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Autonomic nervous system dysfunction may manifest with a variety of symptoms, with orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweating abnormalities (increased or decreased sweating) being common problems requiring medical evaluation and treatment. Determination of the underlying diagnosis for these symptoms is critical in terms of classification of the disorder and its prognosis. Recent advances in evaluation of patients with these conditions and treatment modalities have enabled physicians to improve overall management of patients with these disorders. These advances include testing for ganglionic acetylcholine receptor antibody in patients with suspected autoimmune autonomic neuropathy and use of pyridostigmine for treatment of patients with orthostatic hypotension or tachycardia.

Immunoglobulin A (IgA) is transported across glandular epithelial cells by polymeric immunoglobulin receptor (plgR), with each receptor molecule participating in only one round of transcytosis. Nerve-related stimuli rapidly increase salivary secretion of IgA, while concentrations are increased in the autoimmune disease Sjögren's syndrome. Our aim here was to determine whether autonomic agonists and cytokines present in Sjögren's-affected glands can up-regulate salivary cell plgR expression.Cultures of rat parotid acinar cells (PAR C5) and human submandibular gland ductal cells (HSG) were exposed to carbachol or adrenaline for 24 h and to interleukin-4 and/or interferon-gamma for 48 h. The human colonic cell line HT-29 served as a positive control for cytokine response. plgR mRNA was quantified by reverse transcription and real-time PCR and protein expression was examined by immunoblotting.Carbachol increased plgR mRNA levels significantly in all cells but adrenaline did so only with PAR cells (P0.05). HSG and HT-29 cells both up-regulated plgR gene transcription on exposure to interleukin-4 and interferon-gamma either alone or in combination (P0.05). By contrast, production of plgR mRNA in PAR cells tended to decrease in response to all cytokine treatments. plgR protein levels rose in line with mRNA expression in cytokine-treated HT-29 cultures (P0.05).Autonomimetics can up-regulate plgR transcription in transformed and neoplastic salivary and colonic cells, although intracellular coupling mechanisms require further investigation. Immunomodulatory cytokines increased plgR expression in one of the salivary cell lines, but additional work is needed to establish whether this occurs in Sjögren's patients.

Background Murraya paniculata is traditionally used for management of gut, air way and cardiovascular disorders. The study was conducted for provision of pharmacological rationalization for folkloric uses of Murraya paniculata in gut, air way and cardiovascular problems. Methods Aqueous-ethanolic extract of Mp.Cr was tested using in vitro techniques on isolated tissue of rabbit (jejunum, trachea and aorta) to detect the possible presence of spasmolytic activity. The responses of tissues were recorded using isotonic transducers coupled with PowerLab data acquisition system. Results Application of the extract of Mp.Cr relaxed spontaneous and high K+ (80mM)-induced contraction in rabbit jejunum preparation. Because it shifted the CRCs (Calcium response curve) towards the right side so the possible blockade was of calcium channel similar to verapamil. In rabbit trachea, extract of Mp.Cr produced relaxation of carbachol and high K+ induced contractions. When plant extract was checked further on isolated aorta for its possible vasodilator effect, it caused relaxation of phenylephrine and high K+-induced spastic contractions at different doses. Conclusion These results indicate that Murraya paniculata shows anti-spasmodic, bronchodilator and vasodilator activity facilitated through Ca++ antagonist mechanisms.

Anxiety disorders comprise the most common category of mental illness among US young adults. Art making might be one method to help reduce anxiety, but the few studies investigating this have used only subjective measures of anxiety.This study employed both subjective (self-reported state anxiety from the State-Trait Anxiety Inventory) and objective (heart rate variability) measures to assess whether 30-minute periods of art making reduced anxiety in 47 first-year college students prior to their final examinations.Students participated in free-form painting, mandala coloring, clay modeling, and control sessions.Repeated-measures ANOVA with post hoc analysis revealed significantly greater pre- to post-session reductions in anxiety for all three types of art-making sessions than for the control session, as measured objectively. Measured subjectively, only free-form painting yielded a significant decrease in anxiety compared to the control session.Given the health benefits of anxiety reduction, further study is warranted to determine the duration of art making's anxiety-reducing effect.

One characteristic of the most common types of glaucoma is increased intraocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to progressive loss of retinal ganglion cells. Therefore, ocular hypotensive drugs are the mainstay of pharmacological therapy for glaucoma. This review article, which is the second part of a two-part series, is dedicated to autonomic drugs which lower IOP by decreasing the aqueous humour production. These agents are subdivided into two groups: β-adrenergic antagonists and selective α2-adrenergic agonists. This paper summarizes the current state of knowledge on the mechanism of action of these drugs and their effect on IOP in dogs and cats. Moreover, it discusses their possible undesirable side effects of these medications and presents the current ideas about their role and position in the medical management of glaucoma in small animals.

One characteristic of the most common types of glaucoma is increased intraocular pressure (IOP), which has a damaging effect on optic nerve axons, leading to progressive loss of retinal ganglion cells. Therefore, ocular hypotensive drugs are the mainstay of pharmacological therapy for glaucoma. This review article, which is the first part of a two-part series, is dedicated to autonomic drugs which lower IOP by increasing the outflow of aqueous humour. These agents are subdivided into two groups: (a) drugs that lower IOP by increasing the trabecular outflow and the uveoscleral outflow (i.e. nonselective adrenergic agonists), and (b) medications that lower IOP by opening of the drainage angle and by increasing the conventional outflow via the trabecular outflow (i.e. parasympathomimetics). This paper summarizes the current state of knowledge on the mechanism of action of these drugs and their effect on IOP in dogs and cats. Moreover, it discusses possible undesirable side effects of these medications and presents the current ideas about their role and position in the medical management of glaucoma in small animals

Background: Music can evoke strong emotions and thus elicit significant autonomic nervous system (ANS) responses. However, previous studies investigating music-evoked ANS effects produced inconsistent results. In particular, it is not clear (a) whether simply a musical tactus (without common emotional components of music) is sufficient to elicit ANS effects; (b) whether changes in the tempo of a musical piece contribute to the ANS effects; (c) whether emotional valence of music influences ANS effects; and (d) whether music-elicited ANS effects are comparable in healthy subjects and patients with Crohn´s disease (CD, an inflammatory bowel disease suspected to be associated with autonomic dysfunction). Methods: To address these issues, three experiments were conducted, with a total of n = 138 healthy subjects and n = 19 CD patients. Heart rate (HR), heart rate variability (HRV), and electrodermal activity (EDA) were recorded while participants listened to joyful pleasant music, isochronous tones, and unpleasant control stimuli. Results: Compared to silence, both pleasant music and unpleasant control stimuli elicited an increase in HR and a decrease in a variety of HRV parameters. Surprisingly, similar ANS effects were elicited by isochronous tones (i.e., simply by a tactus). ANS effects did not differ between pleasant and unpleasant stimuli, and different tempi of the music did not entrain ANS activity. Finally, music-evoked ANS effects did not differ between healthy individuals and CD patients. Conclusions: The isochronous pulse of music (i.e., the tactus) is a major factor of music-evoked ANS effects. These ANS effects are characterized by increased sympathetic activity. The emotional valence of a musical piece contributes surprisingly little to the ANS activity changes evoked by that piece.

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

The tachykinins and their receptors are strategically distributed within the gut wall, spinal cord, and central nervous system to be potential targets of therapeutic agents for gastrointestinal motility disorders. However, the development of effective tachykinin receptor agonists or antagonists to treat these disorders has had very limited success so far. This is, in part, due to the complex and multilevel of regulation of gastrointestinal motility function and the challenges faced in targeting the specific type of gut contraction to normalize function in disease state.

Epidemiological studies show that increases in particulate air pollution (PM) are associated with increases in cardiopulmonary morbidity and mortality. However, the mechanism(s) underlying the cardiac effects of PM remain unknown. We used pharmacological strategies to determine whether oxidants are implicated in PM-dependent cardiac dysfunction and whether PM-induced increase in autonomic stimulation on the heart mediates cardiac oxidative stress and toxicity. Adult Sprague-Dawley rats were exposed to either intratracheal instillation of urban air particles (UAP 750 microg) or to inhalation of concentrated ambient particles (CAPs mass concentration 700+/-180 microg/m3) for 5 h. Oxidative stress and cardiac function were evaluated 30 min after UAP instillation or immediately after exposure to CAPs. Instillation of UAP led to significant increases in heart oxidants measured as organ chemiluminescence (UAP: 38+/-5 cps/cm2, sham: 10+/-1 cps/cm2) or thiobarbituric acid reactive substances (TBARS, UAP: 76+/-10, Sham 30+/-6 pmol/mg protein). Heart rate increased immediately after exposure (UAP: 390+/-20 bpm, sham: 350+/-10 bpm) and returned to basal levels over the next 30 min. Heart rate variability (SDNN) was unchanged immediately after exposure, but significantly increased during the recovery phase (UAP: 3.4+/-0.2, Sham: 2.4+/-0.3). To determine the role of ROS in the development of cardiac malfunction, rats were treated with 50 mg/kg N-acetylcysteine (NAC) 1 h prior to UAP instillation or CAPs inhalation. NAC prevented changes in heart rate and SDNN in UAP-exposed rats (340+/-8 and 2.9+/-0.3, respectively). To investigate the role of the autonomic nervous system in PM-induced oxidative stress, rats were given 5 mg/kg atenolol (beta-1 receptor antagonist), 0.30 mg/kg glycopyrrolate (muscarinic receptor antagonist) or saline immediately before exposure to CAPs aerosols. Both atenolol and glycopyrrolate effectively prevented CAPs-induced cardiac oxidative stress (CL(ATEN): 11+/-1 cps/cm2, CL(GLYCO): 10+/-1 cps/cm2, TBARS(ATEN): 40+/-6 pmol/mg protein, TBARS(GLYCO): 38+/-6 pmol/mg protein). These data indicate that PM exposure increases cardiac oxidants via autonomic signals and the resulting oxidative stress is associated with significant functional alterations in the heart.

Purpose: We examined the effects of saw palmetto extract (SPE) on the rat micturition reflex and on autonomic receptors in the lower urinary tract. Materials and Methods: The effect of SPE was examined on cystometrograms of anesthetized rats induced by intravesical infusion of saline or 0.1% acetic acid. SHR/NDmc-cp (cp/cp) rats received repeat oral administration of SPE and nighttime urodynamic function was determined. The autonomic receptor binding activity of SPE in the rat bladder and prostate was examined by radioligand binding assay. Results: Intraduodenal administration of SPE (60 mg/kg) in anesthetized rat cystometry caused a significant increase in the micturition interval, micturition volume and bladder capacity during intravesical saline infusion. Also, similar administration of SPE at doses of 12 and 20 mg/kg significantly reversed the shortened micturition interval as well as the decreased micturition volume and bladder capacity due to 0.1% acetic acid infusion in a dose dependent manner. In conscious SHR/NDmc-cp (cp/cp) rats repeat oral administration of SPE (6 mg/kg daily) constantly increased the micturition interval and concomitantly decreased voiding frequency. SPE inhibited specific binding of [ 3 H]NMS ([N-methyl- 3 H]scopolamine methyl chloride) (bladder) and [ 3 H]prazosin (prostate) with IC 50 values of 46.1 and 183 μg/ml, respectively. Conclusions: SPE significantly alleviates urodynamic symptoms in hyperactive rat bladders by increasing bladder capacity and subsequently prolonging the micturition interval. Our data may support the clinical efficacy of SPE for the treatment of lower urinary tract symptoms.

Chondroitin sulfate proteoglycans are synthesized and deposited in the spinal cord following injury. These proteoglycans may restrict regeneration and plasticity and contribute to the limited recovery seen after an injury. Chondroitinase, a bacterial enzyme that catalyzes the hydrolysis of the chondroitin chains on proteoglycans, has been shown to improve motor and sensory function following partial transection lesions of the spinal cord. To assess the effects of chondroitinase in a clinically relevant model of spinal cord injury, 128 female Long-Evans rats received either a severe, moderate, or mild contusion injury at the vertebral level T9/T10 with a forceps model and were treated for 2 weeks with chondroitinase ABCI at 0.06 Units per dose, penicillinase, or vehicle control via an intrathecal catheter placed near the injury. Motor behavior was measured by open-field testing of locomotion and bladder function monitored by measuring daily residual urine volumes. Animals treated with chondroitinase showed significant improvements in open-field locomotor activity as measured by the Basso, Beattie and Bresnahan scoring system after both severe and moderate SCI (p

The parasympathetic and sympathetic divisions of the autonomic nervous system are involved in homeostatic control of a wide variety of ocular functions, including accommodation, pupillomotor control, lacrimation, eyelid position, and aqueous humor production. Familiarity with the functional anatomy of the autonomic nervous system is paramount to the understanding and application of the large number of autonomic drugs used in veterinary ophthalmology. The cholinergic and adrenergic agents discussed in this article are commonly employed to facilitate routine ophthalmic examination, in the diagnosis of autonomic dysfunction, and in the treatment of a variety of ocular diseases.

Prolonged nearwork has long been associated with myopia development, however, there is no well described linking mechanism. One theory suggests that if accommodation accuracy during nearwork is not maintained, the defocused retinal image leads to myopia development. Here we review the findings of research aimed at determining whether the autonomic inputs to the ciliary smooth muscle are involved in this type of environmental myopia. We examine whether an autonomic imbalance could be a precursor to axial elongation and the resulting myopia. Accommodation responses, such as tonic accommodation and nearwork-induced accommodative adaptation, as a function of refractive error, are described in relation to an autonomic imbalance model. The collective results of this research point to anomalous accommodation responses, possibly as a result of underlying anomalous autonomic input to the ciliary muscle, being involved in myopia development and progression.

The effect of jasmine tea odor on the autonomic nervous system was investigated by a power spectral analysis of the heart rate variability. We assigned eight volunteers to two groups with either a predilection for or antipathy toward the jasmine tea odor. We tested both high- and low-intensity jasmine tea odors. The low-intensity odor was produced by diluting 20-fold the jasmine tea used for the high-intensity odor test. The low-intensity odor produced an increase in parasympathetic nervous activity in both the predilection and antipathy groups. The high-intensity odor produced an increase in parasympathetic nervous activity in the predilection group, but an increase in sympathetic nervous activity in the antipathy group. The odor of Chinese green tea, a basic ingredient of jasmine tea, produced no effects similar to those of the jasmine tea odor. These results suggest that the jasmine tea odor activated the parasympathetic nerve, whereas the higher-intensity odor activated the sympathetic nerve in those subjects who disliked the odor.

We have previously demonstrated that a number of rats fed a moderately high-fat diet (MHFD) become obese and hypertensive and had compromised sympathoinhibitory and vasodilator responses to the gut hormones cholecystokinin (CCK) and gastric leptin. This has implications for increased resistance in vascular beds that attract a large proportion of cardiac output after a meal and may be an important mechanism underlying the development of hypertension in obesity in which food consumption is greatly increased. The aim of this study was to determine whether swapping a MHFD for a low-fat diet (LFD) would induce weight loss in obese animals, reverse the signs of hypertension and restore sympathoinhibitory reflexes. Male Sprague-Dawley rats were placed on a LFD (controls; n = 8) or a MHFD (n = 24) for 11 weeks after which the latter displayed either an obesity-prone (OP) or obesity-resistant (OR) phenotype. All animals were fed a LFD for a further 6 weeks after which they were anaesthetised with isoflurane and artificially ventilated for evaluation of resting arterial pressure (AP) and renal sympathetic nerve responses to CCK (0.1-4 μg/kg) and leptin (15 μg/kg). Weight gain in OP animals remained higher than OR or controls following diet switch (P0.05 for both). Resting AP was not significantly different between OP (103 ± 4 mmHg), OR (102 ± 3 mmHg) or control (104 ± 3 mmHg) animals and sympathoinhibitory responses to CCK or leptin were not different between the groups (P0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction.

Inducible (calcium-independent) nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are important in the regulation of the function of different organs during infection. A single dose of lipopolysaccharide (LPS; 5 mg/kg ip) within 6 h increased NOS activity (20%) and prostaglandin E (PGE) content (100%) in submandibular glands (SMG) and blocked stimulated salivary secretion in adult male rats. The administration of an iNOS synthesis inhibitor, aminoguanidine (AG), with LPS decreased NOS activity and PGE content. Furthermore, the administration of meloxicam (MLX), an inhibitor of COX-2, blocked the increase in PGE and the production of NO. The incubation of slices of SMG in the presence of 3-morpholinosydnonimine, a donor of NO, increased the release of PGE highly significantly. The incubation of SMG in the presence of a PGE1 analog (alprostadil) increased the production of NO. These results indicate that LPS activates NOS, leading to NO release, which activates COX, generating PGEs that act back to further activate NOS, causing further generation of PGEs by activation of COX. Because the alprostadil administration inhibited stimulated salivation, LPS-induced inhibition of salivation appears to be caused by increased PGE production. Diminished salivary secretion produces poor oral health; thus the use of COX-2 inhibitors to counteract the effects of inhibited salivation should be considered.

The venous system contains approximately 70% of the blood volume. The sympathetic nervous system is by far the most important vasopressor system in the control of venous capacitance. The baroreflex system responds to acute hypotension by concurrently increasing sympathetic tone to resistance, as well as capacitance vessels, to increase blood pressure and venous return, respectively. Studies in experimental animals have shown that interference of sympathetic activity by an alpha1- or alpha2-adrenoceptor antagonist or a ganglionic blocker reduces mean circulatory filling pressure and venous resistance and increases unstressed volume. An alpha1- or alpha2-adrenoceptor agonist, on the other hand, increases mean circulatory filling pressure and venous resistance and reduces unstressed volume. In humans, drugs that interfere with sympathetic tone can cause the pooling of blood in limb as well as splanchnic veins; the reduction of cardiac output; and orthostatic intolerance. Other perturbations that can cause postural hypotension include autonomic failure, as in dysautonomia, diabetes mellitus, and vasovagal syncope; increased venous compliance, as in hemodialysis; and reduced blood volume, as with space flight and prolonged bed rest. Several alpha-adrenoceptor agonists are used to increase venous return in orthostatic intolerance; however, there is insufficient data to show that these drugs are more efficacious than placebo. Clearly, more basic science and clinical studies are needed to increase our knowledge and understanding of the venous system.

An international multicenter study entitled Collaborative Study on Drug Use in Pregnancy (DUP) was initiated in 1987 by the Mario Negri Institute (Milano) and co-sponsored by the WHO Regional Office for Europe (Copenhagen). The study covered the use of medicines during pregnancy, labour and postpartum period. The Novi Sad centre contributed with 296 questionnaires. The aim of the study was to evaluate the pharmacotherapy by means of comparison, to identify problems in a particular settings and to plan actions toward improvement. The prescribing of some medicines in the Novi Sad center was found to be at the extreme, being among the lowest in the use of iron preparations during pregnancy and among the highest in the use of ergot alkaloids in the postpartum period. Educational efforts have been made to change this practice after the conclusion of the study in 1989. Ten years later, in 1999, the same questionnaire was applied to 100 women in the postpartum period in the same nursery, the Department of Obstetrics and Gynecology in Novi Sad. The results have shown a distinct improvement with the increase of iron prescribing during pregnancy and almost complete abandonment of postpartum use of ergot alkaloids. In the second study period some other inconsistencies with accepted therapeutical principles were identified. For example, although the use of analgesics fell from 22.3 to 8%, the selection changed towards the high use of metamizole (noraminophenazone) and no use of paracetamol (acetaminophen). It was concluded that international pharmacoepidemiological studies such as DUP, could substantially contribute to the improvement of pharmacotherapy if followed by appropriate actions in changing the prescribing behaviour of the physicians and information directed to the target population. Copyright © 2001 John Wiley & Sons, Ltd.

Whether free choline levels are changeable in vivo in response to different types of autonomic agonists was examined in several mouse organs. Upon one subcutaneous injection of isoproterenol, phenylephrine and pilocarpine, choline levels in whole organ decreased, increased and decreased, respectively, in various organs within 30 min and returned to initial levels in a day. In the three major salivary glands, a delayed choline elevation also appeared on day 2 after one isoproterenol injection and subsided by day 6. Only in the three salivary glands more choline was accumulated after 10 once-a-day injections of isoproterenol than after one isoproterenol injection. Neither phenylephrine nor pilocarpine induced comparable choline accumulation in any organs examined. Isoproterenol injection repeated at a 2-day interval augmented the subsequent, delayed choline elevation. Examination with dobutamine and the adenylyl cyclase activator 6-(3-dimethylaminopropionyl)forskolin suggested that isoproterenol-induced immediate choline lowering was downstream of cAMP synthesis and linked to cAMP more tightly than the choline accumulation, though both choline changes occurred via β1-adrenergic receptors. Choline levels in the salivary glands also changed depending on the form of diet given and particularly in the parotid gland in parallel with gland weights. These results provide the first evidence for the autonomic control of intracellular choline levels; intracellular choline levels might be an integral part of the autonomic signalling pathway.

1. We review literature demonstrating (a) the presence and (b) the actions of substances that mediate or modify neuroeffector transmission to the smooth muscle of the prostrate stroma of a number of species including man. 2. In all species studied prostatic stroma, but not secretory acini, receives rich noradrenergic innervation. Stimulation of these nerves causes contractions of prostate smooth muscle that are inhibited by guanethidine and by alpha1-adrenoceptor antagonists that probably act at the alpha1L-adrenoceptor. Such actions underlie the clinical use of alpha1-adrenoceptor antagonists in benign prostatic hyperplasia (BPH). 3. Acetylcholinesterase-positive nerves innervate prostatic stroma as well as epithelium. Atropine reduces nerve-mediated contractions of stromal muscle in the rat, guinea-pig and rabbit. M1, M2 and M3 muscarinic receptors have been implicated in eliciting or facilitating contraction in the prostate from guinea-pig, dog and rat, respectively. 4. Adenine nucleotides and nucleosides, nitric oxide (NO), opioids, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) may act as co-transmitters or modulators in autonomic effector nerves supplying prostate stroma. Adenosine inhibits neurotransmission to the rat prostate, and NO is inhibitory in prostate from human, rat, rabbit, pig and dog. The activity of peptides present in the relatively sparse sensory innervation of the prostate exhibits species variation, but, when effective, calcitonin gene-related peptide is inhibitory while tachykinins are stimulant. The roles of NPY and VIP in modulating stromal contractility remain unclear. 5. Taken together the current literature indicates that, in addition to noradrenaline, other neurotransmitters and neuromodulators may regulate the tone of prostatic smooth muscle. Whether drugs that mimic or modify their actions might be useful in providing symptomatic relief of the urinary symptoms associated with BPH remains to be established.

Objective: The objective of this study was to investigate the relationship between acute decreases in right ventricular volume during Valsalva strain (with resultant changes in autonomic neural tone) and measures of local endocardial repolarization time independent of heart rate and autonomic neural tone. Methods: Patients implanted with a stimulus to T wave (Stim-T) sensing pacemaker specially adapted to output a validated measure of beat to beat local repolarization ( n =9) performed Valsalva manoeuvers (40 mmHg for 15 s) while paced at a cycle length of 500 ms. Stim-T intervals were measured before and after autonomic blockade (Block: 0.03 mg/kg i.v. atropine±0.15 mg/kg propranolol). Right ventricular end diastolic volume was estimated by simultaneous 2D-echocardiography. Results: Without autonomic blockade, compared to baseline, repolarization significantly prolonged during Valsalva strain (1.1±0.7%) and shortened during release (−1.4±1.0%). After block, strain related repolarization prolongation was also observed (1.0±0.6%), with significantly less release related repolarization shortening (−0.8±0.8%) compared to pre-block ( P

The disorders of autonomic control associated with orthostatic intolerance are a diverse group of infirmities that can result in syncope and near syncope (as well as a host of other complaints). A basic understanding of these disorders is essential to both diagnosis and proper treatment. These infirmities are not new, what has changed is our ability to recognize them. It has been said that "the world undergoes change in the human consciousness. As this consciousness changes, so does the world." On going studies will continue to help better define the broad spectrum of these disorders, and to elaborate better diagnostic and treatment modalities.

Many advances in medical therapy for chronic glaucoma have taken place in the past few years that have altered previous concepts of stepwise medical therapy for glaucoma. beta-adrenergic blockers are still the most common medicine prescribed as monotherapy. However, latanoprost and brimonidine are often given as monotherapy as well as early adjunctive therapy. In addition, newer treatments that are used as early adjunctive therapy are dorzolamide, brinzolamide, apraclonidine, and the combination products, consisting of dorzolamide/timolol maleate and pilocarpine/timolol maleate. Older adjunctive treatments are now often prescribed as late adjunctive therapy including pilocarpine, epinephrine compounds, and acetazolamide. The extent of maximum tolerated medical therapy and the decision to perform either laser or conventional filtration surgery depend on the physician's judgment and on the patient's needs and preferences. In the future, newer medical therapies that may protect the health of the optic nerve directly could be developed including blood flow-based, neuroprotective, and genetically based agents.

Postural (orthostatic) hypotension is defined as a fall in blood pressure of over 20 mm Hg systolic, (or 10 mm Hg diastolic), on standing or during head-up tilt to at least 60°.1 In neurological practice, it may result from diseases or drugs that impair the activity of sympathetic vasoconstrictor nerves. Postural hypotension may be a presenting feature in certain autonomic disorders (such as pure autonomic failure), it may be a pointer towards an alternative diagnosis (as in multiple system atrophy presenting with parkinsonian features), and it may complicate drug therapy (as with levodopa). Postural hypotension is associated with increased morbidity and also mortality, especially in elderly people, in whom falls result in injuries. Advances have resulted in a better understanding of the pathophysiological processes, and in the treatment of postural hypotension. Postural hypotension usually is considered when there are characteristic features resulting from cerebral ischaemia such as loss of consciousness (fainting, syncope). Other symptoms may occur (table1).2 Measuring blood pressure while lying and after 2 minutes of standing often confirms a postural fall. However, the lack of a fall, in the presence of suggestive symptoms, should warrant further investigation. There are various disorders, including the chronic fatigue syndrome and the postural tachycardia syndrome, in which postural intolerance may not be accompanied by hypotension. Additional factors may be needed to unmask postural hypotension (table2), especially in mild to moderate autonomic failure. View this table: Table 1 Some of the symptoms resulting from postural hypotension, and impaired perfusion of various organs View this table: Table 2 Factors that may influence postural hypotension Further evaluation is best undertaken in an autonomic laboratory. Studies ideally should utilise a tilt table, as patients with neurological disabilities or a profound fall in blood pressure can rapidly and safely be returned to the horizontal position. Additional screening tests (the Valsalva manoeuvre, pressor …

BACKGROUND: Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS: In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS: There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS: We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

1. Positive inotropic responses to calcitonin gene-related peptide (CGRP) were evaluated in atria isolated from in vivo rat models of hyper-sensory-motor innervation (following neonatal guanethidine treatment) and hypo-sensory-motor innervation (following neonatal capsaicin treatment), to explore the hypothesis that functional responsiveness of atrial myocardium to CGRP may correlate with tissue levels of the sensory-motor neurotransmitters. Comparative of inotropic responses to CGRP following in vitro treatment of atria with guanethidine was also performed. 2. Following long-term guanethidine treatment, positive inotropic responses to CGRP were significantly attenuated, while supersensitivity to the sympathetic transmitter noradrenaline was shown. Maximal inotropic responses to CGRP (30 nM) were 214.0 +/- 28.1 (n = 8) and 146.8 +/- 21.7 mg (n = 8; P < 0.01) increase of the basal contractile tension in control and treated preparations, respectively. The pD2 values for noradrenaline were 6.71 +/- 0.12 (n = 8) and 7.26 +/- 0.13 (n = 6; P < 0.01) in control and treated atria, respectively. Acute application of guanethidine in vitro did not modify the positive inotropism by CGRP or the beta-adrenoceptor agonist isoprenaline. 3. Sensory-motor hypoinnervation following chronic treatment with capsaicin did not affect the inotropic responses to CGRP. Neither guanethidine nor capsaicin treatment affected the contractile apparatus of myocytes, as demonstrated by similar basal contractile tension as well as calcium-evoked inotropic responses in control and treated preparations. 4. In summary, increased sensory-motor innervation, following long-term sympathectomy with guanethidine, resulted in attenuation of the inotropic responses of the rat atrium to CGRP, while no changes in the inotropic responses were seen following sensory-motor denervation with capsaicin. Down-regulation of CGRP receptors or altered post-receptor signalling may be involved in the reduced responsiveness to CGRP.

Two types of Ca2+ currents with characteristics of T- and L-type Ca2+ currents were recorded in ventricular myocytes of dogfish (Squalus acanthias). The T-type Ca2+ current activated near -70 mV and had a peak current density of 9.8 pA/pF at -34 mV. The L-type Ca2+ current activated near -50 mV and had a peak current density of 10.6 pA/pF near 0 mV. The threshold for activation of the T-type Ca2+ current was 20 mV negative to that of the tetrodotoxin-sensitive Na+ current. Inactivation of the T-type Ca2+ current was rapid with a limiting time constant of 5 ms at positive potentials. The T-type Ca2+ current was not modulated by isoproterenol or acetylcholine. In dogfish the T-type Ca2+ channel has current densities equivalent to the L-type channel and is likely to activate before the Na+ channel, contributing significantly to generation of the foot of the action potential.

The present experiments were designed to examine the site of action of the alpha 2-adrenoceptor agonist, clonidine, and the alpha 2-antagonist, yohimbine, on the salivary secretion response to parasympathetic and sympathetic stimulation in the cat submandibular gland (SMG). The parasympathetic reflex salivary secretion was significantly affected by both clonidine and yohimbine (clonidine reduced and yohimbine increased the amount of saliva secreted) while the reflex vasodilator response was not affected by either agent. No degree of methacholine-induced salivation was affected by prior treatment with either clonidine or yohimbine. The salivation elicited by facial nerve root stimulation was markedly reduced by clonidine but potentiated by yohimbine. Prior treatment with scopolamine completely abolished the salivary secretion induced by either methacholine or facial nerve root stimulation. Clonidine and yohimbine had no effect on SMG salivation elicited by sympathetic stimulation. These results indicate that the alpha 2-agonist and antagonist act specifically on parasympathetic salivary fibers but have no effect on parasympathetic vasodilator fibers. They thus suggest that postganglionic parasympathetic innervation is differentiated into salivary and vasodilator fibers.

Objective Placebo effects on pain and other subjective parameters are well-established, but the evidence for placebo effects on autonomic functions is scarce. Our randomized-controlled trial aimed to investigate autonomic responses after a suggestive placebo intervention intended to increase or decrease blood pressure (BP). Methods 92 healthy subjects inhaled a placebo spray with the prior suggestion that it contained an effective drug to either increase or decrease BP, or the information that a placebo was administered (controls). BP, heart rate, stroke volume, peripheral resistance, heart rate variability and skin conductance level were monitored 30 min before and after placebo administration. The expected and the subjectively perceived drug effect were measured by means of visual analog scales. Results We found no statistically significant differences between the groups with respect to BP, heart rate, stroke volume, total peripheral resistance and heart rate variability responses to the verbal suggestions. Skin conductance response was more pronounced in the BP decrease group compared with controls (p = 0.04), but this finding might be due to chance, given the multiple tests. Within the total study sample, BP, total peripheral resistance, low frequency power of heart rate variability and skin conductance were significantly higher after the placebo spray independent of the associated suggestions. Subjects in the BP increase and BP decrease condition had higher ratings of the expected and the subjectively perceived drug effect compared with controls (all p Conclusion We found no evidence that specific verbal suggestions during placebo interventions affect BP in healthy subjects.

Previous studies including ours showed that cyclosporine (CSA) causes baroreflex dysfunction and hypertension. Here we tested the hypothesis that oxidative damage in central and peripheral tissues underlies the hypertensive, baroreflex and autonomic actions elicited by CSA in rats. We investigated the effects of individual and combined 7-day treatments with CSA (25 mg/kg/day, n=7) and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol, superoxide dismutase mimetic, 100 mg/kg/day, n=7) on blood pressure, reflex heart rate responses to peripherally mediated pressor and depressor responses, and biomarkers of oxidative stress. CSA elevated blood pressure and reduced reflex bradycardic (phenylephrine) and tachycardic (sodium nitroptrusside) responses. The ability of muscarinic (atropine, 1 mg/kg i.v.) or β-adrenoceptor blockade (propranolol, 1 mg/kg i.v.) to reduce reflex heart rate responses was reduced in CSA-treated rats, suggesting the impairment by CSA of reflex cardiac autonomic control. Concurrent administration of tempol abolished CSA-induced hypertension and normalized the associated impairment in baroreflex gain and cardiac autonomic control. Tempol also reversed the CSA-induced increases in aortic and brainstem nitrite/nitrate and malondialdehyde (MDA) and decreases in aortic superoxide dismutase (SOD). These findings implicate oxidative stress in peripheral and central cardiovascular sites in the deleterious actions of CSA on blood pressure and baroreceptor control of heart rate.

Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, blood glucose, and body weight in rats, however, the mechanisms of action of the lactobacilli remain to be clarified. Therefore, the effect of the culture supernatant of Lactobacillus pentosus strain S-PT84 on the autonomic nerve activity in urethane-anesthetized rats was investigated. Intraduodenal injection of the low-molecular-weight (LMW) fraction (molecules less than 10,000 Da) of the S-PT84 culture supernatant elevated the brown adipose tissue sympathetic nerve activity and reduced the gastric vagal nerve activity. Moreover, intraoral administration of this LMW fraction increased the body temperature of rats above the interscapular brown adipose tissue. These results suggest that the LMW fraction of the S-PT84 culture supernatant affects the autonomic nerve activity and thermogenesis, and that the change in thermogenesis may be caused by the change in the sympathetic nerve activity of brown adipose tissue.

Amisulpride is suggested for treatment of clozapine-induced sialorrhea. However, objective measurements of its effectiveness are lacking and, preclinically, amisulpride has no effect. We currently hypothesise that amisulpride acts by reducing the nervous- rather than the clozapine-driven salivary secretion.Effects of intravenous amisulpride (as well as of clozapine and raclopride, a dopamine D2/D3 antagonist) were investigated in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). In duct-cannulated glands, secretion was evoked reflexly, at low and maximum flow rates, and by electrical stimulation of the parasympathetic and sympathetic innervations, and administration of autonomimetics (including substance P).Unlike clozapine, amisulpride had no effect on the reflexly evoked secretion at maximum rate. With respect to reflex secretion at low rate and to the secretion evoked by muscarinic, α-adrenergic, β-adrenergic and substance P receptors, amisulpride (in contrast to raclopride) dose dependently potentiated the responses. Amisulpride had no effect on gland blood flow.No support for any inhibitory influence of amisulpride was found. Conversely, amisulpride universally enhanced secretion, suggesting that amisulpride is a potential drug for dry-mouth treatment. The mechanism behind the potentiation is currently unknown.

Chronic obstructive pulmonary disease (COPD) is associated with impaired exercise tolerance, but it has not been established to what extent cardiac autonomic function impacts on exercise capacity.To evaluate whether there is an association between airflow limitation and cardiac autonomic function and whether cardiac autonomic function plays a role in exercise intolerance and daily physical activity (PA) in patients with COPD.Univariate and multivariate analyses were performed to evaluate the association between both 6-minute walking test (6MWT) and PA (steps per day) and pulmonary function, cardiac autonomic function (HR at rest, HRR and heart rate variability, HRV) in patients with COPD.In 154 COPD patients (87 females, mean [SD]: age 62.5 [10.7] years, FEV(1) %predicted (43.0 [19.2]%), mean HR at rest was elevated (86.4 [16.4] beats/min) and HRV was reduced (33.69 [28.96] ms) compared to published control data. There was a significant correlation between FEV(1) and HR at rest (r = -0.32, p0.001), between HR at rest and 6MWD (r = -0.26, p = 0.001) and between HR at rest and PA (r = -0.29, p = 0.010). No correlation was found between HRV and 6MWD (r = 0.089, p = 0.262) and PA (r = 0.075, p = 0.322). In multivariate analysis both HR and FEV(1) were independent predictors of exercise capacity in patients with COPD.In patients with COPD the degree of airflow limitation is associated with HR at rest. The degree of airflow limitation and cardiac autonomic function, as quantified by HR at rest, are independently associated with exercise capacity in patients with COPD.

Autonomic drugs are used clinically to either imitate or inhibit the normal functions of the sympathetic and parasympathetic nervous systems. A large number of additional drug classes also interact with these systems to produce a stunning number of possible side effects. This article reviews the basic function of the autonomic nervous system and the various drug classes that act within these neural synapses.

There have been only a few reports of the measurement of autonomic receptors in ureteral smooth muscle. Furthermore, it is so difficult to maintain stable spontaneous contractions in the ureter, that either electrical field stimulation or KCl at high concentrations are utilized to induce ureteral contractions in many in vitro ureteral pharmacologic examinations. We used the spiral ureteral strips which generate spontaneous contractions in the ureter in present experiments. Norepinephrine, phenylephrine, clonidine, carbachol, and prostaglandin F2 alpha enhanced the spontaneous contractile force and/or increased the contractile frequency of spontaneous rhythmic contractions in spirally-incised muscle strips from isolated canine ureters. In contrast, isoproterenol, terbutaline, a beta 2-adrenergic agonist, and prostaglandin E2 reduced the spontaneous contractile force and/or decreased the contractile frequency of spontaneous rhythmic contractions. Dobutamine, a beta 1-adrenergic agonist, did not affect significantly the spontaneous rhythmic contractions. The effects of the prostaglandins were not influenced by autonomic antagonists or tetrodotoxin. The existence of alpha 1-, alpha 2-, and beta-adrenoceptors and muscarinic cholinergic receptors were demonstrated in the canine ureter using radioligand techniques. The density of alpha 1-receptors binding sites was significantly greater than that of the other receptors examined. Our data show that the sympathetic nervous system is more involved than the para-sympathetic nervous system in canine ureteral contractile activities, and that alpha- and beta-receptors contained in canine ureteral smooth muscle are comprised mainly of the alpha 1- and beta 2-subtypes. It is also suggested that prostaglandins directly affect canine ureteral contraction.

The aim of this study was to audit cardiac arrest documentation within a UK teaching hospital, survey the regional use of proformas for data collection, and consider the need for a standardised national template. A prospective audit comparing cardiac arrest documentation to General Medical Council (GMC) professional standards and the ‘Utstein’ fields was carried out, along with a survey of regional resuscitation officers for the use of standardised templates. The main outcome measures were the design of ‘best practice’ template using GMC guidelines and the ‘Utstein’ fields. An audit of medical notes involving a cardiac arrest call against the template was performed. There was limited documentation concerning process, events and outcome of arrest calls, as well as minimal regional use of standard templates or consensus on the essential content of medical documentation. Documentation of cardiac arrests in the Leeds Teaching Hospitals does not meet the ‘Utstein’ recommendations to provide enough information for audit of cardiac arrest procedure. The regional survey indicates that this problem is likely to be widespread.

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (1 minute) and reversible hemodynamic changes. PE (0.3-10 μg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 μg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 μM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations10 μM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and β) effects.

Istaroxime is a new luso-inotropic compound. It exerts inotropic action by reducing Na+/K+-ATPase activity, and simultaneously it stimulates sarcoplasmic reticulum Ca(2+)-ATPase function, thus also inducing lusitropic action. The aim of present study is to assess the effect of chronic istaroxime treatment on cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.Bio TO.2 hamsters were daily treated, from 12 to 28 weeks of age, with 30 mg/kg/day oral istaroxime. Age-matched Bio TO.2 and Bio F1B hamsters were treated with vehicle and used as diseased and healthy controls. At the end of treatment, hearts function and autonomic cardiac control were evaluated.Hearts from vehicle-treated Bio TO.2 when compared with hearts from Bio F1B showed higher heart/body weight ratio, and lower left ventricular systolic pressure (LVSP), positive and negative derivative of LV pressure (dP/dT), coronary flow rate (CFR). Hearts from istaroxime-treated when compared with those of vehicle-treated hamsters, showed the reduction of heart/body weight ratio, and the increase of LVSP, of both positive and negative dP/dT, and of CFR. Autonomic cardiac control, evaluated by HRV analysis, indicated in vehicle-treated Bio TO.2 hamsters, when compared to healthy, a shift towards increased sympathetic and decreased parasympathetic activities. Istaroxime-treatment preserved parasympathetic activity.Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.