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The Raphe Pallidus (RPa) is a region of the brainstem that was shown to modulate the sympathetic outflow to many tissues and organs involved in thermoregulation and energy expenditure. In rodents, the pharmacological activation of RPa neurons was shown to increase the activity of the brown adipose tissue, heart rate, and expired CO 2 , whereas their inhibition was shown to induce cutaneous vasodilation and a state of hypothermia that, when prolonged, leads to a state resembling torpor referred to as synthetic torpor. If translatable to humans, this synthetic torpor-inducing procedure would be advantageous in many clinical settings. A first step to explore such translatability, has been to verify whether the neurons within the RPa play the same role described for rodents in a larger mammal such as the pig. In the present study, we show that the physiological responses inducible by the pharmacological stimulation of RPa neurons are very similar to those observed in rodents. Injection of the GABA A agonist GABAzine in the RPa induced an increase in heart rate (from 99 to 174 bpm), systolic (from 87 to 170 mm Hg) and diastolic (from 51 to 98 mm Hg) arterial pressure, and end-tidal CO 2 (from 49 to 62 mm Hg). All these changes were reversed by the injection in the same area of the GABA A agonist muscimol. These results support the possibility for RPa neurons to be a key target in the research for a safe and effective procedure for the induction of synthetic torpor in humans., (© 2019 John Wiley & Sons Australia, Ltd.)

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod., (Copyright © 2019. Published by Elsevier B.V.)

Negative social experiences influence both depression and cardiovascular dysfunction. Many individuals who experience negative mood states or cardiovascular conditions have limited social support. Therefore, investigation of drug treatments that may protect against the consequences of social stress will aid in designing effective treatment strategies. The current study used an animal model to evaluate the protective effect of sertraline administration on behavioral and cardiovascular consequences of social stress. Specifically, male prairie voles (Microtus ochrogaster), which are socially monogamous rodents that share several behavioral and physiological characteristics with humans, were isolated from a socially-bonded female partner, and treated with sertraline (16 mg/kg/day, ip) or vehicle during isolation. Unexpectedly, sertraline did not protect against depression-relevant behaviors, and it was associated with increased short- and long-term heart rate responses. However, sertraline administration improved heart rate variability recovery following a behavioral stressor, including increased parasympathetic regulation, and altered long-term neuronal activity in brain regions that modulate autonomic control and stress reactivity. These results indicate that sertraline may partially protect against the consequences of social stressors, and suggest a mechanism through which sertraline may beneficially influence neurobiological control of cardiac function., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Overactive bladder (OAB) coexists with depression in women. Here, we assessed the effects of a 1-week treatment with blebbistatin, a myosin II inhibitor, on changes in behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA), with the aid of the forced swim test (FST), spontaneous locomotor activity test, and in vivo cystometric investigations in female Wistar rats. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased corticotropin-releasing factor (CRF) level in the plasma, prefrontal cortex (PFC), hippocampus (Hp), Barrington's nucleus (BN), and urinary bladder. Moreover, 13-cis-RA decreased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in plasma, PFC, Hp, and BN, while it increased BDNF and NGF levels in urinary bladder. Blebbistatin exerted antidepressant-like effect and attenuated changes in the cystometric parameters as well as the central and peripheral levels of CRF, BDNF, and NGF that were induced by 13-cis-RA, while it did not affect urine production, mean, systolic or diastolic blood pressure, or heart rate. The results point to blebbistatin as a potential treatment option for OAB coexisting with depression.

Several review articles have been published on the neurobehavioral actions of acetaldehyde and other ethanol metabolites as well as in major alcohol-related disorders such as cancer and liver and lung disease. However, very few reviews dealt with the role of alcohol metabolism in the adverse cardiac and autonomic effects of alcohol and their potential underlying mechanisms, particularly in vulnerable populations. In this chapter, following a brief overview of the dose-related favorable and adverse cardiovascular effects of alcohol, we discuss the role of ethanol metabolism in its adverse effects in the brainstem and heart. Notably, current knowledge dismisses a major role for acetaldehyde in the adverse autonomic and cardiac effects of alcohol because of its low tissue level in vivo. Contrary to these findings in men and male rodents, women and hypertensive individuals are more sensitive to the adverse cardiac effects of similar amounts of alcohol. To understand this discrepancy, we discuss the autonomic and cardiac effects of alcohol and its metabolite acetaldehyde in a model of hypertension, the spontaneously hypertensive rat (SHR) and female rats. We present evidence that enhanced catalase activity, which contributes to cardioprotection in hypertension (compensatory) and in the presence of estrogen (inherent), becomes detrimental due to catalase catalysis of alcohol metabolism to acetaldehyde. Noteworthy, studies in SHRs and in estrogen deprived or replete normotensive rats implicate acetaldehyde in triggering oxidative stress in autonomic nuclei and the heart via (i) the Akt/extracellular signal-regulated kinases (ERK)/nitric oxide synthase (NOS) cascade and (ii) estrogen receptor-alpha (ERα) mediation of the higher catalase activity, which generates higher ethanol-derived acetaldehyde in female heart. The latter is supported by the ability of ERα blockade or catalase inhibition to attenuate alcohol-evoked myocardial oxidative stress and dysfunction. More mechanistic studies are needed to further understand the mechanisms of this public health problem.

Purpose: The blood pressure "error signal" represents the difference between an individual's mean diastolic blood pressure and the diastolic blood pressure at which 50% of cardiac cycles are associated with a muscle sympathetic nerve activity burst (the "T50"). In this study we evaluated whether T50 and the error signal related to the extent of change in blood pressure during autonomic blockade in young and older women, to study potential differences in sympathetic neural mechanisms regulating blood pressure before and after menopause., Methods: We measured muscle sympathetic nerve activity and blood pressure in 12 premenopausal (25 ± 1 years) and 12 postmenopausal women (61 ± 2 years) before and during complete autonomic blockade with trimethaphan camsylate., Results: At baseline, young women had a negative error signal (-8 ± 1 versus 2 ± 1 mmHg, p < 0.001; respectively) and lower muscle sympathetic nerve activity (15 ± 1 versus 33 ± 3 bursts/min, p < 0.001; respectively) than older women. The change in diastolic blood pressure after autonomic blockade was associated with baseline T50 in older women (r = -0.725, p = 0.008) but not in young women (r = -0.337, p = 0.29). Women with the most negative error signal had the lowest muscle sympathetic nerve activity in both groups (young: r = 0.886, p < 0.001; older: r = 0.870, p < 0.001)., Conclusions: Our results suggest that there are differences in baroreflex control of muscle sympathetic nerve activity between young and older women, using the T50 and error signal analysis. This approach provides further information on autonomic control of blood pressure in women.

Primary neurodegenerative autonomic disorders are characterized clinically by loss of autonomic regulation of blood pressure. The clinical picture is dominated by orthostatic hypotension, but supine hypertension is also a significant problem. Autonomic failure can result from impairment of central autonomic pathways (multiple system atrophy) or neurodegeneration of peripheral postganglionic autonomic fibers (pure autonomic failure, Parkinson's disease). Pharmacologic probes such as the ganglionic blocker trimethaphan can help us in the understanding of the underlying pathophysiology and diagnosis of these disorders. Conversely, understanding the pathophysiology is crucial in the development of effective pharmacotherapy for these patients. Autonomic failure patients provide us with an unfortunate but unique research model characterized by loss of baroreflex buffering. This greatly magnifies the effect of stimuli that would not be apparent in normal subjects. An example of this is the discovery of the osmopressor reflex: ingestion of water increases blood pressure by 30-40 mm Hg in autonomic failure patients. Animal studies indicate that the trigger of this reflex is related to hypo-osmolality in the portal circulation involving transient receptor potential vanilloid 4 receptors. Studies in autonomic failure patients have also revealed that angiotensin II can be generated through noncanonical pathways independent of plasma renin activity to contribute to hypertension. Similarly, the mineralocorticoid receptor antagonist eplerenone produces acute hypotensive effects, highlighting the presence of non-nuclear mineralocorticoid receptor pathways. These are examples of careful clinical research that integrates pathophysiology and pharmacology to advance our knowledge of human disease., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Multiple chemical sensitivity (MCS) is a prevalent medically unexplained symptom characterized by symptom reactions to everyday chemical exposure below hygienic thresholds. The aim of this study was to investigate the expressions of hyper-reactivity in MCS during whole-body exposure to low concentrations of the odorant n-butanol., Methods: We exposed 18 participants with MCS and 18 non-ill controls to a low concentration of the odorant n-butanol using an exposure chamber. The first 10 min constituted blank exposure, after which the n-butanol concentration increased and reached a plateau at 11.5 mg/m(3)., Results: MCS participants, compared with controls, reported greater perceived odor intensities, more unpleasantness to the exposure and increasing symptoms over time. MCS participants also expressed higher pulse rate and lower pulse rate variability than controls did. No group differences were found for breathing rate or tonic electrodermal activity responses., Conclusions: We conclude that MCS sufferers differ from healthy controls in terms of autonomic responses, symptoms and chemosensory perception during chemical exposure.

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.

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 (P < 0.05 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 (P > 0.05). These results demonstrate that diet modification can have beneficial effects on sympathetic function and restore normotension without the need for weight reduction., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell.

Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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 30min 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<0.05)., Conclusion: We found no evidence that specific verbal suggestions during placebo interventions affect BP in healthy subjects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Rationale: Pupillometry can be used to characterize autonomic drug effects., Objective: This study was conducted to determine the autonomic effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), administered alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin, on pupillary function., Methods: Infrared pupillometry was performed in five placebo-controlled randomized studies. Each study included 16 healthy subjects (eight men, eight women) who received placebo-MDMA (125 mg), placebo-placebo, pretreatment-placebo, or pretreatment-MDMA using a crossover design., Results: MDMA produced mydriasis, prolonged the latency, reduced the response to light, and shortened the recovery time. The impaired reflex response was associated with subjective, cardiostimulant, and hyperthermic drug effects and returned to normal within 6 h after MDMA administration when plasma MDMA levels were still high. Mydriasis was associated with changes in plasma MDMA concentration over time and longer-lasting. Both reboxetine and duloxetine interacted with the effects of MDMA on pupillary function. Clonidine did not significantly reduce the mydriatic effects of MDMA, although it produced miosis when administered alone. Carvedilol and doxazosin did not alter the effects of MDMA on pupillary function., Conclusions: The MDMA-induced prolongation of the latency to and reduction of light-induced miosis indicate indirect central parasympathetic inhibition, and the faster recovery time reflects an increased sympathomimetic action. Both norepinephrine and serotonin mediate the effects of MDMA on pupillary function. Although mydriasis is lasting and mirrors the plasma concentration-time curve of MDMA, the impairment in the reaction to light is associated with the subjective and other autonomic effects of MDMA and exhibits acute tolerance.

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.

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: 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., Material and Methods: 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)., Results: 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., Conclusions: 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., (© 2012 John Wiley & Sons A/S.)

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.

Purpose: 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., Methods: 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., Results: 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., Conclusions: Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.

It has been estimated that more than 80% of alcoholics are also nicotine dependent and that, vice versa, the rate of alcoholism is substantially increased by a factor of 4-10 in the nicotine-dependent population. However, the cause for this very high degree of comorbidity is still largely unknown. At the molecular and cellular level, both drugs have very different mechanisms of action. Nicotine specifically activates ligand-gated ion channels in the brain, which are normally gated by acetylcholine, while alcohol interacts with various neurotransmitter receptors. Despite this diversity, both drugs seem to engage the endogenous opioid system as a modulator of some of its pharmacological effect. An acute exposure to nicotine or alcohol leads to a release of opioid peptides in specific brain regions, thus resulting in an activation of their corresponding receptors. If the brain is exposed repeatedly or chronically to these drugs, adaptive changes in the level and expression of opioid peptides and receptors occur. These adaptive changes are thought to contribute to the homeostatic or allostatic adaptations of the brain, which have been associated with drug dependence. This review summarizes pharmacological and genetic studies in animal models and in humans that have addressed the role of specific opioid peptides and receptors in various stages of the addiction process., (Copyright 2009. Published by Elsevier Ltd.)

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.

Two distinct intracellular mechanisms have been proposed to affect the firing rate of cardiac pacemaker cells: one involves modulation of the I(f) current by the second messenger cAMP, and one relies upon disruption or alteration of SR Ca2+ transients during activity. Although both mechanisms are necessary for proper automaticity and autonomic rate control, the specific contribution of each to pacemaking is still debated. We investigated if the two processes can be separated based on potentially different effects on action potential characteristics during rate modulation. To identify specific I(f)-mediated effects, we used the selective I(f) blocker ivabradine and found that ivabradine (3 microM) slows rate (-16.2%) by selectively reducing (-31.9%) the steepness of early diastolic depolarization (EDD). On the other hand ryanodine (3 microM), used to evaluate the effects of abolishment of SR Ca2+ transients, slowed rate (-31.3%) by depolarizing the take-off potential (TOP, 18.1%) without affecting EDD. We therefore used these two parameters to identify I(f)-based or SR Ca2+ transients-based processes and analyzed the effects on action potential's characteristics of Rp-cAMPs (50 microM), a membrane permeable cAMP analogue directly activating f-channels; we found that Rp-cAMPs accelerates rate by increasing EDD (+42.3%) without modifying TOP. Finally, rate modulation was achieved by muscarinic (ACh 0.01 microM) or beta-adrenergic (Iso 1 microM) stimulation; in both cases, rate changes were associated with modifications of EDD (ACh, -29.3% and Iso, +47.6%) and not of TOP. We conclude that rate-related changes in the EDD induced by autonomic agonists are mediated by I(f) and not by processes involving SR Ca2+ transients.

Social experiences, both positive and negative, may influence cardiovascular regulation. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that form social bonds similar to those seen in primates, and this species may provide a useful model for investigating neural and social regulation of cardiac function. Cardiac regulation has not been studied previously in the prairie vole. Radiotelemetry transmitters were implanted into adult female prairie voles under anesthesia, and electrocardiographic parameters were recorded. Autonomic blockade was performed using atenolol (8 mg/kg ip) and atropine methyl nitrate (4 mg/kg ip). Several variables were evaluated, including heart rate (HR), HR variability and the amplitude of respiratory sinus arrhythmia. Sympathetic blockade significantly reduced HR. Parasympathetic blockade significantly increased HR, and reduced HR variability and the amplitude of respiratory sinus arrhythmia. Combined autonomic blockade significantly increased HR, and reduced HR variability and respiratory sinus arrhythmia amplitude. The data indicate that autonomic function in prairie voles shares similarities with primates, with a predominant vagal influence on cardiac regulation. The current results provide a foundation for studying neural and social regulation of cardiac function during different behavioral states in this socially monogamous rodent model.

Conventional spectral analyses of heart rate variability (HRV) have been limited to stationary signals and have not allowed the obtainment of information during transient autonomic cardiac responses. In the present study, we evaluated the ability of the short-time Fourier transform (STFT) method to detect transient changes in vagal effects on the heart. We derived high-frequency power (HFP, 0.20-0.40 Hz) as a function of time during active orthostatic task (AOT) from the sitting to standing posture before and after selective vagal (atropine sulfate 0.04 mg/kg) and sympathetic (metoprolol 0.20 mg/kg) blockades. The HFP minimum point during the first 30 s after standing up was calculated and compared with sitting and standing values. Reactivity scores describing the fast and slow HFP responses to AOT were calculated by subtracting the minimum and standing values from the sitting value, respectively. The present results, obtained without controlled respiration, showed that in the drug-free condition, HFP decreased immediately after standing up (P < 0.001) and then gradually increased toward the level characteristic for the standing posture (P < 0.001), remaining lower than in the sitting baseline posture (P < 0.001). The magnitudes of the fast and slow HFP responses to AOT were abolished by the vagal blockade (P < 0.001) and unaffected by the sympathetic blockade. These findings indicate that HFP derived by the STFT method provided a tool for monitoring the magnitude and time course of transient changes in vagal effects on the heart without the need to interfere with normal control by using blocking drugs.

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 [H]NMS ([N-methyl-H]scopolamine methyl chloride) (bladder) and [H]prazosin (prostate) with IC50 values of 46.1 and 183 microg/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<0.05 and 0.01, respectively). No significant locomotor differences were observed in the mild injury group. In the moderate injury group, residual urine volumes were reduced with chondroitinase treatment by 2 weeks after injury (p<0.05) and in the severe injury group, by 6 weeks after injury (NS). These results demonstrate that chondroitinase is effective at promoting both somatic and autonomic motor recovery following a clinically relevant contusion spinal cord injury and is a candidate as a therapeutic for human spinal cord injury.

The present study was designed to investigate Substance P (SP) and a related tachykinin, Neurokinin A (NKA), contributions to the excitatory neurotransmission to the circular smooth muscle of the hamster ileum. In the presence of atropine (0.5 microM), guanethidine (3 microM) and NG-nitro-L-arginine methyl ester (L-NAME) (200 microM), electrical field stimulation (EFS) evoked a non-adrenergic, non-cholinergic (NANC) excitatory junction potential (EJP) and contraction of circular smooth muscle. Applications of SP and NKA produced depolarizing and contractile responses in a concentration-dependent fashion. The EJP and contraction were almost abolished by the non-specific tachykininergic antagonist, spantide (3 microM). Application of SP antagonist, L-732,138, (1 microM) markedly inhibited EJP (82.5%) and contraction (68.9%) and completely blocked excitatory responses produced by exogenous application of SP. While application of NKA antagonist, SR48968 (1 microM) completely blocked the depolarising and contractile responses to NKA, it only slightly inhibited those to EFS (17.2% and 31.4% respectively). These results provide evidence that, in the circular muscle of hamster ileum, endogenous tachykinins are the main NANC excitatory neurotransmitters and their action is mediated by both NK1 and NK2 receptors.

The "push-pull" effect denotes the reduced tolerance to +Gz (hypergravity) when +Gz stress is preceded by exposure to hypogravity, i.e., fractional, zero, or negative Gz. Previous studies have implicated autonomic reflexes as a mechanism contributing to the push-pull effect. The purpose of this study was to test the hypothesis that nonautonomic mechanisms can cause a push-pull effect, by using eye-level blood pressure as a measure of G tolerance. The approach was to impose control (30 s of 30 degrees head-up tilt) and push-pull (30 s of 30 degrees head-up tilt immediately preceded by 10 s of -15 degrees headdown tilt) gravitational stress after administration of hexamethonium (10 mg/kg) to inhibit autonomic ganglionic neurotransmission in four dogs. The animals were chronically instrumented with arterial and venous catheters, an ascending aortic blood flow transducer, ventricular pacing electrodes, and atrioventicular block. The animals were paced at 75 beats/min throughout the experiment. The animals were sedated with acepromazine and lightly restrained in lateral recumbency on a tilt table. After the onset of head-up tilt, the magnitude of the fall in eye-level blood pressure from baseline was -27.6 +/- 2.3 and -37.9 +/- 2.7 mmHg for the control and push-pull trials, respectively (P < 0.05). Cardiac output fell similarly in both conditions. Thus a push-pull effect attributable to a rise in total vascular conductance occurs when autonomic function is inhibited.

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 investigated the neuronal locus, the role of PKC activation, and utilization of extracellular Ca(2+) and intracellular Ca(2+) release in smooth muscle cells for the generation of giant migrating contractions (GMCs) and rhythmic phasic contractions (RPCs) in intact normal and inflamed canine ileum. Calcitonin gene-related peptide (CGRP), administered close intra-arterially, stimulated GMCs at higher doses and RPCs at smaller doses. These effects were blocked by prior close intra-arterial infusions of CGRP(8-37), atropine, hexamethonium, and TTX but not by tachykinin, serotonin, and histaminergic receptor subtype antagonists. Both types of contractions were blocked by verapamil in normal and inflamed ileums. Dantrolene and ruthenium red blocked only the RPCs in normal ileum but blocked both GMCs and RPCs in the inflamed ileum. PKC inhibition by chelerythrine blocked GMCs only in inflamed ileum but blocked RPCs in both normal and inflamed ileums. The inhibition of phospholipase C by neomycin blocked both RPCs and GMCs in normal and inflamed ileums. In conclusion, acetylcholine is the common neurotransmitter for the stimulation of both GMCs and RPCs, but the signaling cascades for their stimulation are partially divergent, and they differ also in the normal and inflamed states.

We previously demonstrated that the overexpression of endothelial nitric oxide synthase (eNOS) in the rostral ventrolateral medulla (RVLM) decreases blood pressure, heart rate (HR), and sympathetic nerve activity and that these effects are enhanced in stroke-prone spontaneously hypertensive rats (SHRSP). The aim of this study was to determine if an increase in NO production in the RVLM caused by the overexpression of eNOS improves the impaired baroreflex control of HR in SHRSP. We transfected adenovirus vectors encoding eNOS (AdeNOS) into the RVLM of SHRSP or Wistar-Kyoto rats (WKY). Mean arterial pressure and HR were measured by a radio-telemetry system in the conscious state. Reflex changes in HR were elicited by intravenous infusion of either phenylephrine, sodium nitroprusside, or hydralazine at day 7 after the gene transfer. The maximum gain of the baroreflex control of HR was significantly decreased in SHRSP compared with WKY. Overexpression of eNOS in the RVLM of SHRSP improved the impaired maximum gain of the baroreflex control of HR. After treatment with atropine, the maximum gain was still significantly greater in SHRSP in the AdeNOS-transfected group than in the nontransfected group, although it was decreased in both groups. In contrast, after treatment with metoprolol, the maximum gain did not differ between the two groups. These results indicate that an increase in NO production in the RVLM improves the impaired baroreflex control of HR in SHRSP and that these effects may have resulted from a cardiac sympathoinhibitory effect of NO in the RVLM of SHRSP.

Background: We reported sex difference in the urethral pressure (UP) response to electrical stimulation (ES) of the hypogastric nerve in rats. The purpose of the present study was to report on sex difference in the UP response to ES of the pudendal nerves (PN) in rats before and after injection of d-tubocurarine (d-tc)., Methods: Wistar rats were anesthetized with urethane and alpha-chloralose. The L6-S1 trunk was exposed on the left side and resected. After resection of the motor branch of the PN the peripheral end of the L6-S1 trunk was stimulated. Fluid was infused into the urethra through a catheter inserted into the bladder neck at a constant rate (0.5 mL/10 min) and the infusion resistance was measured as the UP. When d-tc was injected, the rats were ventilated with an artificial respirator., Results: Though ES of the L6-S1 trunk caused fibrillation of the muscles near the tail and steep reduction of the UP, it caused elevation and reduction of UP in male and female rats, respectively, after intravenous injection of d-tc (0.3 mg/kg). ES of the sensory branch of the PN caused the elevation in male rats and reduction of the UP without injection of d-tc, and prazosin inhibited the UP elevation but the reduction was not inhibited by Nomega-nitro-L-arginine methyl ester., Conclusion: In the sensory branch of the PN, the nerves innervating the smooth muscles in the urethral sphincter were contained. In male rats norepinephrine mediates the UP elevation, but the neurotransmitter that mediates the UP reduction in female rats is not known.

Background: The superior vena cava (SVC) has been proved to be a focal point in the initiation of paroxysmal atrial fibrillation. The autonomic nervous system plays an important role in the genesis of atrial fibrillation. However, the arrhythmogenic potentials of SVC and its responses to autonomic agents are not clear. The purpose of this study was to isolate single SVC cardiomyocytes and to investigate their electrophysiological characteristics, as well as the direct effects of autonomic agents., Methods and Results: Canine SVC cardiomyocytes were isolated by perfusion with digestive enzymes. The action potentials and ionic currents were investigated in single SVC cardiomyocytes using the whole-cell clamp technique. Dissociation of the SVC yielded rod-shaped single cardiomyocytes with (n=74, 51%) or without (n=71, 49%) pacemaker activities. There were similar densities of inward Ca2+, delayed rectifier K+, transient inward, inward rectifier K+, and pacemaker currents between SVC cardiomyocytes with and without pacemaker activity. SVC cardiomyocytes with pacemaker activity have, however, greater transient outward currents than those without pacemaker activity. In SVC cardiomyocytes, acetylcholine (5.5 micromol/L) abolished the spontaneous activities, but isoproterenol (10 nmol/L), atropine (10 micromol/L), and phenylephrine (10 micromol/L) accelerated the spontaneous activity and induced the occurrences of early or delayed afterdepolarizations., Conclusions: These findings suggest that SVC cardiomyocytes have distinct action potentials and ionic current profiles that may be responsible for the arrhythmogenic activity of the SVC.

Previous studies have demonstrated that certain pesticides, including carbaryl and endosulfan, can modulate the expression of predator-induced morphology in Daphnia. These pesticides affect the transmission of nervous impulses in vertebrates and invertebrates. The aim of this study was to determine the role of two neurotransmitter systems, excitatory cholinergic transmission and inhibitory gamma-aminobutyric acid (GABA)-mediated transmission, in the regulation of inducible defenses of Daphnia. The effects of chemicals with four different modes of action on the expression of Chaoborus-induced neckteeth in Daphnia pulex were measured. These chemicals included chemicals that could enhance transmission at cholinergic synapses (physostigmine, nicotine), inhibit cholinergic transmission (atropine), stimulate or enhance the effects of GABA (diazepam, muscimol, cis-4-aminocrotonic acid), or antagonise the action of GABA (picrotoxin, bicuculline, SR95531). The development of Chaoborus-induced neckteeth in D. pulex was enhanced by physostigmine and picrotoxin and suppressed by atropine. It was proposed that these chemicals were acting on neurosecretory cells that release the hormones necessary to induce neckteeth development. The results also indicate mechanisms through which anthropogenic pollutants could influence the expression of inducible defenses, leading to inappropriate expression in environments with low predator intensity or to suppression in environments with high risks of predation.

Recent results in normotensive Wistar-Kyoto (WKY) rats show that nonlinear method may be more specific to quantify sympathetic and parasympathetic activities than the low (LF) and high frequencies (HF) spectral powers of blood pressure (BP) and R-R interval (RR). The present study extends this conclusion to spontaneously hypertensive rats (SHR). Blood pressure was recorded for 30 min before and after intravenous injection of saline, hexamethonium, atropine, atenolol, or prazosin. Mean level, standard deviation (SD), spectral LF and HF components, and three nonlinear indexes (percentage of recurrence, percentage of determinism, and length index of the recurrence plot method) were used to analyze the BP and RR signals. In conscious SHR, sympathetic but not parasympathetic blockade reduced BP level and LF-BP, and increased nonlinear indexes of BP. RR increased after beta-sympathetic and ganglionic blockade, decreased after parasympathetic blockade, and remained unchanged after alpha(1)-sympathetic blockade. SD-RR decreased after ganglionic and alpha(1) blockade, whereas HF-RR increased after beta-sympathetic blockade. The effects on nonlinear indexes of RR are clear and consistent: only alpha(1)-blockade increased the indexes. Our nonlinear indexes may be useful to investigate cardiovascular functions in normotension and hypertension.

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 PGE(1) 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.

Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

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 down-stream of cAMP synthesis and linked to cAMP more tightly than the choline accumulation, though both choline changes occurred via beta1-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.

The contractile behaviour and effects of several autonomic drugs on the motor activity of human isolated ejaculatory ducts were investigated. Ejaculatory ducts exhibited spontaneous contractions characterised by an amplitude of 2.35 +/- 0.28 mN, a duration of 62. 9 +/- 3.72 s and a frequency of 0.64 +/- 0.014 waves min-1. Acetylcholine (10-5-10-4 m) induced a slight increase in basal tone and in the frequency of the contraction waves. These effects were suppressed by atropine (10-4 m). Noradrenaline (norepinephrine) increased the basal tone and frequency of spontaneous contractions in a dose-dependent manner. These responses were competitively inhibited by HEAT, a selective a1-adrenoceptor antagonist. These preliminary functional findings, indicating the presence of spontaneous motor activity of human ejaculatory ducts and its possible control by adrenergic agonists, suggests a physiological role for human ejaculatory duct in the propulsion of semen from the seminal vesicle towards the urethra.

beta-Domain deleted recombinant factor VIII (GC-rAHF), newly developed by Korea Green Cross Co., is a novel therapeutic for hemophiliacs and is currently under clinical evaluation. The general pharmacological properties of this drug were evaluated using mice, rats, guinea pigs and rabbits. Intravenous doses of 5 to 500 IU/kg were assayed in several tests to analyze their effects in vivo on various systems. The effect of the substance under study was also tested in vitro on isolated guinea pig ileum preparations at final concentrations of 5 to 50 IU/kg. The result of this study showed that GC-rAHF did not affect general behavior in the Irwin test. Similarly the drug was not found to affect neither normal body temperature nor the spontaneous activity in mice. In addition, it was not found to induce pharmacologically significant alterations of the cardiovascular and respiratory parameters in rats. No effects were observed either in the pentobarbital sodium-induced sleep-induction time and duration, in writhing test or in the test of pentetrazole-induced convulsion. Finally, the tested drug did not modify the gastrointestinal motility, acetylcholine or histamine-induced contraction of the isolated guinea pig ileum, nor gastric secretion. The results demonstrated that GC-rAHF has no effects on the central nervous, cardiovascular, respiratory and digestive systems in the doses of 5, 50 and 500 IU/kg in vivo and 5, 10, 50 and 100 IU/kg in vitro.

Junctional transmissions and their modulation by DQ-2511, a novel prokinetic agent, were investigated in smooth muscle of the guinea pig duodenum. Transmural nerve stimulation evoked a cholinergic excitatory junction potential, a nonadrenergic, noncholinergic inhibitory junction potential, and a substance P mediated slow depolarization. DQ-2511 showed dual effects on the slow depolarization: a low concentration (10(-9) mol/l) enhanced and high concentrations (>10(-6) mol/l) tended to inhibit. The depolarization produced by exogenously applied substance P was enhanced by low concentrations of DQ-2511. The results suggest that the prokinetic actions of DQ-2511 involve an enhancement of transmission from substance P neurons due to an increase in sensitivity of postjunctional receptors to substance P.

The aim of this study was to contribute to the characterization of the entactogen (ecstasy) substance group. The psychopathological, neuroendocrine and autonomic effects of common recreational doses of the entactogen 3,4-methylenedioxyethylamphetamine (MDE), the hallucinogen psilocybin, the stimulant d-methamphetamine and placebo were investigated in a double-blind study with healthy volunteers (n = 32). Psychological effects of the drugs were assessed by means of standardized rating scales, self assessment inventories and free descriptions. The most characteristic effects of MDE were pleasant emotional experiences of relaxation, peacefulness, content and closeness to others. However, significant stimulant and hallucinogen-like effects were also present, although the latter were weaker than the effects of psilocybin. MDE elicited the strongest endocrine and autonomic effects among the three drugs, including robust rises of serum cortisol and prolactin, elevations of blood pressure and heart rate, and a moderate, but significant rise of body temperature. The apparent contrast between psychological and autonomic effects (subjective relaxation versus physical activation) was a unique feature of the MDE state. Our findings are in line with both users' reports and results from previous experimental studies, and support the view that entactogens constitute a distinct psychoactive substance class taking an intermediate position between hallucinogens and stimulants.

Protein secretion from rat parotid acinar cells occurs in both the absence and presence of secretory agonists. Release takes place by four pathways that are distinguished by combined examination of their timing following biosynthetic labeling, their relative composition of salivary proteins, and their sensitivity to secretagogue stimulation. Following pulse-labeling with a radioactive amino acid, two unstimulated export pathways are detected--a constitutive-like pathway that is coupled to maturation of secretory granules and the later unstimulated exocytosis of secretory granules. In both cases, protein release is insensitive to secretory antagonists. Two regulated secretory pathways are also detected. The major regulated pathway comprises stimulated exocytosis of secretory granules and requires application of beta-adrenergic agonists (> or = 1 microM). A newly discovered minor regulated pathway resembles the constitutive-like pathway in secretory composition but requires low-dose stimulation by either beta-adrenergic or cholinergic agonists. The latter pathway may provide a significant component of basal secretion by the parotid gland during periods between meals.

Stimulation of parasympathetic innervation of the submandibular gland (2 or 20 Hz continuously or 20 Hz for 1 s at 10 s intervals), in the ferret, produced secretion of fluid and protein and a fall in vascular resistance. The responses following the administration of N omega-nitro-L-arginine methyl ester (L-NAME; 2 mmol kg-1 i.a.) to block the synthesis of nitric oxide (NO) were reduced, and the persisting responses were abolished (at 2 Hz continuously and 20 Hz intermittently) or further reduced (at 20 Hz continuously) by the additional administration of atropine. The output of vasoactive intestinal peptide (VIP) from the gland was not affected. Neither the secretory nor the vascular response to intra-arterial infusions of acetylcholine (1.25 nmol kg-1) was affected by L-NAME, whereas the vascular responses to both VIP (10 pmol kg-1) and pituitary adenylate cyclase-activating peptide (1-38) (PACAP) (0.5 pmol kg-1) were reduced thereby. Neither peptide evoked a fluid secretion per se. However, when infused during parasympathetic stimulation of saliva secretion, VIP increased both flow rate and the output of protein. These effects of VIP were abolished by L-NAME. The experiments were performed in the presence of sodium nitroprusside at doses (4-8 nmol min-1 kg-1 i.v.) aimed to counterbalance the systemic effects of L-NAME. The results show that, in the ferret, parasympathetic nerve activity increases submandibular blood flow, and elicits the flow of saliva and output of protein by mechanisms that involve in situ generation of NO, upon which the effects of VIP and PACAP but not acetylcholine are largely dependent.