Postganglionic Parasympathetic Fibers Research Articles

Modified technique improves efficacy for in-office posterior nasal nerve ablation.

Posterior nasal nerve (PNN) ablation is a minimally invasive treatment option for patients with chronic rhinitis. Recent evidence shows that parasympathetic innervation of the nasal cavity is more extensive and there are many fibers posterior to the lateral attachment of the middle turbinate. We describe a modified ablative technique that targets the extensive innervation of the posterior nasal nerves. Description of the technique and retrospective cohort analysis. In addition to the traditional radiofrequency and cryoablation targets, three additional treatment sites posterior to the middle turbinate were targeted using radiofrequency ablation, as well as one focused treatment posteroinferior to the middle turbinate attachment using cryotherapy ablation. The primary outcome collected was a 30% improvement in overall rhinitis symptoms. Forty-five patients received treatment and completed 3-month follow-up using the modified technique for radiofrequency and cryotherapy PNN ablation. Previously, our institution documented a 64.5% responder rate at 3 months. After introducing the modified technique, the response rate at 3 months significantly improved (64.5% vs. 91.1%, p = .004). This report suggests improved efficacy with implementation of the modified technique for in-office PNN ablation. Given the extensive nature of the post-ganglionic parasympathetic fibers of the nasal cavity which often emerge posterior to the middle turbinate attachment, a modified technique to target these branches should be considered. Prospective randomized studies comparing this modified technique to the traditional technique are needed. III.

Autonomic Nerve Fibers Aberrantly Reinnervate Denervated Facial Muscles and Alter Muscle Fiber Population.

The surgical redirection of efferent neural input to a denervated muscle via a nerve transfer can reestablish neuromuscular control after nerve injuries. The role of autonomic nerve fibers during the process of muscular reinnervation remains largely unknown. Here, we investigated the neurobiological mechanisms behind the spontaneous functional recovery of denervated facial muscles in male rodents. Recovered facial muscles demonstrated an abundance of cholinergic axonal endings establishing functional neuromuscular junctions. The parasympathetic source of the neuronal input was confirmed to be in the pterygopalatine ganglion. Furthermore, the autonomically reinnervated facial muscles underwent a muscle fiber change to a purely intermediate muscle fiber population myosin heavy chain type IIa. Finally, electrophysiological tests revealed that the postganglionic parasympathetic fibers travel to the facial muscles via the sensory infraorbital nerve. Our findings demonstrated expanded neuromuscular plasticity of denervated striated muscles enabling functional recovery via alien autonomic fibers. These findings may further explain the underlying mechanisms of sensory protection implemented to prevent atrophy of a denervated muscle.SIGNIFICANCE STATEMENT Nerve injuries represent significant morbidity and disability for patients. Rewiring motor nerve fibers to other target muscles has shown to be a successful approach in the restoration of motor function. This demonstrates the remarkable capacity of the CNS to adapt to the needs of the neuromuscular system. Yet, the capability of skeletal muscles being reinnervated by nonmotor axons remains largely unknown. Here, we show that under deprivation of original efferent input, the neuromuscular system can undergo functional and morphologic remodeling via autonomic nerve fibers. This may explain neurobiological mechanisms of the sensory protection phenomenon, which is because of parasympathetic reinnervation.

Primary sialorrhea and its surgical treatment with denervation of the submandibular glands in combination with sublingual gland excision

ObjectivesThe purpose of this study was to evaluate the effectiveness of ablating postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision in the treatment of primary sialorrhea. Materials and methodsHealthy volunteers were initially chosen to determine a basic saliva flow rate value by saliva collection. Next, unstimulated and stimulated saliva flow rates, and a visual analog scale index for sialorrhea were recorded in all the patients pre- and postoperatively. In addition, the generalized anxiety disorder scale was used to assess preoperative anxiety symptoms. The follow-up durations ranged from 24 to 36 months after surgery. ResultsA total of 10 patients were included in this study. Preoperatively, the mean unstimulated saliva flow rate for the 10 patients was 11.26 ± 4.19 ml/10 min, the stimulated saliva flow rate was 16.76 ± 3.49 ml/6 min, and the visual analog scale index was 66.29 ± 14.86. Postoperatively, the mean unstimulated and stimulated saliva flow rates were significantly reduced to 5.99 ± 1.33 ml/10 min (p = 0.001) and 13.28 ± 1.86 ml/6 min (p = 0.013), respectively, and the visual analog scale index was 25.41 ± 5.6 (p < 0.001). No complications were found after operation. ConclusionThis study demonstrates that ablation of postganglionic parasympathetic fibers of the submandibular ganglion in combination with sublingual gland excision by an intraoral approach is a simple, safe, and efficient approach for treating primary sialorrhea.

Comparison of the 3-D patterns of the parasympathetic nervous system in the lung at late developmental stages between mouse and chicken

Although the basic schema of the body plan is similar among different species of amniotes (mammals, birds, and reptiles), the lung is an exception. Here, anatomy and physiology are considerably different, particularly between mammals and birds. In mammals, inhaled and exhaled airs mix in the airways, whereas in birds the inspired air flows unidirectionally without mixing with the expired air. This bird-specific respiration system is enabled by the complex tubular structures called parabronchi where gas exchange takes place, and also by the bellow-like air sacs appended to the main part of the lung. That the lung is predominantly governed by the parasympathetic nervous system has been shown mostly by physiological studies in mammals. However, how the parasympathetic nervous system in the lung is established during late development has largely been unexplored both in mammals and birds. In this study, by combining immunocytochemistry, the tissue-clearing CUBIC method, and ink-injection to airways, we have visualized the 3-D distribution patterns of parasympathetic nerves and ganglia in the lung at late developmental stages of mice and chickens. These patterns were further compared between these species, and three prominent similarities emerged: (1) parasympathetic postganglionic fibers and ganglia are widely distributed in the lung covering the proximal and distal portions, (2) the gas exchange units, alveoli in mice and parabronchi in chickens, are devoid of parasympathetic nerves, (3) parasympathetic nerves are in close association with smooth muscle cells, particularly at the base of the gas exchange units. These observations suggest that despite gross differences in anatomy, the basic mechanisms underlying parasympathetic control of smooth muscles and gas exchange might be conserved between mammals and birds.

Left paraaortic, inframesenteric lymphadenectomy preserving the superior hypogastric plexus supported by indocyanine green (ICG) labeling of the lymphatic compartment in cervical cancer

Superior hypogastric plexus (SHG) contains mainly sympathetic and most probably also postganglionic parasympathetic fibers. Thus, surgical damage of SHG may cause autonomic pelvic organ dysfunction (Kraima et al., 2015). As already shown for rectal cancer, preservation of the autonomic nerves is facilitated by robotic surgery and may avoid sexual dysfunctions and voiding disorders (Kim et al., 2015). In this educational video, we demonstrate left lower paraaortic lymph node dissection preserving the SHG using ICG fluorescence to label the lymphatic compartment.Prior to total mesometrial resection (TMMR) with therapeutic lymphadenectomy for cervical cancer (Höckel et al., 2009; Kimmig et al., 2013) 4×0.5ml of a 1.66mg/ml Indocyanine green solution (ICG Pulsion®, PMS SE, Feldkirchen, Germany) was injected into the uterine cervix at all four quadrants, 0.5cm in depth (Kimmig et al., 2016).The lymphatic network of the downstream common iliac and inferior paraaortic lymph compartments of the uterine cervix is visualized (ICG fluorescence) including the individual connecting vessels between the different compartments. As can be demonstrated, the medial upper common iliac (subaortic) compartment drains preferentially into the anterior (mesenteric) compartment, whereas lateral common iliac lymphatic vessels mainly drain to the posterior (lumbar) paraaortic compartment. The autonomic nerve fibers of the SHP may easily be identified and preserved due to the excellent image resolution and the discrimination from fluorescent lymphatic structures. The video shows the preparation of left lower paraaortic nodes in cervical cancer following ICG labeling using a da Vinci Xi system®. This technique seems not only advantageous for preserving SHP, but even more highly educational to learn surgical anatomy for trainees.

Careful Dissection of the Distal Ureter Is Highly Important in Nerve-sparing Radical Pelvic Surgery: A 3D Reconstruction and Immunohistochemical Characterization of the Vesical Plexus.

Radical hysterectomy with pelvic lymphadenectomy (RHL) is the preferred treatment for early-stage cervical cancer. Although oncological outcome is good with regard to recurrence and survival rates, it is well known that RHL might result in postoperative bladder impairments due to autonomic nerve disruption. The pelvic autonomic network has been extensively studied, but the anatomy of nerve fibers branching off the inferior hypogastric plexus to innervate the bladder is less known. Besides, the pathogenesis of bladder dysfunction after RHL is multifactorial but remains unclear. We studied the 3-dimensional anatomy and neuroanatomical composition of the vesical plexus and describe implications for RHL. Six female adult cadaveric pelvises were macroscopically dissected. Additionally, a series of 10 female fetal pelvises (embryonic age, 10-22 weeks) was studied. Paraffin-embedded blocks were transversely sliced in 8-μm sections. (Immuno) histological analysis was performed with hematoxylin and eosin, azan, and antibodies against S-100 (Schwann cells), tyrosine hydroxylase (postganglionic sympathetic fibers), and vasoactive intestinal peptide (postganglionic parasympathetic fibers). The results were 3-dimensionally visualized. The vesical plexus formed a group of nerve fibers branching off the ventral part of the inferior hypogastric plexus to innervate the bladder. In all adult and fetal specimens, the vesical plexus was closely related to the distal ureter and located in both the superficial and deep layers of the vesicouterine ligament. Efferent nerve fibers belonging to the vesical plexus predominantly expressed tyrosine hydroxylase and little vasoactive intestinal peptide. The vesical plexus is located in both layers of the vesicouterine ligament and has a very close relationship with the distal ureter. Complete mobilization of the ureter in RHL might cause bladder dysfunction due to sympathetic and parasympathetic denervation. Hence, the distal ureter should be regarded as a risk zone in which the vesical plexus can be damaged.

Clinical Anatomy of the Lesser Petrosal Nerve

Context: The human lesser petrosal nerve (LPN) is a branch of the glossopharyngeal nerve (IX), with contributions from the facial (VII) and vagus (X) nerves. Its formation and course are highly variable and complicated. The purpose of this article was to review the literature regarding the clinical anatomy of the LPN. Evidence Acquisition: The existing literature regarding this nerve was critically reviewed, with emphasis on its clinical significance. Results: The LPN conveys the preganglionic parasympathetic fibers derived from the superior and inferior salivary nucleus. It is composed of fibers from the tympanic branch of the IX, the nervus intermedius of the VII, and the auricular branch of the X. The fibers from the nervus intermedius and the auricular branch of the X separate from the VII as the communicating branch, which then joins the tympanic branch of the IX to form the LPN. The LPN leaves the middle ear and enters the middle cranial fossa through canaliculus innominatus. It runs under the dura in its own groove. In the infratemporal fossa, it reaches the otic ganglion. The postganglionic parasympathetic fibers distribute mainly to the parotid gland. Combined damage to the greater superficial petrosal nerve (GSPN) and the LPN is associated with face hyperemia and profuse salivation from the parotid gland (following atropine administration), lacrimation (crocodile tears syndrome), and mucus nasal secretion. These phenomena are explained by the development of an ephaptic relation between the damaged nerves. An understanding of the relationships of the LPN will reduce the likelihood of confusing it with the GSPN during surgical approaches to the middle cranial fossa. Conclusions: The LPN is anatomically one of the most complicated nerves in humans. Quite thin and small, it follows a variable and complicated course to serve primarily the preganglionic part of the parasympathetic innervation of the parotid gland. Its clinical significance results mainly from its close relation to the GSPN on the floor of the middle cranial fossa.

New insights in the neuroanatomy of the human adult superior hypogastric plexus and hypogastric nerves.

The superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP. Eight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres. All tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN. The human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri-aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation.

Cholinergic Drugs as Therapeutic Tools in Inflammatory Diseases: Participation of Neuronal and Non-Neuronal Cholinergic Systems.

Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) from acetylcoenzime A and choline. This reaction occurs not only in pre-ganglionic fibers of the autonomic nervous system and post-ganglionic parasympathetic nervous fibers but also in non neuronal cells. This knowledge led to expand the role of ACh as a neurotransmitter and to consider it as a "cytotransmitter" and also to evaluate the existence of a non-neuronal cholinergic system comprising ACh, ChAT, acetylcholinesterase, and the nicotinic and muscarinic ACh receptors, outside the nervous system. This review analyzes the participation of cholinergic system in inflammation and discusses the role of different muscarinic and nicotinic drugs that are being used to treat skin inflammatory disorders, asthma, and chronic obstructive pulmonary disease as well as, intestinal inflammation and systemic inflammatory diseases, among others, to assess the potential application of these compounds as therapeutic tools.

Síndrome de Frey – Uma visão global do tema

IntroductionFrey's syndrome is caused by a mechanical irritative lesion of the vegetative fibers from the auriculotemporal nerve. This lesion causes an abnormal regeneration of the post-ganglionic parasympathetic fibers to the receptors sweat gland and blood vessels, causing increases sensitivity, skin erythema and sudation during meals. MethodsA literature search was performed in PubMed, using a combination of words (Mesh terms), such as «Frey's syndrome» or «syndrome Auriculotemporal» or «gustatory sweating». Results262 articles, published between 1974 and 2012, were found. Papers were selected and categorized into several groups after reading their abstracts, to facilitate their analysis and exclude the less relevant to the study. This selection led to the achievement of the objectives of this paper, presenting the most relevant aspects of Frey's syndrome, including neuroanatomy, physiopathology, incidence, etiology, diagnosis, prevention and treatment. ConclusionAmong the patients who had parotidectomies only a few mentioned spontaneously symptoms suggestive of Frey's syndrome. Therefore the routine use of preventive procedures must be previously and thoroughly considered since it may mask tumoral relapse in the long term. When treatment is needed, the first choice is, still, the injection of botulinum toxin type A.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Potently Dilates Middle Meningeal Arteries: Implications for Migraine

Migraine is a debilitating neurological disorder characterized by mild to severe headache that is often accompanied by aura and other neurological symptoms. Among proposed mechanisms, dilation of the dural vasculature especially the middle meningeal artery (MMA) has been implicated as one component underlying this disorder. Several regulatory peptides from trigeminal sensory and sphenopalatine postganglionic parasympathetic fibers innervating these vessels have been implicated in the process including pituitary adenylate cyclase-activating polypeptide (PACAP). Although PACAP has been well described as a potent dilator in many vascular beds, the effects of PACAP on the dural vasculature are unclear. In the current study, we examined the ability of PACAP to dilate MMAs that were isolated from rats and pressurized ex vivo. PACAP38 potently dilated pressurized MMAs with an EC(50) of 1 pM. The PAC1 receptor antagonist, PACAP(6-38), abolished MMA dilation caused by picomolar concentrations of PACAP. In contrast, cerebellar arteries isolated from the brain surface were ~1,000-fold less sensitive to PACAP than MMAs. Although cerebellar arteries expressed transcripts for all three PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 receptors) by RT-PCR analyses, MMA demonstrated only PAC1 and VPAC2 receptor expression. Further, multiple variants of the PAC1 receptor were identified in the MMA. The expression of PAC1 receptors and the high potency of PACAP to induce MMA vasodilation are consistent with their potential roles in the etiology of migraine.

The "nicotinic" and "muscarinic" receptors of the urinary bladder of the guinea-pig.

Abstract The action of acetylcholine and nicotine on the urinary bladder of the guinea-pig has been examined using three techniques of physiological denervation. Nicotine was neurogenic and equiactive concentrations of acetylcholine were myogenic. Whilst acetylcholine has both “muscarinic” and “nicotinic” effects on the guinea-pig bladder, the concentration required to stimulate the nicotinic receptors was approximately 100 times that required for the muscarinic receptors. These results indicate that the nicotinic receptors are confined to nervous tissue, and do not support the suggestion that there might be non-neuronal nicotinic receptors in the bladder musculature of the guinea-pig. The possibility of a non-cholinergic component in the post-ganglionic parasympathetic fibres to the bladder should still be considered.

Frey’s syndrome - unusually long delayed clinical onset postparotidectomy: a case report

Frey's syndrome is a complication of parotidectomy that is thought to occur as a result of aberrant regeneration of the postganglionic parasympathetic nerve fibres supplying the parotid gland to severed postganglionic sympathetic fibres which innervate the sweat glands of the face. Frey's syndrome is difficult to treat but is a preventable phenomenon and surgeons must be aware of the available preventative methods during the initial surgery. An unusual case is presented involving a patient with delayed onset of Frey's syndrome 40 years after parotidectomy in childhood. The potential for this long-delayed clinical presentation should be discussed with the patient before surgery in the parotid gland. Diagnostic methods, preventive measures and management options are briefly discussed.

Mydriatic pupil in giant cell arteritis

A mydriatic pupil has been infrequently reported as a manifestation of giant cell arteritis. We report a patient with acute, evolving pupil dilation who was diagnosed with biopsy-proven giant cell arteritis. We document the time course for the development of pupillary near-light dissociation and denervation hypersensitivity. We discuss the possible mechanisms leading to mydriasis, including 1) parasympathetic dysfunction due to ischemia of the ciliary ganglion and post-ganglionic parasympathetic fibers and 2) direct iris ischemia. Repeated episodes of pupil dilation in this patient suggested ongoing microvascular insufficiency.

Tonic Pupil Following Pars Plana Vitrectomy and Endolaser

Tonic pupil was observed in a 67 year-old patient following a retinal detachment repair with pars plana vitrectomy, endolaser and silicone oil tamponade performed under retrobulbar anesthesia. The probable location of disturbance is the postganglionic parasympathetic fibers in the short ciliary nerves along their course to the pupil in the suprachoroidal space. A likely explanation for this phenomenon is injury to short ciliary nerves by endolaser treatment.

Neural Control of Substance P Induced Up-Regulation and Release of Macrophage Migration Inhibitory Factor in the Rat Bladder

Macrophage migration inhibitory factor is increased in intraluminal fluid after experimental inflammation and it mediates proinflammatory effects on the bladder. We examined the contribution of nerve activity and specific neurotransmitter systems to the mechanism of macrophage migration inhibitory factor release from the bladder during inflammation. Male Sprague-Dawley rats were anesthetized. The bladders were emptied and filled with saline. Rats received saline as a control (0.1 ml/100 gm body weight) or substance P (Sigma) (40 microg/kg in saline, 0.1 ml/100 gm body weight) subcutaneously as well as hexamethonium (Sigma) (50 mg/kg) intraperitoneally in saline (0.1 ml/100 gm body weight), lidocaine (2%, 0.3 ml) intravesically, atropine (Sigma) (3 mg/kg in saline, 0.1 ml/100 gm body weight) intravenously, propranolol (Sigma) (3 mg/kg in saline, 0.1 ml/100 gm body weight) intravenously or phentolamine (Sigma) (10 mg/kg in saline, 0.1 ml/100 gm body weight) intravenously. After 1 hour the intravesical fluid was removed and the bladder was excised. Macrophage migration inhibitory factor levels in intraluminal fluid were measured by enzyme-linked immunosorbent assay and Western blotting. MIF expression in bladder homogenates was examined using reverse transcriptase-polymerase chain reaction. Intravesical lidocaine or ganglionic blockage with hexamethonium prevented substance P induced macrophage migration inhibitory factor release. In addition, pretreatment with atropine and phentolamine but not propranolol also prevented macrophage migration inhibitory factor release. While MIF up-regulation in the bladder was increased with substance P treatment, it was only prevented by intravesical lidocaine. Substance P induced macrophage migration inhibitory factor release in the bladder is mediated through nerve activation. Postganglionic parasympathetic (via muscarinic receptors) and sympathetic (via alpha-adrenergic receptors) fibers mediate macrophage migration inhibitory factor release, while activating bladder afferent nerve terminals up-regulates MIF.

Sympathetic (Adrenergic) Innervation Modulates But Does Not Generate Basal Tone in the Internal Anal Sphincter Smooth Muscle

Sympathetic (Adrenergic) Innervation Modulates But Does Not Generate Basal Tone in the Internal Anal Sphincter Smooth Muscle

Endoscopic posterior nasal neurectomy: An alternative to vidian neurectomy

Vidian neurectomy is a proven surgical treatment for the symptoms of allergic and nonallergic rhinitis. However, complications such as dry eye, cheek and dental numbness, disturbance of eye movements, and even blindness remain. I describe a method for endoscopic resection of the posterior superior and inferior nasal nerves. My approach exposes postganglionic parasympathetic nerve fibers (the posterior superior nasal nerve) at the sphenopalatine foramen to allow resection of a segment of the nerve under direct vision. The surgeon is able to control intraoperative bleeding without resection of the sphenopalatine artery and achieve the effectiveness of vidian neurectomy without the complications. Vidian neurectomy is a proven surgical treatment for the symptoms of allergic and nonallergic rhinitis. However, complications such as dry eye, cheek and dental numbness, disturbance of eye movements, and even blindness remain. I describe a method for endoscopic resection of the posterior superior and inferior nasal nerves. My approach exposes postganglionic parasympathetic nerve fibers (the posterior superior nasal nerve) at the sphenopalatine foramen to allow resection of a segment of the nerve under direct vision. The surgeon is able to control intraoperative bleeding without resection of the sphenopalatine artery and achieve the effectiveness of vidian neurectomy without the complications.

Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.

Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

Nitric oxide facilitates vagal control of heart rate via actions in the cardiac parasympathetic ganglia of the anaesthetised dog.

The effects of neuronal inhibition of nitric oxide (NO) production on the bradycardia resulting from stimulation of preganglionic and postganglionic parasympathetic fibres were investigated in an anaesthetised dog preparation following transection of the cervical vagi and in the presence of a beta-adrenoreceptor antagonist. Injection of 1-(2-trifluoromethylphenyl) imidazole (TRIM), an inhibitor of neuronally released NO, into the sinus node artery reduced the bradycardia evoked by right cervical vagal stimulation. In contrast, when the response to preganglionic stimulation had been abolished by hexamethonium (10 mg kg(-1)), the bradycardia following stimulation of postganglionic parasympathetic fibres on the atrial epicardium was unaffected by TRIM. First, these results confirm the facilitatory actions of neuronally released NO on vagal heart responses in the dog. Second, they indicate that this modulatory and facilitatory role of NO is likely to be exerted at vagal preganglionic-postganglionic synaptic mechanisms in the cardiac parasympathetic ganglia and not at the postganglionic-sinoatrial node synapse.