Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys.

Studies were conducted to investigate the role of renal sympathetic nerves in the process of acquiring ischaemic tolerance in ischaemic preconditioned ischaemia-reperfused rat kidneys. Two periods of 3-min occlusion of bilateral renal arteries was performed prior to 30-min bilateral ischaemia and 90-min reperfusion in acute renal denervated or innervated kidneys. The glomerular filtration rate (GFR), fractional excretion of sodium (FENa) and lithium (FELi), and renal blood flow (RBF) were assessed in reperfused kidneys. Ischaemic preconditioning significantly improved values for all these parameters as compared with no treated ischaemia-reperfused kidneys. Denervation caused slight increase in GFR, diuresis and natriuresis without improving RBF after reperfusion. However, protecting effects of ischaemic preconditioning on renal function were disappeared in denervated kidneys, while in innervated kidneys the effects of ischaemic preconditioning were maintained. These results clearly showed that ischaemic preconditioning pre-treatment protects kidneys against ischaemia-reperfusion injury, and the effects are, at least in part, mediated by sympathetic nerves, as the protective effects were abolished by denervation.

Animals↗

PubMed2000

Risk and prognostic factors of postherpetic neuralgia and focal sensory denervation: a prospective evaluation in acute herpes zoster ophthalmicus.

OBJECTIVES: To determine the general risk and the prognostic factors of postherpetic neuralgia and focal sensory denervation in ophthalmic zoster disease. STUDY DESIGN: A prospective clinical study. SETTING: An ophthalmic practice participating in an eye-care network. PATIENTS: A cohort of 81 immunocompetent adult patients with herpes zoster ophthalmicus and referred by their general practitioner during the acute phase of the disease. METHODS: Various acute phase clinical parameters were determined via patient history and regular ophthalmic examinations. At a 2-month follow-up, the intensity of postherpetic neuralgia, rated on a 4-point verbal scale, and focal sensory denervation was determined. Skin tactile sensation within the ophthalmic dermatomes was tested with use of a cotton-wool tip, and corneal sensitivity was measured with use of a Cochet-Bonnet esthesiometer by comparing each eye. Statistical analysis was performed via chi2 analysis or Fisher exact test to identify prognostic factors of postherpetic neuralgia and focal sensory denervation at a 2-month follow-up. RESULTS: At a 2-month follow-up, pain of varying intensity was reported by 38 participants (47%). Of these patients, 25 patients (31%) rated their pain as mild, 8 patients (10%) rated their pain as moderate pain, and 5 patients (6%) rated their pain as severe. At that time, focal loss of normal skin or corneal sensation was detected in 49 patients (60%). Patient age, acute neuralgia score, manifestation and extent of acute skin rash, signs of ocular inflammation, and nontrigeminal cranial nerve involvement were all associated with prolonged pain and tactile sensory loss. CONCLUSIONS: The severity of acute skin rash, based on a specific manifestation of cutaneous herpes zoster eruptions, and the extent of infection to other neural pathways were clearly associated with postherpetic neuralgia and focal sensory denervation at a 2-month follow-up. These findings suggest that the inability of the immune system to control the spread of replicating varicella-zoster virus in the initial phase of the disease is an important factor in the pathogenesis of chronic zoster-related neuropathy.

Acute Disease↗

PubMed1996

Natural killer cells and macrophages in immature denervated rat muscles.

Neonatally denervated muscle fibers of rat atrophy, degenerate, and eventually vanish unless they are reinnervated. Immunohistochemistry of hindlimb muscles denervated for 4 to 8 weeks showed OX8+ and also 3.2.3+ natural killer (NK) cells and ED1+ macrophages, which were much more frequent between atrophic non-reinnervated fibers than between reinnervated fibers. OX19+ T cells and OX33+ B cells were rare. Electron micrographs 4 to 15 weeks after denervation showed typical medium-sized lymphocytes and large lymphocytes with dense granules in close contact with muscle fibers of 1 to 3 micrometer diameter. Blunt projections of lymphocytes penetrated the basal lamina of the muscle fibers and established membrane contacts. The basal lamina of atrophic fibers had been invaded by slender projections of cytoplasm-rich stellate or fusiform cells, which seemed to strip them of their basal lamina. Thin fibers without basal lamina were engulfed by the stellate cells that in several aspects resembled fibrocytes but that presumably corresponded to the ED1+ macrophages seen by light microscopy. Electron microscopy and in situ nick translation demonstrated the rare appearance of apoptotic myonuclei. It is suggested that lymphocytes and macrophages are involved in the breakdown of neonatally denervated muscle fibers, and that apoptosis following contact with NK cells may represent the mode of cell death.

Animals↗

PubMedDate not supplied

Wound healing in denervated rat skin.

Recently, several reports have suggested that innervation influences wound healing. However, some investigators have reported that nerve injury prevented wound healing while others have suggested it had no influence on full-thickness skin wound healing. We created denervated skin areas on rats by dissection of the spinal hemicord. Subsequently, 15-mm-diameter skin defects were made symmetrically within the denervated area on the right side of the back and the normal innervated area on the left side. Biopsies were performed at 3, 7, and 14 days after wounding. We measured changes of the wound surface area, the rate of wound contraction, and the rate of epithelialization. The differences were not significant at 3 or 7 days after the operation. However, we could observe significantly delayed wound healing of the denervated skin areas compared to the normal areas at 14 days. Both wound contraction and epithelialization were delayed in the denervated groups. Our results suggest that sensory disturbance is a negative factor for skin wound healing.

Animals↗

PubMedDate not supplied

Autonomic denervation may be a prerequisite of diabetic neuropathic foot ulceration.

Studies using visceral (cardiovascular) autonomic function testing have left doubt as to the importance of autonomic neuropathy in the development of diabetic neuropathic foot ulceration. A test for peripheral autonomic denervation has been developed (acetylcholine sweatspot test), dependent on intradermal acetylcholine causing secretion by innervated sweat glands, detected by starch/iodine discoloration. The response is photographed and quantified using a grid (normal score = 0 or 1; abnormal = 5 to 60). The sweatspot test was applied to the feet of 19 diabetic patients with a history of foot ulceration, 17 with neuropathic pain, 8 complaining of numbness, and to 15 diabetic control patients. The sweatspot test score of the foot ulcer patients (median 54) was very much greater than that of the other groups (pain group, 4, p less than 0.005; numbness group, 2, p less than 0.01; diabetic control group, 2, p less than 0.0001). All the patients with neuropathic foot ulceration had peripheral autonomic denervation. The results suggest that autonomic denervation in the feet is always present in patients with diabetic neuropathic foot ulceration. Tests of peripheral autonomic denervation such as the acetylcholine sweatspot test may be useful to identify patients at risk of neuropathic foot ulceration.

Acetylcholine↗

PubMed1990

Effects of sympathetic denervation on liver fibroblasts: prevention by adenosine.

1. The effect of chemical denervation with 6-hydroxydopamine (6-OHDA) upon portal tract fibroblasts of dogs and rabbits was studied. 2. Denervation led to a significant increase in the density of portal tract fibroblasts both in the dog and in the rabbit. 3. Mast cells, present in the dog but not in the rabbit liver, were also significantly increased by denervation. 4. Noradrenaline depletion induced by reserpine did not increase the density of fibroblasts in the liver portal spaces of the dog. Mast cell density, however, was actually decreased when compared with control. 5. Continuous i.v. infusions of adenosine (10 micrograms kg-1h-1) to dogs totally prevented the effects of 6-OHDA-induced denervation upon fibroblast and mast cell densities in the portal space connective tissue. 6. It is concluded that the sympathetic nervous system is exerting a repressive effect on liver fibroblasts, as was found to occur in various other mammalian tissues. Mast cells, which are known to be activated in various pathological processes of fibrosis, appear to share with fibroblasts a modulating effect from the sympathetic nervous system. 7. The results strongly support the hypothesis of adenosine being the sympathetic trophic factor involved in the control of fibroblasts in the connective tissue of dog liver. A similar role for adenosine had previously been found in the dog saphenous vein.

Adenosine↗