Parasympathetic Decentralization Research Articles

Anandamide injected into the lateral ventricle of the brain inhibits submandibular salivary secretion by attenuating parasympathetic neurotransmission

Our objective was to determine the effect of arachidonylethanolamide (anandamide, AEA) injected intracerebroventricularly (icv) into the lateral ventricle of the rat brain on submandibular gland (SMG) salivary secretion. Parasympathetic decentralization (PSD) produced by cutting the chorda tympani nerve strongly inhibited methacholine (MC)-induced salivary secretion while sympathetic denervation (SD) produced by removing the superior cervical ganglia reduced it slightly. Also, AEA (50 ng/5 microL, icv) significantly decreased MC-induced salivary secretion in intact rats (MC 1 microg/kg: control (C), 5.3 +/- 0.6 vs AEA, 2.7 +/- 0.6 mg; MC 3 microg/kg: C, 17.6 +/- 1.0 vs AEA, 8.7 +/- 0.9 mg; MC 10 microg/kg: C, 37.4 +/- 1.2 vs AEA, 22.9 +/- 2.6 mg). However, AEA did not alter the significantly reduced salivary secretion in rats with PSD, but decreased the slightly reduced salivary secretion in rats with SD (MC 1 microg/kg: C, 3.8 +/- 0.8 vs AEA, 1.4 +/- 0.6 mg; MC 3 microg/kg: C, 14.7 +/- 2.4 vs AEA, 6.9 +/- 1.2 mg; P < 0.05; MC 10 microg/kg: C, 39.5 +/- 1.0 vs AEA, 22.3 +/- 0.5 mg; P < 0.001). We showed that the inhibitory effect of AEA is mediated by cannabinoid type 1 CB1 receptors and involves GABAergic neurotransmission, since it was blocked by previous injection of the CB1 receptor antagonist AM251 (500 ng/5 microL, icv) or of the GABA A receptor antagonist, bicuculline (25 ng/5 microL, icv). Our results suggest that parasympathetic neurotransmission from the central nervous system to the SMG can be inhibited by endocannabinoid and GABAergic systems.

Effect of parasympathetic decentralization on interferon-gamma release from rat submandibular lymph nodes in vitro

The aim of this study was to examine the regulation of interferon (IFN)-gamma release by cells from submandibular lymph nodes of rats subjected to a unilateral parasympathetic decentralization by severing the ipsilateral chorda tympani 7 days earlier. Cells obtained from contralateral sham-operated submandibular lymph nodes were employed as control. Parasympathetic decentralization of lymph nodes resulted in significantly less IFN-gamma release as compared to that found in innervated lymph nodes. Mitogens (lipopolysaccharide, concanavalin A) stimulated IFN-gamma release in cells derived from the innervated lymph nodes only. The muscarinic agonist metacholine decreased IFN-gamma release in cells derived from innervated lymph nodes. At the highest concentration employed (10 −4 M), metacholine suppressed the stimulatory effect of mitogens on IFN-gamma release in cells of innervated lymph nodes while the muscarinic antagonist atropine (10 −8–10 −4 M) lacked to affect IFN-gamma release. Addition of nicotine (10 −5–10 −3 M) failed to modify IFN-gamma release. The results support the occurrence of significant effects of local parasympathetics in modulating IFN-gamma release by submandibular lymph nodes.

Effect of local autonomic denervation on in vitro responsiveness of lymphocytes from rat submaxillary lymph nodes

The local autonomic denervation of rat submaxillary lymph nodes was achieved by a unilateral sympathetic superior cervical ganglionectomy and/or the unilateral section of chorda tympani (that resulted in ipsilateral parasympathetic decentralization of the submandibular territory). This study was performed to determine: (1) whether local sympathetic and/or parasympathetic denervation of rat submaxillary lymph nodes brought about changes in lymph node cellularity, natural killer activity and lipopolysaccharide (LPS)- and concanavalin A (Con A)-induced cell proliferation in Freund's adjuvant-injected rats; (2) whether the effect of the immunosuppressive drug cyclosporine in rat submaxillary lymph nodes was affected by a single or combined unilateral ganglionectomy plus decentralization. A unilateral ganglionectomy, or the combination of ganglionectomy plus decentralization, performed 7 days earlier, decreased significantly cellularity in ipsilateral submaxillary lymph nodes, while a unilateral decentralization failed to affect it. Natural killer activity increased ipsilaterally after ganglionectomy or decentralization, and decreased after the combined surgical procedure. LPS-induced cell proliferation augmented significantly after ganglionectomy or decentralization, while Con A-induced T lymphocyte proliferation remained unaffected. In the sham-operated side, cyclosporine decreased submaxillary lymph node cell number and natural killer activity, while it increased the proliferative response to LPS. The depressive effect of cyclosporine on lymph node cellularity was no longer observed in ganglionectomized or decentralized lymph nodes, but was found after the combined surgical denervation. Decentralization, or decentralization plus ganglionectomy, blunted the depressive effect of cyclosporine on natural killer activity. The stimulatory effect of cyclosporine on lymphocyte proliferation induced by LPS was reversed both by ganglionectomy or by decentralization and was suppressed by the combined surgical procedure. Neither treatment affected Con A-induced proliferation of T lymphocytes. The results further indicate that an appropriate sympathetic and parasympathetic local environment may be needed for immunomodulation, as well as for cyclosporine activity in lymphoid tissue.

Age-dependent effect of pituitary transplants on immune responses in rat submaxillary lymph nodes: modulatory effect of the autonomic nervous system.

An anterior pituitary was grafted into the breast muscles of male rats on day 5, or under the kidney capsule on day 30 or 60 of life. At the 70th day of life (rats operated at the 5th or 30th day) or at the 100th day of life (rats operated at the 60th day), rats were injected subcutaneously with Freund's complete adjuvant, being killed 2 days later. Rats pituitary-grafted at the 30th day showed a greater hyperprolactinemia than rats grafted at the 5th or 60th day. Submaxillary lymph node natural killer (NK) activity decreased in neonatally pituitary-grafted rats and increased in rats grafted at the 30th or 60th day of life, while lymph node cellularity decreased in rats grafted at the 30th or 60th day. In the case of lipopolysaccharide (LPS)-and concanavalin A (Con A)-induced cell proliferation in lymph nodes, the only significant factor detected was age of transplantation, the effect being less evident in older animals. To examine whether the autonomic denervation of submaxillary lymph nodes affected immune responses in pituitary-grafted rats, animals were subjected to a unilateral superior cervical ganglionectomy (Gx) and/or a parasympathetic decentralization (Dc; by chorda tympani section), 10 days before immunization with Freund's adjuvant. A unilateral Gx blunted the stimulation of lymph node NK activity in rats receiving a pituitary transplant at the 30th or 60th day, but not at the 5th day. Only in sympathetically denervated lymph nodes a significant effect of pituitary transplants on LPS mitogenic effect was found, with significantly less effect of LPS in rats pituitary-grafted at the 5th or 30th day of life. Regarding Con A, a unilateral Gx or unilateral Gx plus Dc uncovered a significant depressive effect of pituitary transplants with a significantly smaller Con A mitogenic effect at each studied age in ipsilaterally Gx lymph nodes, and at 30 and 60 days of age in ipsilaterally Gx plus Dc lymph nodes. Pituitary grafts augmented Con A- induced proliferation in submaxillary lymph nodes at the 5th day of life while they decreased it at the 60th day of life. Pituitary transplants augmented cellularity at the sympathetically denervated lymph nodes and decreased it at the contralateral sham-operated side. Pituitary transplants also diminished lymph node cellularity at the Dc side, the effect being significant in rats transplanted at the 30th day of life. The results are compatible with age-dependent, inhibitory as well as promoting activities of hyperprolactinemia on immune responses in submaxillary lymph nodes, depending in part on intact autonomic nerves.

Diurnal changes in cyclosporine effect on ornithine decarboxylase and noradrenergic and cholinergic activities in submaxillary lymph nodes

Diurnal changes in cyclosporine efficacy to affect ornithine decarboxylase activity, [ 3H]norepinephrine uptake and [ 3H]choline conversion into [ 3H]acetylcholine were examined in rat submaxillary lymph nodes. Cyclosporine (5 or 20 mg/kg) caused a dose-dependent decrease in lymph node ornithine decarboxylase, being active at 5 or 20 mg/kg in Freund's adjuvant-treated rats, and at 20 mg/kg in rats treated with the adjuvant's vehicle. In immunized rats the lower cyclosporine dose was ineffective when injected during the night. Cyclosporine increased lymph node [ 3H]norepinephrine uptake dose dependently, with significant differences between the 20 mg/kg dose and controls in vehicle-treated rats and between 5 or 20 mg/kg and controls in Freund's adjuvant-treated rats. In immunized rats, 5 mg/kg cyclosporine increased [ 3H]norepinephrine uptake when injected at 13:00 or 17:00 h. Both doses of cyclosporine augmented lymph node synthesis of [ 3H]acetylcholine to a similar extent. In immunized and non-immunized rats cyclosporine suppressed the diurnal rhythm of lymph node adrenergic and cholinergic activity found in controls. After unilateral sympathetic denervation (by superior cervical ganglionectomy) and/or unilateral parasympathetic decentralization (by chorda tympani section), cyclosporine (5 mg/kg) decreased Freund's adjuvant-induced activation of lymph node ornithine decarboxylase when injected at 17:00 or 01:00 h. On the sham-operated side, cyclosporine was effective when injected at 17:00 h only. Decentralization, or a combined ganglionectomy plus decentralization, decreased lymph node ornithine decarboxylase activity. The results indicate active regulation of the effects of cyclosporine in submaxillary lymph nodes by local autonomic nerves.

Diurnal rhythm in ornithine decar☐ylase activity and noradrenergic and cholinergic markers in rat submaxillary lymph nodes

Diurnal variations in lymph node ornithine decar☐ylase activity were examined in submaxillary lymph nodes of rats injected with Freund's complete adjuvant or its vehicle. After immunization, lymph node ornithine decar☐ylase activity increased by about 10-fold. Both in immunized and non-immunized rats, a significant diurnal variation in ornithine decar☐ylase activity at early (i.e. 13.00 h, vehicle) or late afternoon (i.e. 17.00 h, Freund's adjuvant). Injection of Freund's adjuvant during daylight or at night resulted in similar day-night differences in submaxillary lymph node ornithine decar☐ylase activity. In rats subjected to the sympathetic postganglionic denervation (by ipsilateral superior cervical ganglionectomy) or the preganglionic parasympathetic decentralization (by chorda tympani section) of submaxillary lymph nodes, nyctohemeral variations in ornithine decar☐ylase were still present, showing a maximum at 17.00 h. Superior cervical ganglionectomy augmented lymph node ornithine decar☐ylase while chorda tympani section decreased it. When a unilateral superior cervical ganglionectomy plus chorda tympani section was performed, the diurnal changes in ornithine decar☐ylase were abolished. [ 3H]Norepinephrine uptake and tyrosine hydroxylase activity attained their maxima in submaxillary lymph nodes at early night. After immunization, these two presynaptic indicators of sympathetic activity in submaxillary lymph nodes augmented significantly. Neuronal [ 3H]choline uptake and [ 3H]choline conversion into acetylcholine (two indicators of cholinergic activity) also augmented in lymph nodes of rats injected with Freund's adjuvant. In immunized rats, maxima in [ 3H]choline uptake and [ 3H]acetylcholine synthesis were found at 13.00–17.00 h while in non-immunized rats, a maximum in acetylcholine synthesis was found at 17.00 h. The results are compatible with the view that the autonomic nervous system plays a role in circadian changes of immune responsiveness in lymphoid tissue and that a significant augmentation of presynaptic autonomic activity takes place during immunization in lymphoid tissue.

Effect of stress and cyclosporine on ornithine decarboxylase activity in rat submaxillary lymph nodes

This study was performed: (1) to assess whether the stress produced in rats by daily turpentine oil injections for 5 days, or by restraining the animals for 30 min during 5 days, affected basal and Freund's adjuvant-stimulated submaxillary lymph node ornithine decarboxylase activity, an indicator of cell proliferation; (2) to analyze whether the activity of the immunosuppressive drug cyclosporine on submaxillary lymph node ornithine decarboxylase activation after Freund's adjuvant injection was modified in stressed rats; (3) to examine the mediation of stress effects on submaxillary lymph node ornithine decarboxylase activation by regional sympathetic or parasympathetic nerves. Animals subjected to a unilateral superior cervical ganglionectomy, or to a unilateral chorda tympani section, together with a contralateral sham-operation were employed. After turpentine oil or restraint stress, a significant decrease in submaxillary lymph node ornithine decarboxylase was found. A unilateral sympathetic denervation of submaxillary lymph nodes counteracted in part the inhibitory effect of stress on ornithine decarboxylase activation, as well as augmented the enzyme response in innervated submaxillary lymph nodes. Ornithine decarboxylase activation attained similar values in parasympathetic decentralized or intact submaxillary lymph nodes and the unilateral parasympathetic decentralization did not interfere with the inhibition of enzyme activity found in turpentine oil-stressed rats. Cyclosporine administration (5 or 20 mg/kg) significantly decreased Freund's adjuvant-induced ornithine decarboxylase activity in the submaxillary lymph nodes of control rats, but failed to modify it in turpentine oil-stressed animals. In this latter group, a higher (40 mg/kg) dose of cyclosporine decreased ornithine decarboxylase activity on the innervated side only. A diminished inhibitory response to cyclosporine was found in the parasympathetic decentralized submaxillary lymph nodes of unstressed rats. The results support the view that the immunosuppressive effects of cyclosporine may diminish during stress, in part due to changes in the traffic of neural signals in local sympathetic nerves.

Cyclosporine effect on ornithine decarboxylase activity in rat submaxillary lymph nodes. Modulation by parasympathetic nerves

This study was performed: (1) to assess whether cyclosporine affected the increase in submaxillary lymph node ornithine decarboxylase activity induced by complete Freund's adjuvant injection to rats bearing a regional parasympathetic decentralization; (2) to examine the effect of cyclosporine on cholinergic markers in submaxillary lymph nodes of rats injected with complete Freund's adjuvant or its vehicle. The unilateral parasympathetic decentralization of the submaxillary lymph nodes was achieved by unilateral chorda tympani section; each rat was also contralaterally sham-operated. A 73% decrease of choline acetyltransferase activity and a 78% decrease of neuronal [ 3H]choline uptake, were found in the ipsilateral side 2 weeks after surgery. Cyclosporine (5 or 20 mg/kg) or its vehicle was s.c. injected once daily for 5 days. Freund's complete adjuvant or its vehicle was injected s.c. 1 h before the 3rd injection of cyclosporine. The animals were killed 2 h after the last cyclosporine injection. Parasympathetic decentralization of the submaxillary lymph nodes was followed, 2 weeks later, by a significant inhibition of cyclosporine activity on Freund's adjuvant-induced ornithine decarboxylase. In rats injected with complete Freund's adjuvant or its vehicle, sympathetic denervation of submaxillary lymph nodes achieved by unilateral superior cervical ganglionectomy, augmented the stimulatory activity of cyclosporine on choline acetyltransferase and neuronal choline uptake. Cyclosporine treatment did not modify the total [ 3H]choline uptake, regardless of Freund's adjuvant injection or of intactness of the sympathetic innervation. Choline acetyltransferase and choline uptake were significantly augmented by the injection of Freund's adjuvant alone. The results indicate that an appropriate parasympathetic local environment is needed for cyclosporine immunomodulation in lymphoid tissue, and that cyclosporine augmented cholinergic activity in submaxillary lymph nodes, an effect amplified by regional sympathetic denervation. Cholinergic markers in lymphoid tissue increased during the immune reaction.

Local regulation of the immune response by the autonomic nervous system.

The autonomic innervation of the lymphoid tissue is currently visualized as a channel for neural regulation of immunity. Several reports have dealt with the alteration of antibody responses of spleen and lymph nodes following sympathectomy, and less often, parasympathectomy. This article reviews published data on the local effects of sympathetic and parasympathetic neurons innervating immunocompetent organs on immune responsiveness. A model comprising bilateral lymphoid organs (the submaxillary lymph nodes) and the local ipsilateral manipulation of their regional sympathetic nerves (derived from the superior cervical ganglia) and of their regional parasympathetic nerves (conveyed through the lingual nerve-chorda tympani) allowed the description of purely local effects of the autonomic nerves independent of the systemic effects of the surgical manipulation itself. By employing this model, the following were observed. (1) After the unilateral sympathetic denervation of murine submaxillary lymph nodes by superior cervical ganglionectomy (SCGx), ipsilateral increases in plate-forming cell (PFC) activity, delayed hypersensitivity and graft-versus-host reactions were observed as compared to the contralateral, sham-operated, submaxillary lymph nodes. During degeneration of peripheral sympathetic nerves shortly after SCGx, PFC activity in ipsilateral submaxillary lymph nodes decreased significantly. (2) The local parasympathetic decentralization of murine submaxillary lymph nodes, achieved by the unilateral section of the chorda tympani, resulted in decreases of PFC activity, when challenged 10-20 days after denervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Local Regulation of the Immune Response by the Autonomic Nervous System (Part 2 of 2)

The autonomic innervation of the lymphoid tissue is currently visualized as a channel for neural regulation of immunity. Several reports have dealt with the alteration of antibody responses of spleen and lymph nodes following sympathectomy, and less often, parasympa-thectomy. This article reviwes published data on the local effects of sympathetic and parasympathetic neurons innervating immunocompetent organs on immune responsiveness. A model comprising bilateral lymphoid organs (the submaxillary lymph nodes) and the local ipsilateral manipulation of their regional sympathetic nerves (derived from the superior cervical ganglia) and of their regional parasympathetic nerves (conveyed through the lingual nerve-chorda tympani) allowed the description of purely local effects of the autonomic nerves independent of the systemic effects of the surgical manipulation itself. By employing this model, the following were observed. (1) After the unilateral sympathetic denervation of murine submaxillary lymph nodes by superior cervical ganglionectomy (SCGx), ipsilateral increases in plate-forming cell (PFC) activity, delayed hypersensitivity and graft-versus-host reactions were observed as compared to the contralateral, sham-operated, submaxillary lymph nodes. During degeneration of peripheral sympathetic nerves shortly after SCGx, PFC activity in ipsilateral submaxillary lymph nodes decreased significantly. (2) The local parasympathetic decentralization of murine submaxillary lymph nodes, achieved by the unilateral section of the chorda tympani, resulted in decreases of PFC activity, when challenged 10-20 days after denervation. (3) In the course of the immune reaction induced by the injection of complete Freund's adjuvant in rats, an augmented activity of local autonomic nerves was found in the submaxillary lymph nodes, as shown by the increase of neuronal norepinephrine uptake and tyrosine hydroxylase activity (two markers of noradrenergic activity), and of neuronal choline uptake and choline acetyltransferase activity (two markers of cholinergic activity). (4) Coincident with the augmented immune response after local sympathetic denervation of submaxillary lymph nodes, the growth of transplanted tumors in the cutaneous territory was significantly impaired in rats. (5) In the absence of an intact local sympathetic innervation, the effect of the immunosuppressive drug cyclosporine in rat submaxillary lymph nodes [as assessed by the inhibition of ornithine decarboxylase (ODQ induction after complete Freund's adjuvant injection] became significantly attenuated. (6) A similar impairment of cyclosporine activity on submaxillary lymph node ODC was found in Freund's-adjuvant-treated rats subjected to a regional unilateral parasympathetic decentralization by chorda tympani section 2 weeks later. (7) In rats injected with either Freund's adjuvant or its vehicle, the sympathetic denervation of submaxillary lymph nodes by unilateral SCGx augmented the stimulatory activity of cyclosporine on choline acetyltransferase and neuronal choline uptake. The results indicate that an appropriate sympathetic and parasympathetic local environment is needed for normal immune responsiveness and immunomodu-lation.

Effects of parasympathetic decentralization on some nerve‐mediated functions in the feline urinary bladder

Isolated detrusor muscle from control cats and cats parasympathetically decentralized for 3 and 10 weeks responded to electrical field stimulation by tetrodotoxin-sensitive, frequency-dependent contractions. There were no significant differences in the frequencies producing 50% response. However, the amplitude of the scopolamine-resistant contraction was distinctly lower in decentralized bladder preparations than in controls. Decentralized detrusor muscle (10 weeks) showed no increased response to alpha-adrenoceptor stimulation (phenylephrine, clonidine, noradrenaline), but the sensitivity to carbachol (at 3 and 10 weeks) was significantly decreased compared with controls. The release of [3H]noradrenaline was decreased by carbachol 10(-7) to 10(-5) M both in controls and in decentralized (10 weeks) detrusor muscle, the decrease being significantly more pronounced in the decentralized group at carbachol concentrations of 10(-7) and 10(-6) M. There were no differences between controls and decentralized bladders of muscarinic receptor concentration, but decentralization significantly reduced the affinity for the radioligand used to label the receptors. Thus, the main changes caused by parasympathetic decentralization of the feline bladder seem to be a reduced post-junctional, but an increased prejunctional response to muscarinic receptor stimulation.

Parasympathetic postganglionic pathways to the sinoatrial node

Vagal ganglia that innervate the canine sinoatrial node (SAN) have been localized to a fat pad overlying and surrounding the right pulmonary vein complex (PVFP). The ventral epicardial surface of the right atrium was mapped in seven dogs anesthetized with alpha-chloralose after beta-blockade (timolol) and cardiac sympathetic and parasympathetic decentralization. A small, concentric bipolar exploring electrode was used to stimulate (during the atrial refractory period and using trains of five to eight stimuli per beat) systematically in the epicardial regions between the PVFP and the SAN. Changes in SAN rate with stimulation were measured, and the anatomic location was identified on a 150-point grid fitted to conform to size and shape of the atrium. Mapping was performed before and after local (PVFP) and systemic ganglionic blockade (hexamethonium). Data reveal that the primary vagal postganglionic pathways to the sinoatrial nodal region are subepicardial and adjacent to the SAN artery along the sulcus terminalis. Hexamethonium in the PVFP abolishes SAN inhibition during preganglionic vagal excitation, without interrupting vagal suppression of atrioventricular conduction. However, SAN slowing (with varying attenuation) continued to occur after hexamethonium (either PVFP or systemically) when the exploring electrode was applied directly over intramural postganglionic fibers between PVFP and sinus node. Attention is directed to existence of a very few synapses closer to SAN, probably in isolated ganglia immersed in fatty connective tissues along the sulcus terminalis.

"Paralytic' secretion after parasympathectomy of rabbit submandibular glands includes a cholinergic component.

Chronic parasympathetic decentralization of submandibular glands in rabbits has been studied after 3 weeks, in acute experiments under urethane anaesthesia. A "paralytic' secretion occurred from the supersensitive denervated glands and it was not attributable to an increase in the "spontaneous' flow, that is present in normal glands. The "paralytic' secretion was completely inhibited by atropine, after which a "spontaneous' flow, that was similar to the contralateral glands, persisted. The alpha-adrenergic blocker dihydroergotamine, when given before atropine, reduced the "paralytic' secretion by 50-75% but when this drug was given after atropine it had no additional effect. The beta-adrenergic blocker propanolol did not cause a reduction in the "paralytic' secretion. Superior cervical ganglionectomy, in contrast, did not give rise to a significant "paralytic' flow. The results suggest that acetylcholine, released spontaneously from terminals of postganglionic parasympathetic nerves, plays an essential part in the "paralytic' secretion that occurs from rabbit submandibular glands after preganglionic denervation. Circulating catecholamines make a secondary contribution, acting synergistically with the acetylcholine on the supersensitive secretory cells.

Current concepts in the treatment of disorders of micturition.

Disorders of micturition may be divided into disturbances of the storage function of the bladder, and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency and incontinence. Hyperactivity of the bladder may lead to urge incontinence, and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating bladder hyperactivity, but their efficacy as judged from controlled clinical trials (when available) is often limited. Bladder contraction in man is mediated by stimulation of muscarinic receptors, and when given parenterally anticholinergic drugs have been shown to depress bladder hyperactivity irrespective of the underlying cause. Clinically, however, treatment of urge incontinence with anticholinergic drugs is often unsatisfactory. Lack of effect of oral treatment and systemic side effects limit the use of available agents. Drugs with "mixed" actions (anticholinergic and 'direct' muscle effects), for example oxybutynin and terodiline, have well-documented efficacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems to be well tolerated. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of orally active alpha-adrenoceptor agonists (e.g. phenylpropanolamine) and/or oestrogens. The main symptom of disturbed bladder emptying is urinary retention. Drug therapy is aimed at improving the contractile activity of the detrusor or reducing urethral outflow resistance. Drugs used for improving bladder contractility include parasympathomimetic agents, e.g. bethanechol or carbachol, and intravesical instillation of prostaglandins. Although the efficacy of both types of treatment is open to question, bethanechol seems to be widely used. Increased outflow resistance may be seen in patients with parasympathetic decentralization of the lower urinary tract or in patients with benign prostatic hypertrophy. These patients may respond favourably to alpha-adrenoceptor blockers such as phenoxybenzamine or prazosin.

Intrinsic neuromuscular defects in the neurogenic bladder: VIII. Effects of unilateral pelvic and pelvic plexus neurectomy on ultrastructure of the feline bladder base

AbstractIt has been shown previously that unilateral parasympathetic decentralization of the feline bladder by sacral ventral rhizotomy results in early degenerative and eventual regenerative ultrastructural neuromuscular changes in the bladder base. The present study was conducted to define the effects of unilateral parasympathetic decentralization by pelvic neurectomy and postganglionic “denervation” by pelvic plexus neurectomy on the neuromuscular ultrastructure of the feline bladder base. Eighteen sexually mature male cats were used. Three cats provided the control material; six cats underwent unilateral pelvic and nine unilateral pelvic plexus neurectomy. Bladders were collected for study 2, 3, and 10 weeks following the former and 1–4 days, 3 weeks, and 7–12 weeks following the latter procedure. Samples from both the neurectomized and the intact sides of each bladder were obtained for electron microscopic study. The ultrastructural neuromuscular changes observed after pelvic neurectomy were identical to those previously described following unilateral sacral ventral rhizotomy, except for early developing and persistent, widespread degeneration of myelinated axons in the former model. As in the rhizotomy model, there was cholinergic axonal regeneration, adrenergic hyperinnervation, and a prominent population of probable copeptidergic axons in long‐term samples of the bladder base following pelvic neurectomy. In contrast, pelvic plexus neurectomy (a postganglionic “denervation” procedure) resulted in early developing and persistent degeneration of all axons in the bladder base: i.e., myelinated, cholinergic and adrenergic, with long‐term hypoinnervation by both cholinergic and adrenergic neural elements. Our observations indicate that two forms of the experimentally induced lower‐motor neurogenic bladder can be distinguished ultrastructurally.

Intrinsic neuromuscular defects in the neurogenic bladder: IX. Effects of combined parasympathetic decentralization and hypogastric neurectomy on neuromuscular ultrastructure of the feline bladder base

AbstractPrevious studies have shown that unilateral decentralization of the feline bladder by sacral ventral rhizotomy results in ultrastructural neuromuscular changes in the bladder base. In the present study, the neuromuscular ultrastructure of the feline bladder base was studied in twenty sexually mature adult male cats 1–4 and 6–10 weeks following bilateral sacral rhizotomy, alone and combined with hypogastric neurectomy. The former procedure resulted in initial degeneration of cholinergic axons with loss of their neuroeffector junctions, but the adrenergic axons and neuroeffector junctions were preserved; within 6–10 weeks, the bladder base became re‐innervated by regenerated cholinergic, increased adrenergic, and abundant probable copeptidergic axons. In contrast, combined sacral rhizotomy and hypogastric neurectomy resulted in persistent (up to 10 weeks) degeneration of both cholinergic and adrenergic axons with loss of their neuroeffector junctions, and no adrenergic hyperinnervation, with only a modest increase in probable copeptidergic axons in long‐term samples. Our observations indicate that intact efferent sympathetic pathways are essential for eventual cholinergic re‐innervation and adrenergic hyperinnervation of the decentralized bladder and suggest that the latter is an important factor in the development of vesical hypertonicity in lower‐motor neuron lesions. On this basis, we introduce the concept that two functional types of the lower motor neurogenic bladder–i.e., the hypertonic with intact and the normotonic with injured efferent sympathetic pathways–may be distinguishable morphologically by ultrastructural study of the vesical muscularis.

Influence of Thyroid Function Upon “Substance P” Induced Secretion of Saliva by Submaxillary Glands

The effects of changes in thyroid function on the action of "Substance P" upon the secretion of saliva by the submaxillary glands was studied in male Wistar rats, with parasympathetic decentralization on the left side. The dose-response curves to increasing doses of "Substance P" showed in hyperthyroid animals increased salivary secretion while in hypothyroid animals the dose-response curve to the drug was decreased. Every animal showed supersentivity to "Substance P" in the decentralized gland. The influence of changes in thyroid function in the denervated glands was the same as that in the unoperated side, increased salivary secretion in hyperthyroidism and decreased in hypothyroidism.

The Effect of Parasympathetic Decentralization on the Feline Urinary Bladder

To examine the pharmacologic nature of parasympathetic decentralization on feline vesical smooth muscle, male cats were subjected to bilateral ventral rhizotomy from levels lumbar 7 to coccygeal 1 and studied at 1 and 3 months. By employing manual bladder decompression twice daily, compensatory bladder hypertrophy was absent or minimal in all specimens. In vitro muscle bath studies of bladder body demonstrated no significant end organ pharmacologic supersensitivity to cholinergic or alpha and beta adrenergic stimulation. Membrane receptor assays displayed a rise in muscarinic cholinergic and beta adrenergic receptors at 1 month which decreased at 3 months. The cholinergic receptor data parallels ultrastructural studies which demonstrate early cholinergic nerve terminal degeneration after motor decentralization followed by subsequent regrowth of cholinergic axons. Alpha 1 and alpha 2 adrenergic receptor densities remained constant in control, 1 month, and 3 month preparations. This lack of classic end organ denervation supersensitivity in the decentralized urinary bladder suggests that other mechanisms may be responsible for eliciting a positive response with the clinical denervation supersensitivity test.

Benzodiazepine binding sites in rat submaxillary gland: Absence of markers of GABA system

1. Specific binding of [ 3H]diazepam to the nuclear, mitochondrial and microsomal subcellular fractions of the rat submaxillary gland is reported. Apparent K d values were similar in the three fractions studied (around 80 nM). 2. The nuclear and mitochondrial fractions contain 95% of the total sites detected (20 pmoles/mg prot.). 3. The sites exhibit a much higher affinity for Ro 5-4864 than for clonazepam or Ro 15-1788, and are not modified by 10 −6 to 10 −4 GABA or 10 −5M bicuculline. 4. Neither sympathetic denervation or parasympathetic decentralization modified [ 3H]Dz binding, which is found to be considerably lower in the early post-natal state as well as following duct ligation of the gland of adult rats. 5. The results suggest that these peripheral Bz binding sites are mainly located in the acini. 6. No specific GABA binding or GAD activity was detected either in the presence or absence of NaCl. 7. Very low levels of endogenous GABA (58 ± 3 nmoles/g tissue) were found in homogenates of the gland.

Vasoactive intestinal peptide and substance P in salivary glands of the rat following denervation or duct ligation.

Immunoreactive vasoactive intestinal peptide (VIP) and substance P (SP) were studied in parotid, submaxillary and sublingual glands of the rat. The concentration of VIP was highest in the submaxillary gland and lowest in the parotid gland. The concentration of SP was highest in the parotid gland; it was at, or below the limit of detection in the sublingual gland. In the parotid gland the total amounts of VIP and SP were reduced by 95% after parasympathetic denervation (section of the auriculo-temporal nerve). In the submaxillary gland the total amounts of the peptides were unchanged after parasympathetic decentralization (section of the chorda-lingual nerve). In this gland the total amount of SP was reduced by 92% and that of VIP by 50%, when the chorda tympani nerve fibres were cut deep into the hilum. Cutting the nerve fibres at the hilum left the total amounts of the peptides unchanged in the submaxillary gland, whereas in the sublingual gland the total amount of VIP was reduced by 70%. Sympathetic denervation did not reduce the total amounts of the peptides. Duct ligation caused gland atrophy. In the parotid gland the total amounts of VIP and SP were reduced by 40%. In the submaxillary gland the same percentage reduction occurred with regard to SP; however, the total amount of VIP was reduced by 99%. The VIP- and SP-containing nerve fibres reach the salivary glands by the parasympathetic nerves. In both submaxillary and sublingual glands a certain fraction of VIP originates within the glands.