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Highlights: [•] Intraplantar dexmedetomidine ameliorated mechanical allodynia by spinal nerve ligation. [•] The effect of dexmedetomidine was reversed by α2A, α2B, and α2C-adrenoceptors antagonist. [•] The expression levels of α2B- and α2C-adrenoceptor of skin were increased. [ABSTRACT FROM AUTHOR]

Hypertension and diabetes have been related to noradrenergic system impairment, especially to the response mediated by alpha-1 receptors. The aim of this work was to investigate possible changes in the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of Wistar Kyoto and spontaneously hypertensive rats after 4 weeks of the onset of diabetes. Our results suggest that early diabetes modifies the expression of alpha-1 adrenergic receptors in aorta and carotid arteries of both WKY and SHR strains in a different way. [ABSTRACT FROM AUTHOR]

This review is focused on the role of noradrenalin and its receptors in the pathogenesis of primary headaches, in particular, migraine headaches. The data are summarized on the involvement of different adrenoreceptors in the regulation of tone of cerebral vessels and modulation of transmission of nociceptive information in the trigeminovascular system and at the supraspinal level of the CNS. We discuss the pharmacodynamics of several adrenergic drugs that are used for prophylactic treatment of migraine headaches. [ABSTRACT FROM AUTHOR]

Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial-temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction (NMJ) is important for postsynaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor (AChR), PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, α-calcitonin-related peptide, as well as catecholamines are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of β2- adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMPdependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity. [ABSTRACT FROM AUTHOR]

The adult prostate gland grows and develops under hormonal control while its physiological functions are controlled by the autonomic nervous system. The prostate gland receives sympathetic input via the hypogastric nerve and parasympathetic input via the pelvic nerve. In addition, the hypogastric and pelvic nerves also provide sensory inputs to the gland. This review provides a summary of the innervation of the adult prostate gland and describes the changes which occur with age and disease. Growth and development of the prostate gland is age dependent as is the occurrence of both benign prostate disease and prostate cancer. In parallel, the activity and influence of both the sympathetic and parasympathetic nervous system changes with age. The influence of the sympathetic nervous system on benign prostatic hyperplasia is well documented and this review considers the possibility of a link between changes in autonomic innervation and prostate cancer progression. [ABSTRACT FROM AUTHOR]

Sympathoadrenergic pathways are crucial to the communication between the nervous system and the immune system. The present review addresses emerging issues in the adrenergic modulation of immune cells, including: the specific pattern of adrenoceptor expression on immune cells and their role and changes upon cell differentiation and activation; the production and utilization of noradrenaline and adrenaline by immune cells themselves; the dysregulation of adrenergic immune mechanisms in disease and their potential as novel therapeutic targets. A wide array of sympathoadrenergic therapeutics is currently used for non-immune indications, and could represent an attractive source of non-conventional immunomodulating agents. [ABSTRACT FROM AUTHOR]

Background/Aims: Imidazoline α2-adrenergic agents exert complex effects on mammalian platelet aggregation. Although non-adrenergic, imidazoline (I) receptors have been revealed in human platelets, there is limited information about imidazoline's action on platelet aggregation. This study aimed to investigate aggregatory and anti-aggregatory effects of various imidazoline or non-imidazoline α-adrenergic agents on rabbit platelets. Methods: Aggregatory responses of agents on rabbit platelets were examined by turbidimetric method. Radioligand binding assay to platelet I1 and I2 receptors was performed using [3H]-clonidine and [3H]-idazoxan, respectively. Results: Aggregation was not induced by α-adrenoceptor agonists alone. Adrenaline and noradrenaline produced dose-dependent potentiation of ADP- or collagen-induced aggregation. Imidazoline adrenoceptor agonists clonidine and p-aminoclonidine also potentiated ADP-induced platelet aggregation. The α2-adrenoceptor antagonists and/or certain imidazoline adrenergic agents inhibited adrenaline-potentiated aggregation in a dose-dependent manner, whereas α1-adrenoceptor antagonists and non-imidazoline α-adrenergic agents were either ineffective or less effective in inhibiting adrenaline-potentiated aggregation. Rabbit platelets did not have I1 receptors, but had I2 receptors, indicating that adrenaline-potentiated platelet aggregation was inhibited by idazoxan, but not by imidazoline compounds clonidine and oxymetazoline. Conclusions/Implications: These results demonstrated that α2-adrenoceptor-blocking agents and/or imidazoline α-adrenergic agents effectively inhibit adrenaline-potentiated platelet aggregation. It is proposed that imidazoline structure in part plays a role in the inhibition of adrenaline-potentiated aggregation. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and β-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α2A and β2), skeletal muscle (α1A and β2), liver (α1A & B and β2) and adipose tissue (α1A and β1 & 3) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α1, α2, and β-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disorder of the CNS characterized by inflammation, demyelination and axonal loss. Classical evidence in experimental allergic encephalomyelitis, the animal model of MS, support the relevance of sympatoadrenergic as well as of dopaminergic mechanisms. In MS patients, dysregulation of adrenergic and dopaminergic pathways contribute to the disease in immune system cells as well as in glial cells. Available evidence is summarized and discussed also in the light of the novel role of dopamine, noradrenaline and adrenaline as transmitters in immune cells, providing a conceptual frame to exploit the potential of several dopaminergic and adrenergic agents, already in clinical use for non-immune indications and with a usually favourable risk-benefit profile, as add-on drugs to conventional immunomodulating therapies in MS. [ABSTRACT FROM AUTHOR]

Abstract: Small oligomeric beta amyloid (Aβ1–42) injected 45min prior to single-trial bead discrimination training resulted in impaired learning in day-old chickens. A new experimental protocol was used where the injections of drugs were at times around the time of injection of Aβ. It was found that the Na+ levels of the saline used to dissolve Aβ affected cognitive impairment. Na+ levels above the normal plasma value (140mM) reduced Aβ-induced learning deficits whereas levels below increased sensitivity to Aβ. The new protocol was also used to examine the ability of certain noradrenergic adrenoceptor antagonist and agonists, insulin, glucose and minocycline to reduce learning disruption caused by Aβ. The drugs (made up in 154mM sodium chloride) were injected before, at the same time or after the injection of Aβ and although all drugs prevented Aβ-induced disruption of learning when given in the same injection as Aβ, some injected before could prevent Aβ disrupting learning, whereas others could rescue learning ability when given after Aβ injection. These results are interpreted in the light of possible actions of noradrenaline on microglia and various processes: astrocytic metabolism, cerebral microcirculation, and removal of Aβ away from the site of injection. The possible importance of hypernatremia and hyponatremia in the incidence of Alzheimer’s disease is discussed. [Copyright &y& Elsevier]

The influence of noradrenaline acting at α-AR and β-ARs on the turnover of glycogen after learning has been investigated. The role of glycogen turnover in memory formation was examined using weakly-reinforced, single trial bead discrimination training in day-old domestic chickens. This study follows our previous work that focused on the need for glycogen breakdown (glycogenolysis) during learning. Inhibition of glycogenolysis by 1,4-dideoxy-1,4-imino- d-arabinitol (DAB) prevented the consolidation of strongly-reinforced learning and inhibited memory. The action of DAB could be prevented by stimulating glycogenolysis with the selective β-AR agonist, zinterol. Stimulation of α-ARs has been shown to lead to an increase in the turnover and synthesis of glycogen. In the present study, we examined the effect of inhibition of α-AR stimulated glycogen turnover (measured asC-glucose incorporation into glycogen) on the ability of zinterol to promote the consolidation of weakly reinforced memory. In astrocytes, the selective α-AR agonist clonidine stimulated C-glucose incorporation into glycogen in chick astrocytes and this was inhibited by the selective α-AR antagonist, ARC239. The critical importance of the timing of ARC239 injection relative to training and intracerebral administration of zinterol was examined. It is concluded that our data provides evidence for a readily accessible labile pool of glycogen in brain astrocytes. If glycogen synthesis is inhibited, the can be depleted within 10 min, thus preventing zinterol from promoting consolidation. [ABSTRACT FROM AUTHOR]

Abstract: Medial amygdaloid nucleus (MeA) neurotransmission has an inhibitory influence on cardiovascular responses in rats submitted to restraint, which are characterized by both elevated blood pressure (BP) and intense heart rate (HR) increase. In the present study, we investigated the involvement of MeA adrenoceptors in the modulation of cardiovascular responses that are observed during an acute restraint. Male Wistar rats received bilateral microinjections of the selective α1-adrenoceptor antagonist WB4101 (10, 15, and 20nmol/100nL) or the selective α2-adrenoceptor antagonist RX821002 (10, 15, and 20nmol/nL) into the MeA, before the exposure to acute restraint. The injection of WB4101 reduced the restraint-evoked tachycardia. In contrast, the injection of RX821002 increased the tachycardia. Both drugs had no influence on BP increases observed during the acute restraint. Our findings indicate that α1 and α2-adrenoceptors in the MeA play different roles in the modulation of the HR increase evoked by restraint stress in rats. Results suggest that α1-adrenoceptors and α2-adrenoceptors mediate the MeA-related facilitatory and inhibitory influences on restraint-related HR responses, respectively. [Copyright &y& Elsevier]

Abstract: Repeated exposure to laboratory stressors often results in behavioral changes that are commonly referred to as depressive-like behaviors. Here, we examined the contribution fear conditioning may play in altering an animals’ behavior in a repeated stress paradigm. Fischer rats were exposed daily to different stressors in a complex environment (context A). After four days of stressor exposure, exploratory behavior (10min in new cage) and social interaction (5min with juvenile) were tested on day 5 in either the same environment or a new environment (context B). Rats showed decreased exploration and social interaction when tested in context A compared to control rats or rats tested in context B. Additionally, chronic infusion of propranolol (beta-adrenergic receptor antagonist that crosses the blood–brain barrier), but not nadolol (beta-adrenergic receptor antagonist that does not readily cross the blood–brain barrier), prevented the behavioral changes following repeated stressor exposure. Propranolol treatment did not affect the acute or chronic elevation of corticosterone, the decrease in body weight gain, or adrenal hypertrophy observed in animals exposed to stress. These data demonstrate that conditioned fear responses can contribute to behavioral changes in a repeated stress paradigm. Additional studies revealed, Sprague-Dawley rats do not demonstrate decreased exploration or social interaction when testing occurs in the same context as repeated stressor exposure suggesting Fischer rats may have a greater propensity to associate distal cues with aversive events in a complex environment. This may be due to greater stress responses in Fischer animals that are known to enhance consolidation of emotionally arousing events. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE β-Adrenoceptors are expressed in human and experimental animal breast cancer cells. However, the effect of the agonists and antagonists reported on cell proliferation and tumour growth was paradoxical, precluding their utilization as possible adjuvant therapy, mainly in the cases of refractory tumours. EXPERIMENTAL APPROACH β-Adrenoceptor expression was analysed by immunofluorescence and RT-PCR. Cell proliferation was assessed by [3H]-thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting. KEY RESULTS β2-Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α2-adrenoceptor action) and decreased in every tested cell line by the β-adrenoceptor agonist isoprenaline and the β2-adrenoceptor agonist salbutamol. Isoprenaline and salbutamol reduced tumour growth in every tumour tested (mouse C4-HD and CC4-3-HI and human IBH-4, IBH-6 and MDA-MB-231 cell lines growing as xenografts in nude mice). These effects were reversed by the β-adrenoceptor antagonist propranolol. The α2-adrenoceptor antagonist rauwolscine and the β2-adrenoceptor agonist salbutamol were equally effective in diminishing tumour growth. ERK 1/2 activation analysed in IBH-4 tumours correlated with tumour growth, with the β-adrenoceptor agonists decreasing its activation. Inhibition of ERK 1/2 phosphorylation in vitro was mainly mediated by the PKA pathway. CONCLUSIONS AND IMPLICATIONS In our experimental models, the β-adrenoceptor agonists inhibited breast cancer cell proliferation and tumour growth, probably mediated by inhibition of ERK 1/2 phosphorylation. The β-adrenoceptor agonists were as effective as the α2-adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family Alliaceae, most commonly associated with onions and garlic. In South Africa, this herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension and stomach problems. The aim of this study was to evaluate the effect of methanol leaf extracts (MLE) of Tulbaghia violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats; and to find out the mechanism(s) by which it acts. Materials and methods: The MLE of Tulbaghia violacea (5–150mg/kg), angiotensin I human acetate salt hydrate (ang I, 3.1–100μg/kg), angiotensin II human (ang II, 3.1–50μg/kg), phenylephrine hydrochloride (phenylephrine, 0.01–0.16mg/kg) and dobutamine hydrochloride (dobutamine, 0.2–10.0μg/kg) were infused intravenously, while the BP and HR were measured via a pressure transducer connecting the femoral artery and the Powerlab. Results: Tulbaghia violacea significantly (p <0.01) reduced the systolic, diastolic, and mean arterial BP; and HR dose-dependently. Ang I, ang II, phenylephrine and dobutamine all increased the BP dose-dependently. The hypertensive effect of ang I and the HR-increasing effect of dobutamine were significantly (p <0.01) decreased by their co-infusion with Tulbaghia violacea (60mg/kg). However, the co-infusion of ang II or phenylephrine with Tulbaghia violacea (60mg/kg) did not produce any significant change in BP or HR when compared to the infusion of either agent alone in the same animal. Conclusions: Tulbaghia violacea reduced BP and HR in the SHR. The reduction in BP may be due to actions of the MLE on the ang I converting enzyme (ACE) and β1 adrenoceptors. [Copyright &y& Elsevier]

Abstract: The adrenal gland plays a fundamental role in the response to a variety of stress situations. After a stress condition, adrenal medullary chromaffin cells release, by exocytosis, high quantities of catecholamine (epinephrine, EP; norepinephrine, NE), especially EP. Once in the blood stream, catecholamines reach different target organs, and induce their biological actions through the activation of different adrenoceptors. Adrenal gland cells may also be activated by catecholamines, through hormonal, paracrine and/or autocrine system. The presence of functional adrenoceptors on human adrenal medulla and their involvement on catecholamines secretion was not previously evaluated. In the present study we investigated the role of β1-, β2- and β3-adrenoceptors on catecholamine release from human adrenal chromaffin cells in culture. We observed that the β-adrenoceptor agonist (isoproterenol) and β2-adrenoceptor agonist (salbutamol) stimulated catecholamine (NE and EP) release from human adrenal chromaffin cells. Furthermore, the β2-adrenoceptor antagonist (ICI 118,551; 100nM) and β3-adrenoceptor antagonist (SR 59230A; 100nM) inhibited the catecholamine release stimulated by isoproterenol and nicotine in chromaffin cells. The β1-adrenoceptor antagonist (atenolol; 100nM) did not change the isoproterenol- neither the nicotine-evoked catecholamine release from human adrenal chromaffin cells. Moreover, our results show that the protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and phospholipase C (PLC) are intracellular mechanisms involved in the catecholamine release evoked by salbutamol. In conclusion, our data suggest that the activation of β2- and β3-adrenoceptors modulate the basal and evoked catecholamine release, NE and EP, via an autocrine positive feedback loop in human adrenal chromaffin cells. [Copyright &y& Elsevier]

Rationale: The clinical efficacy of the monoamine and noradrenaline transporter inhibitors methylphenidate and atomoxetine in attention deficit/hyperactivity disorder implicates noradrenergic neurotransmission in modulating inhibitory response control processes. Nonetheless, it is unclear which adrenoceptor subtypes are involved in these effects. Objectives: The present study aimed at investigating the effects of adrenoceptor agonists on inhibitory response control as assessed in the rodent 5-choice serial reaction time task, a widely used translational model to measure this executive cognitive function. Results: Consistent with the previous reported effects of atomoxetine, the noradrenaline transporter inhibitor desipramine improved inhibitory response control, albeit the effect size was smaller compared to that of atomoxetine. Methylphenidate exerted a bimodal effect on inhibitory response control. Interestingly, the preferential β2-adrenoceptor agonist clenbuterol improved inhibitory response control. Moreover, clenbuterol improved visuospatial attention in the task, an effect that was also observed with the preferential β1-adrenoceptor agonist dobutamine. By contrast, although the preferential α1-adrenoceptor and α2-adrenoceptor agonists (phenylephrine and clonidine, respectively) and the non-selective β-adrenoceptor agonist (isoprenaline) were found to alter inhibitory response control, this was probably secondary to the simultaneous increments in response latencies and omissions observed at effective doses. Conclusions: Taken together, these findings further strengthen the notion of noradrenergic modulation of inhibitory response control and attentional processes and particularly reveal the involvement of β2-adrenoceptors therein. [ABSTRACT FROM AUTHOR]

Abstract: Bilateral injections of moxonidine, an α2-adrenoceptor and imidazoline receptor agonist, into the lateral parabrachial nuclei (LPBN) enhance sodium appetite induced by extracellular dehydration. In the present study, we examined whether LPBN moxonidine treatments change taste reactivity to hypertonic NaCl solution administered into the mouth by intra-oral (IO) cannula. Male Holtzman rats prepared with IO and bilateral LPBN cannulas received subcutaneous injections of furosemide (FURO; 10mg/kg) and captopril (CAP; 5mg/kg) to induce hypovolemia with mild hypotension and an accompanying salt appetite and thirst before testing the taste reactivity to oral infusions of 0.3M NaCl (1.0ml/min). In the first experiment 45min after subcutaneous injections of FURO+CAP or vehicle, moxonidine was bilaterally injected into the LPBN, and then 15min later both bodily and oral–facial ingestive and rejection responses to 0.3M NaCl delivered through the IO cannula were assessed. Both LPBN vehicle and moxonidine treated rats showed increased ingestive and decreased rejection responses to the IO hypertonic solution. The IO 0.3M NaCl infusion-evoked ingestive and rejection taste related behaviors were comparable in the LPBN vehicle- vs. the LPBN moxonidine-injected groups. In a second experiment, rats received the same FURO+CAP treatments and LPBN injections. However, beginning 15min after the LPBN injections, they were given access to water and 0.3M NaCl and were allowed to consume the fluids for most of the next 60min with the free access intake being interrupted only for a few minutes at 15, 30 and 60min after the fluids became available. During each of these three brief periods, a taste reactivity test was conducted. On the three taste reactivity tests rats that received LPBN vehicle injections showed progressive declines in ingestive responses and gradual increases in rejection responses. However, in contrast to the LPBN vehicle treated rats, animals receiving bilateral injections of LPBN moxonidine maintained a high number of ingestive responses and a low number of rejection responses throughout the test period even in spite of evidencing substantial water and 0.3M NaCl consumption during the periods of free access. The results suggest that after α2-adrenoceptor agonist delivery to the LPBN the acceptance of 0.3M NaCl is sustained and the negative attributes of the solution are minimized. The maintained positive rewarding qualities of 0.3M NaCl are likely to account for why LPBN moxonidine treated rats show such a remarkable salt appetite when assayed by the volume of hypertonic 0.3M NaCl consumed. [Copyright &y& Elsevier]

Purpose: The present work was carried out to determine the effects of ethanolic extracts of Arachis hypogaea and its active ingredient resveratrol on the isolated tail melanophores of the Bufo melanostictus to find the mechanism of skin lightening at the cellular level. Methods: The tail melanophores of the tadpole B. melanostictus were assayed using the mean melanophore size index and their responses were recorded in presence of various concentrations of the plant extract and its active ingredient along with specific antagonists and potentiator. Results: Significant skin lightening activity of the extract of A. hypogaea and its active ingredient resveratrol was observed on the tail melanophores of tadpole. The pigment cells responded by distinct aggregation leading to skin lightening, this effect was reversible, as re-immersion in physiological saline made the melanophores return to their normal intermediate state. These melanin aggregating effects were completely blocked by propanolol (beta blocker) and partially blocked by prazosin (alpha blocker) and were also found to be highly potentiated by reserpine. Conclusion: These studies suggest that the active ingredient of A. hypogaea such as resveratrol can act as a sympathomimetic compound and induce aggregation of melanophores of tadpole B. melanostictus via the induction of beta type of the adrenoceptors. The present study opens new vistas for the use of A. hypogaea and its active ingredient, resveratrol for its clinical application as a nontoxic melanolytic compound for the treatment of hyperpigmentation. [ABSTRACT FROM AUTHOR]

Abstract: The role played by spinal adrenergic and cholinergic receptors in the antinociceptive effects of intrathecal sildenafil in formalin-induced nociception was examined. Intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats, and nociception was assessed using the formalin test, consisting of a subcutaneous injection of 50μL of 5% formalin solution into the hind paw. We examined the effects of an alpha 1 adrenergic receptor antagonist (prazosin), an alpha 2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) on sildenafil-induced antinociception. Intrathecal sildenafil (3, 10, and 30μg) suppressed, in a dose-dependent manner, formalin-induced flinching during phases 1 and 2 of the test. Intrathecal sildenafil (30μg) could not show any effects against intrathecal prazosin (3μg), yohimbine (10μg), atropine (10μg), and mecamylamine (10μg) pretreatment during both phases of the formalin test. These results suggest that intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Additionally, spinal alpha 1, alpha 2, muscarinic and nicotinic receptors might play a role in sildenafil-induced antinociception. [Copyright &y& Elsevier]

The thymus plays a critical role in establishing and maintaining the peripheral T-cell pool. It does so by providing a microenvironment within which T-cell precursors differentiate and undergo selection processes to create a functional population of major histocompatibility complex-restricted, self-tolerant T cells. These cells are central to adaptive immunity. Thymic T-cell development is influenced by locally produced soluble factors and cell-to-cell interactions, as well as by sympathetic noradrenergic and endocrine system signalling. Thymic lymphoid and non-lymphoid cells have been shown not only to express β- and α1-adrenoceptors (ARs), but also to synthesize catecholamines (CAs). Thus, it is suggested that CAs influence T-cell development via both neurocrine/endocrine and autocrine/paracrine action, and that they serve as immunotransmitters between thymocytes and nerves. CAs acting at multiple sites along the thymocyte developmental route affect T-cell generation not only numerically, but also qualitatively. Thymic CA level and synthesis, as well as AR expression exhibit sex steroid-mediated sexual dimorphism. Moreover, the influence of CAs on T-cell development exhibits glucocorticoid-dependent plasticity. This review summarizes recent findings in this field and our current understanding of complex and multifaceted neuroendocrine-immune communications at thymic level. [ABSTRACT FROM AUTHOR]

ims/hypothesis: It is well documented that melatonin influences insulin secretion mediated by G-protein-coupled melatonin receptor isoforms MT1 and MT2, which are present in rat and human pancreatic islets, as well as in rat insulinoma cells. Recent investigations have proven that hyperinsulinaemic Goto-Kakizaki (GK) rats, which are a rat model of type 2 diabetic rats, and humans have decreased melatonin plasma levels, whereas a streptozotocin-induced rat model of diabetes developed reduced insulin levels combined with increased melatonin levels. Methods: Plasma levels of glucose, insulin and melatonin as well as RNA expression of pineal Aanat, Hiomt (also known as Asmt), insulin receptor, adrenoceptor β1 and the clock genes Per1 and Bmal1 (also known as Arntl) were determined in male and female LEW.1AR1- iddm rats as well as in insulin-substituted LEW.1AR1- iddm rats. Results: Severe hypoinsulinaemia in diabetic LEW.1AR1- iddm rats was associated with decreased body weight and increased melatonin plasma levels combined with mainly elevated expression of Aanat, Hiomt, pineal insulin receptor and adrenoceptor β1. The changes were normalised by insulin substitution. Diurnal profiles of plasma melatonin and of antagonistic clock genes Per1 and Bmal1 were maintained in diabetic and insulin-substituted rats. Conclusions/interpretation: The assumed causal relation between elevated melatonin and reduced insulin levels in LEW.1AR1- iddm rats is supported by the observation that insulin substitution normalised these changes. Further support for this interpretation comes from the observation that in GK rats an increase of plasma insulin was combined with a decrease of plasma noradrenaline (norepinephrine), the most important activator of melatonin synthesis. These relationships between the noradrenergic and insulin pathway support the existence of melatonin-insulin antagonism. [ABSTRACT FROM AUTHOR]

Abstract: Dynamic exercise evokes sustained blood pressure and heart rate (HR) increases. Although it is well accepted that there is a CNS mediation of cardiovascular adjustments during dynamic exercise, information on the role of specific CNS structures is still limited. The bed nucleus of the stria terminalis (BST) is involved in exercise-evoked cardiovascular responses in rats. However, the specific neurotransmitter involved in BST-related modulation of cardiovascular responses to dynamic exercise is still unclear. In the present study, we investigated the role of local BST adrenoceptors in the cardiovascular responses evoked when rats are submitted to an acute bout of exercise on a rodent treadmill. We observed that bilateral microinjection of the selective α1-adrenoceptor antagonist WB4101 into the BST enhanced the HR increase evoked by dynamic exercise without affecting the mean arterial pressure (MAP) increase. Bilateral microinjection of the selective α2-adrenoceptor antagonist RX821002 reduced exercise-evoked pressor response without changing the tachycardiac response. BST pretreatment with the nonselective β-adrenoceptor antagonist propranolol did not affect exercise-related cardiovascular responses. BST treatment with either WB4101 or RX821002 did not affect motor performance in the open-field test, which indicates that effects of BST adrenoceptor antagonism in exercise-evoked cardiovascular responses were not due to changes in motor activity. The present findings are the first evidence showing the involvement of CNS adrenoceptors in cardiovascular responses during dynamic exercise. Our results indicate an inhibitory influence of BST α1-adrenoceptor on the exercise-evoked HR response. Data also point to a facilitatory role played by the activation of BST α2-adrenoceptor on the pressor response to dynamic exercise. [Copyright &y& Elsevier]

Abstract: The insular cortex (IC) has been reported to be involved in central cardiovascular control. In the present study, we investigated the cardiovascular responses evoked by microinjection of noradrenaline into the IC as well as the central and peripheral mechanisms involved in their mediation. Microinjection of noradrenaline into the IC (3, 7, 10, 15, 30 and 45nmol/100nL) caused long-lasting dose-related pressor and bradycardiac responses. The cardiovascular responses evoked by 15nmol of noradrenaline were blocked by IC pretreatment with WB4101 or 5-methyl-urapidil, selective α1-adrenoceptor antagonists. IC pretreatment with either the selective α2-adrenoceptor antagonists RX821002 or the β-adrenoceptor antagonist propranolol did not affect noradrenaline cardiovascular responses. Noradrenaline cardiovascular responses were mimicked by microinjection of the selective α1-adrenoceptor agonist phenylephrine into the IC, thus reinforcing the idea that α1-adrenoceptors mediate cardiovascular responses to noradrenaline microinjected into the IC. The pressor response to noradrenaline microinjection was potentiated by i.v. pretreatment with the ganglion blocker pentolinium and inhibited by i.v. pretreatment with the selective V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP. The bradycardiac response to noradrenaline microinjection into the IC was abolished by pretreatment with either pentolinium or the V1-vasopressin receptor antagonist, indicating its reflex origin. In conclusion, our results suggest that pressor response evoked by microinjection of noradrenaline into the IC involve the activation of IC α1-adrenoceptors to cause the release of vasopressin into the circulation. [Copyright &y& Elsevier]

The N-phenylpiperazine structures exhibit very extensive multiple receptor activities including the influencing of α1-adrenoceptors (α1-AR). Their antagonistic activity towards α1-AR is intensively applied in the therapy of cardiovascular system diseases - e. g. hypertension as well as in the treatment of benign prostatic hyperplasia. The limited ratio of selective effect on the specific subtypes of the α1-AR by certain drugs used in the practice (azosine-type structures) leads to multiple side effects which includes postural hypotension, syncope or first dose phenomena. The existence of multiple α1-AR subtypes holds promise for the discovery, projection and development of more specific selective drug molecules targeting only one α1-adrenoceptor subtype and making them free from side effects. Towards this aim wide-ranging modifications have been reported in the literature on the „basic“ structure of the N-phenylpiperazine-based molecules. The present paper deals with the affinity features of (substituted) N-phenylpiperazines towards α1-ARs in which the structure is a connecting chain formed by (unsubstituted) ethane-1,2-diyl moiety bonded through certain atom or group (S, O, NH, NHCO-fragment, respectively) at the lipophilic part of the molecule. [ABSTRACT FROM AUTHOR]

Circadian rhythms influence the incidence of adverse cardiac events but the underlying mechanisms are not well defined. We sought to investigate the role of the β3-adrenoceptor (β3-AR) in cardiac circadian disorders and arrhythmia severity after myocardial infarction (MI). MI was created by ligating the left anterior descending coronary artery of the rat heart in situ. Circadian variations of the myocardial expressions of β3-AR and clock genes Bmal1 and Npas2 were examined by real time reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Electrocardiograms and myocardial contraction were recorded in vivo and/or ex vivo. Ventricular tachyarrhythmias were induced by isoprenaline. Normal rats showed circadian oscillations in both the myocardial transcriptional expression of β3-AR and the β3-AR-induced positive chronotropic and negative inotropic cardiac effects. However, these circadian rhythms were significantly blunted or even abolished in rats with either acute MI (within 24 h) or healed MI (14 days after coronary ligation). The nocturnal level of β3-AR protein was higher in MI rats than in normal rats. In contrast, the circadian oscillations of the transcripts of Bmal1 and Npas2 in the myocardium were significantly augmented in rats with either acute MI or healed MI. BRL37344, a preferential β3-AR selective agonist, reduced the occurrence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in rats with either acute MI or healed MI. We conclude that circadian rhythms of myocardial β3-AR activities are disturbed after MI and β3-AR activation offers anti-arrhythmic protection. [ABSTRACT FROM AUTHOR]

The release of gastrointestinal hormones has been reported to modulate reflex cardiovascular responses caused by gastric distension, although the role played by gastrin 17 is as yet unknown. The present study was therefore planned to determine the primary in vivo effect of gastrin 17 on coronary blood flow and cardiac function and the involvement of autonomic nervous system, CCKI/2 receptors, and nitric oxide (NO). In 40 anesthetized pigs, gastrin 17 was infused into the left anterior descending coronary artery at constant heart rate and arterial blood pressure. In 35 of the 40 pigs, the mechanisms of the observed hemodynamic responses were analyzed by repeating gastrin 17 infusion after autonomic nervous system and NO blockade, and after specific CCK receptors agonists/antagonists administration. Intracoronary gastrin 17 administration caused dose-related increases of both coronary blood flow and cardiac function. The intracoronary coadministration of CCK33/pentagastrin and gastrin 17 potentiated the coronary effects observed when the above agents were given alone (P <0.05). The potentiation of the cardiac response was observed only with the co-administration of pentagastrin and gastrin 17 (P <0.05). Moreover, blockade of muscarinic cholinoceptors (intravenous atropine) and of α-adrenoceptors (intravenous phentolamine) did not abolish the hemodynamic responses to gastrin 17. The cardiac and vascular effects of the hormone were prevented by blockade of β-adrenoceptors (intravenous atenolol and butoxamine), CCKI/2 receptors (intracoronary lorglumide and CAM-1028), and NO synthase (intracoronary Nω-nitro-L-arginine methyl ester). In conclusion, gastrin 17 primarily increased coronary blood flow and cardiac function through the involvement of CCK receptors, β-adrenoceptors, and NO release. [ABSTRACT FROM AUTHOR]

Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α > α ≥ α > α ≥ α >> α. Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α- but a lower affinity at α-adrenoceptors. In functional studies in which adrenoceptor-mediated Ca signals were measured, both, oxymetazoline and xylometazoline behaved at α-adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α-adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α-adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. [ABSTRACT FROM AUTHOR]

Aim: In rat afferent arterioles we investigated the role of Na+ entry in noradrenaline (NA)-induced depolarization and voltage-dependent Ca2+ entry together with the importance of the transient receptor potential channel (TRPC) subfamily for non-voltage-dependent Ca2+ entry. Methods: R340/380 Fura-2 fluorescence was used as an index for intracellular free Ca2+ concentration ([Ca2+]i). Immunofluorescence detected the expression of TRPC channels. Results: TRPC 1, 3 and 6 were expressed in afferent arteriolar vascular smooth muscle cells. Under extracellular Na+-free (0 Na) conditions, the plateau response to NA was 115% of the baseline R340/380 (control response 123%). However, as the R340/380 baseline increased (7%) after 0 Na the plateau reached the same level as during control conditions. Similar responses were obtained after blockade of the Na+/Ca2+ exchanger. The L-type blocker nifedipine reduced the plateau response to NA both under control (from 134% to 116% of baseline) and 0 Na conditions (from 112% to 103% of baseline). In the presence of nifedipine, the putative TRPC channel blockers SKF 96365 (30 μm) and Gd3+ (100 μm) further reduced the plateau Ca2+ responses to NA (from 117% to 102% and from 117% to 110% respectively). Conclusion: We found that Na+ is not crucial for the NA-induced depolarization that mediates Ca2+ entry via L-type channels. In addition, the results are consistent with the idea that TRPC1/3/6 Ca2+-permeable cation channels expressed in afferent arteriolar smooth muscle cells mediate Ca2+ entry during NA stimulation. [ABSTRACT FROM AUTHOR]

Catecholamines are among first compounds released during stress, and they regulate many functions of the organism, including immune system, via adrenergic receptors (ARs). Spleen, as an immune organ with high number of macrophages, possesses various ARs, from which β-ARs are considered to be the most important for the modulation of immune functions. Nevertheless, little is known about the regulation and involvement of ARs in the splenic function by stress. Therefore, the aim of this work was to measure the gene expression of ARs and several cytokines in the spleen of rats exposed to a single and repeated (14×) immobilization stress (IMO). We have found a significant increase in β-AR mRNA after a single IMO, but a significant decrease in β-AR mRNA and protein level after repeated (14×) IMO. The most prominent decrease was detected in the gene expression of the α- and α-AR after repeated IMO. However, changes in mRNA were translated into protein levels only for the α-subtype. Other types of ARs remained unchanged during the stress situation. Since we proposed that these ARs might affect production of cytokines, we measured gene expression of pro-inflammatory (TNF-α, IL-1β, IL-6 and IL-18) and anti-inflammatory (IL-10 and TGF-β1) cytokines. We detected changes only in IL-6 and IL-10 mRNA levels. While IL-6 mRNA was increased, IL-10 mRNA dropped after repeated IMO. According to these results we suggest that changes of β- and α-ARs participate in IL-6-mediated processes in the spleen, especially during chronic stress situations. [ABSTRACT FROM AUTHOR]

Abstract: Taste buds signal the presence of chemical stimuli in the oral cavity to the central nervous system using both early transduction mechanisms, which allow single cells to be depolarized via receptor-mediated signaling pathways, and late transduction mechanisms, which involve extensive cell-to-cell communication among the cells in the bud. The latter mechanisms, which involve a large number of neurotransmitters and neuropeptides, are less well understood. Among neurotransmitters, multiple lines of evidence suggest that norepinephrine plays a yet unknown role in the taste bud. This study investigated the expression pattern of adrenergic receptors in the rat posterior taste bud. Expression of α1A, α1B, α1D, α2A, α2B, α2C, β1, and the β2 adrenoceptor subtypes was observed in taste buds using RT-PCR and immunocytochemical techniques. Taste buds also expressed the biosynthetic enzyme for norepinephrine, dopamine β-hydroxylase (DβH), as well as the norepinephrine transporter. Further, expression of the epinephrine synthetic enzyme, phenylethanolamine N-methyltransferase (PNMT), was observed suggesting a possible role for this transmitter in the bud. Phenotyping adrenoceptor expression patterns with double labeling experiments to gustducin, synaptosomal-associated protein 25 (SNAP-25), and neural cell adhesion molecule (NCAM) suggests they are prominently expressed in subsets of cells known to express taste receptor molecules but segregated from cells known to have synapses with the afferent nerve fiber. Alpha and beta adrenoceptors co-express with one another in unique patterns as observed with immunocytochemistry and single cell reverse transcription polymerase chain reaction (RT-PCR). These data suggest that single cells express multiple adrenergic receptors and that adrenergic signaling may be particularly important in bitter, sweet, and umami taste qualities. In summary, adrenergic signaling in the taste bud occurs through complex pathways that include presynaptic and postsynaptic receptors and likely play modulatory roles in processing of gustatory information similar to other peripheral sensory systems such as the retina, cochlea, and olfactory bulb. [Copyright &y& Elsevier]

Aims: α2-Adrenoceptors modulate cardiovascular function by vasoconstriction or dilatation, by central inhibition of sympathetic activity, or by feedback inhibition of norepinephrine release from sympathetic neurons. Despite detailed knowledge about subtype-specific functions of α2-receptors, the relative contributions of sympathetic vs. non-sympathetic receptors involved in these cardiovascular effects have not been identified. The aim of this study was to define the physiological and pharmacological role of α2A-adrenoceptors in adrenergic vs. non-adrenergic cells at baseline and during sympathetic stress. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: Prune belly syndrome (PBS) presents with large-capacity bladders, high compliance and post-void residual volumes. Operative and conservative treatments are controversial. When histologically compared to normal bladder, bladder outlet obstruction results in an up- or down-regulation of adrenoceptors. Our goal was to study the immunoexpression of adrenoceptors in detrusor from patients with PBS. Materials and methods: Bladder domes from PBS patients (n =14) were studied (PBG). For normal controls, bladder specimens were obtained at adult surgery (n =13) (CG1) and at child autopsy (n =5) (CG2). Staining was performed using antibodies to α1a, α1b, α1d and β3 adrenoceptors. Five to 10 images were captured on an optic microscope with a digital camera and analysed with Photoshop®. The immunocyhistochemical index with arbitrary units was calculated and compared. Results: Mean age was 1.28, 64 and 1.41 years for PBG, CG1 and CG2, respectively. The immunohistochemical index with arbitrary units of α1a receptors was 0.06 in PBG, 0.16 in CG1 and 0.14 in CG2 (p =0.008); of α1b 0.06, 0.06 and 0.07 (p =0.781); and of α1d 0.04, 0.04 and 0.05 (p =0.618). Regarding β3 the respective values were 0.07, 0.14 and 0.10 (p =0.378). Conclusion: Our results show a decrease in α1a-adrenoceptor immunostaining intensity in detrusor from children with PBS. Further in vitro studies are needed to determine whether these observations are physiologically significant. [Copyright &y& Elsevier]

Abstract: Spatial learning is a widely studied type of animal behavior often considered as a model of higher human cognitive functions. Noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. The present study aimed at studying the effects of separate or combined systemic administration of the alpha1-adrenergic antagonist prazosin (1 and 2mg/kg) and beta-blocker propranolol (5 and 20mg/kg) on the hippocampus-dependent learning in the active allothetic place avoidance (AAPA) task. Both centrally active drugs impaired spatial learning when administered together, exerting no effect in separate applications. Locomotion was impaired only in a combined application of higher doses of both drugs (2mg/kg prazosin and 20mg/kg propranolol). These results suggest an in vivo interaction between these two types of receptors in spatial navigation regulation. [Copyright &y& Elsevier]

BackgroundThe adrenergic receptor (adrenoceptor) family genes have been extensively studied as candidate genes in hypertension but the results of individual genetic association studies (GAS) are controversial and inconclusive. To clarify these data, a systematic assessment of GAS for adrenoceptor family genes in hypertension was conducted.MethodsData from 163 GAS involving 7 genes and 37 distinct genetic variants were analyzed and cataloged in CUMAGAS-HYPERT (Cumulative Meta-analysis of Genetic Association Studies–HYPERTension; a web-based information system, which allows the retrieval and synthesis of data from GAS in hypertension, available at http://biomath.med.uth.gr). Data from genome-wide association studies involving the adrenoceptor family genes were also systematically searched.ResultsIndividual GAS reported inconsistent associations and had limited power to detect modest genetic effects, with only 1.2% having power >80%. Thirteen variants were investigated by three or more studies and their results were subject to meta-analysis. In the main meta-analyses, significant results were shown for five variants (ADRB1 p.Arg389Gly, ADRB1 p.Ser49Gly, ADRB2 g.9368308A>G, ADRB3 p.Trp64Arg, and ADRA1A p.Cys347Arg) under the allelic contrast and/or the dominant model. Subgroup analyses by ethnicity and gender detected significant associations for three variants (ADRB1 p.Arg389Gly in east Asians, ADRB2 p.Gln27Glu in whites, and ADRB3 p.Trp64Arg in whites and in males). Heterogeneity ranged from none to high. No significant associations were recorded from genome-wide studies.ConclusionsThere is evidence to implicate adrenoceptor genes in hypertension, although future studies designed to investigate epistatic and gene–environment interactions would allow more solid conclusions to be drawn about the role of these genes in hypertension.American Journal of Hypertension 2010; doi:10.1038/ajh.2009.251 [ABSTRACT FROM AUTHOR]

Knowledge of neural circuits, neurotransmitters and receptors involved in the sympathetic regulation of gastrointestinal (GI) function is well established. However, it is only recently that the interaction of sympathetic neurons, and of sympathetic transmitters, with the GI immune system and with gut flora has begun to be explored. Changes in the behaviour of sympathetic nerves when gut function is compromised, for example in ileus and in inflammation, have been observed, but the roles of the sympathetic innervation in these and other pathologies are not adequately understood. In this article, we first review the principal roles of the sympathetic innervation of the GI tract in controlling motility, fluid exchange and gut blood flow in healthy individuals. We then discuss the evidence that there are important interactions of sympathetic transmitters with the gut immune system and enteric glia, and evidence that inflammation has substantial effects on sympathetic neurons. These reciprocal interactions contribute to pathological changes in ways that are not yet clarified. Finally, we focus on inflammation, diabetes and postoperative ileus as conditions in which there is sympathetic involvement in compromised gut function. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that single and repeated immobilization stress affect densities of α1-adrenoceptor (α1-AR) and β-AR subtypes, muscarinic receptors (MR), adenylyl cyclase activity (AC) and phospholipase C activity (PLC) in lungs of male and female wild type (WT) and corticotropin-releasing hormone gene (CRH-knockout (KO)) disrupted mice. We found sex differences in the basal levels of α1-AR subtypes (females had 2–3 times higher density of receptors than males) and MR (males had twice the density found in females). In marked contrast, β-AR subtype densities did not differ between sexes. CRH gene disruption decreased all three studied receptors in intact mice (to 20–50% of WT) in both sexes (except β1-AR in females). Stress induced sexually dimorphic responses, while all α1-AR subtypes decreased in females (to 30% of control approximately), only α1A-AR level diminished (about 50%) in males. β1-AR decreased in males (to about 40%) but remained stable in females. β2-AR diminished in females (to about 20–60%) and also in males (to about 30–60%). MR decreased in both sexes (approximately to 50%). AC activity diminished in males (to < 50%) while PLC activity was not changed. In CRH-KO mice, the stress response was severely diminished. Paradoxically, the receptor response to stress was less affected by CRH-KO in males than in females. AC activity did not change in CRH-KO mice. In conclusion, in mice the stress reaction is sexually dimorphic and an intact hypothalamo-pituitary–adrenocortical system is required for the normal reaction of pulmonary adrenergic and MR to stress. [ABSTRACT FROM AUTHOR]

Vessels from pregnant animals show a blunted response to adrenergic agonists. In this work, we explored if pregnancy reduces α1-adrenergic receptor (α1-AR)-mediated vascular smooth muscle protein expression as well as agonist-induced contraction in rat aorta, and if angiotensin II (Ang II) levels during pregnancy are related to these changes. Female Wistar rats were divided randomly into nonpregnant (NP) and pregnant groups (first week: P1, second week: P2, third week: P3). Subsets of animals were treated with captopril (5 mg kg–1 day–1 for 7 days; n = 6). Phenylephrine (PHE) concentration-response curves were constructed (1 × 10–9 to 3.1 × 10–5 mol/l) and α1A-, α1B- and α1D-AR were measured in the aorta by immunoblot. Captopril decreased α-AR expression in the NP group. In contrast, pregnancy decreased α1A-, α1B- and α1D-AR levels and captopril prevented this reduction. PHE sensitivity was decreased in the thoracic and abdominal aorta in the P2 group, with no changes in Emax , and Emax was decreased in the abdominal aorta in all experimental groups. Our results suggest that Ang II levels during pregnancy are related to a decrease in aortic α1-AR expression. The physiological meaning of this finding remains to be established. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The progression of pregnancy is associated with attenuation in vasopressor response to adrenergic agonists. In pregnancy-induced hypertension this attenuation is reverted. It is not known if this reversion involves alpha-1 adrenoceptor expression. Objective. In this work we propose that in pregnant rats with subrenal aortic coarctation there are changes in the expression of alpha-1 adrenergic receptors in the thoracic and abdominal aorta during pregnancy. Methods. We used non-pregnant, normal pregnant and pregnant with subrenal aortic coarctation female Wistar rats. Pregnancy-induced hypertension indicators, systolic blood pressure, 24 hours proteinuria, pup weight and maternal weight were measured. Dose response curves to phenylephrine were carried out to determine vascular reactivity along pregnancy. Alpha 1-adrenoceptors were detected from thoracic and abdominal aorta using immunoblot. Results. Results show significant increases in arterial pressure and proteinuria in pregnant rats with SRAC at the end of the third week. Pregnancy reduces alpha-1-A, -B and -D adrenoceptor expression and this event is reverted by subrenal aortic coarctation. This phenomenon is more apparent in the abdominal segment of the aorta. Conclusions. These findings suggest that subrenal aortic coarctation is a good animal model of pregnancy-induced hypertension and that α1-adrenoceptors participate in its physiopathology increasing their expression in a segment-dependent manner. [ABSTRACT FROM AUTHOR]

beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension. [ABSTRACT FROM AUTHOR]

The aim of this work was to test the hypothesis that the bed nucleus of the stria terminalis (BST) and noradrenergic neurotransmission therein mediate cardiovascular responses to acute restraint stress in rats. Bilateral microinjection of the non-specific synaptic blocker CoCl2 (0.1 nmol/100 nl) into the BST enhanced the heart rate (HR) increase associated with acute restraint without affecting the blood pressure increase, indicating that synapses within the BST influence restraint-evoked HR changes. BST pretreatment with the selective α1-adrenoceptor antagonist WB4101 (15 nmol/100 nl) caused similar effects to cobalt, indicating that local noradrenergic neurotransmission mediates the BST inhibitory influence on restraint-related HR responses. BST treatment with equimolar doses of the α2-adrenoceptor antagonist RX821002 or the β-adrenoceptor antagonist propranolol did not affect restraint-related cardiovascular responses, reinforcing the inference that α1-adrenoceptors mediate the BST-related inhibitory influence on HR responses. Microinjection of WB4101 into the BST of rats pretreated intravenously with the anticholinergic drug homatropine methyl bromide (0.2 mg/kg) did not affect restraint-related cardiovascular responses, indicating that the inhibitory influence of the BST on the restraint-evoked HR increase could be related to an increase in parasympathetic activity. Thus, our results suggest an inhibitory influence of the BST on the HR increase evoked by restraint stress, and that this is mediated by local α1-adrenoceptors. The results also indicate that such an inhibitory influence is a result of parasympathetic activation. [ABSTRACT FROM AUTHOR]

Adrenoceptors (ARs) are G protein–coupled receptors found throughout the vertebrates. Their pharmacology and preliminary phylogenetic analyses suggest that ARs are classified as α1, α2 (and their subtypes), and β1, β2, and β3. However, the relationships among subtypes of this superfamily, as well as both the pattern and the timing of their diversification, are poorly understood. In addition, fish AR subtypes possess pharmacologies and tissue distributions that only partially overlap with those of their mammalian counterparts, in spite of their apparent orthologous relationships within subtypes. Here we analyze 136 sequences in a range of vertebrates, including fish, to resolve these issues. We show that diversification of ARs occurred during duplication events that occurred within distinct time periods. Each period maps to whole-genome duplication events, two in vertebrates and one in fish. We also show that ARs underwent multiple duplications within these broad windows and that fish ARs underwent extensive gene loss after duplications that promoted their functional divergence with respect to other vertebrates. [ABSTRACT FROM AUTHOR]

Abstract: Pharmacological modulators of β-adrenoceptors can influence bone mineral density and fracture risk in humans. Studies reported that β-adrenoceptor ligands stimulate bone resorption by enhancing the expression of RANK-L, whereas the mechanisms by which β-adrenoreceptors regulate bone formation are poorly understood. Here we show that β2-adrenoceptor is predominantly expressed by bone cells, although low levels of β1- and β3-adrenoceptors were detectable. Noradrenaline and the selective β2-adrenoceptor agonists isoprenaline and salmeterol stimulated osteoclast formation and bone resorption in BM osteoblast co-cultures and increased expression of RANK-L by osteoblasts. All three ligands enhanced RANK-L induced osteoclast formation and increased osteoclast multinuclearity. There was no significant effect of noradrenaline or isoprenaline on osteoblast growth, differentiation or function. These findings confirm the importance of the sympathetic nervous system in the regulation of bone mass, and demonstrate that pharmacological agonists of β2-adrenoceptors directly and indirectly stimulate osteoclast formation, but have no direct effect on osteoblast growth, differentiation or function. [Copyright &y& Elsevier]

In the present study, we investigated the role of noradrenergic transmission in unconditioned and conditioned responses to predatory threats. First, we examined the effects of systemically injectedβ-blockers on unconditioned and contextual conditioned response to cat odor. The centrally acting β-blocker (propranolol) was able to impair unconditioned responses, as well as the acquisition of the contextual fear to cat odor; however, the peripherally acting (nadolol) was not effective. Next, we examined the neural substrate underlying the noradrenergic modulation of the defensive response to cat odor and focused on the dorsal premammillary nucleus (PMd), because it represents the hypothalamic site most responsive to predatory threats and, at the same time, presents a dense plexus of noradrenergic fibers. We were able to see that propranolol significantly reduced PMd-Fos expression in response to cat odor and thatβ-adrenoceptor blockade in the PMd, before cat odor exposure, reduced defensive responses to the cat odor and to the cat odor-related environment. We have also shown that β-adrenoceptor blockade in the PMd, before the exposure to cat odor-related context, impaired the contextual conditioned responses. Overall, the present results provide convincing evidence suggesting that central noradrenergic mediation is critical for the expression of unconditioned and contextual conditioned antipredatory responses. We have further shown that the PMd appears to be an important locus to mediate these β-adrenoceptor effects. [ABSTRACT FROM AUTHOR]

Although stress is tightly connected with elevated levels of catecholamines, stress effects on target structures of catecholamine action—adrenoceptors (ARs)—has not been deeply studied yet. Similarly, very little is known about changes of muscarinic receptors (MRs) during stress. We determined changes in these receptors in the individual parts of the heart (right atria and ventricles) of animals (rats and mice) exposed to a single and repeated immobilization stress. Changes of tissue catecholamines, β2-AR gene expression, protein levels, and binding sites were determined in rat right ventricles, and changes in β1-, β2-, and β3-AR gene expression were followed in murine right atria. Tissue catecholamines were elevated, while β2-AR mRNA levels and β2-AR proteins and binding were decreased, in rat right ventricles. In murine right atria, β1- and β2-AR gene expression was elevated, while β3-AR mRNA levels and M2-MR were reduced. Taken together, our data show that interaction of AR and MR is important for the organism coping with stress and that different heart regions reveal distinct reactions to stress. [ABSTRACT FROM AUTHOR]

Changes in the heart rate and force of contraction are regulated by catecholamines via adrenoceptors (AR). In this work, we measured gene expression of AR in left heart atria and ventricles in rats exposed to cold stress and in cold-acclimated rats exposed to a novel stressor (immobilization). We found a significant increase in β3-AR in left ventricle of rats exposed to acute (1 day) and long-term (28 days) cold, but no changes in β1- and β2-AR mRNA levels. However, single immobilization significantly decreased β2-AR mRNA levels both in left atria and ventricles compared to acute cold stress. Application of a novel stressor (immobilization) to previously cold-acclimated animals did not show decrease of β2-AR mRNA levels as seen in intact animals. Moreover, β1- and β2-AR did not show any significant changes. Surprisingly, the most prominent changes in the heart were detected for α1B-AR gene expression. We found decreased levels of α1B-AR mRNA in the heart of rats exposed to cold and immobilization. We also found that exposure of cold-acclimated rats to immobilization is responsible for additional decrease of α1B-AR mRNA levels in heart. It seems that while β-AR undergoes adaptation, α1B-AR is probably prepared to modulate heart functions. Proposed mechanism of β-AR adaptation needs to be elucidated. Thus, we have shown that gene expression of different AR subtypes in the heart is regulated differently by various stressors. A protective role of β2-, β3-AR, and α1B-AR in the process of heart adaptation to chronic stress exposure is proposed. [ABSTRACT FROM AUTHOR]

A pheochromocytoma is an endocrine tumor that can uniquely mimic numerous stress-associated disorders, with variations in clinical manifestations resulting from different patterns of catecholamine secretion and actions of released catecholamines on physiological systems. [ABSTRACT FROM AUTHOR]

It is well-documented that melatonin influences insulin secretion. The effects are mediated by specific, high-affinity, pertussis-toxin-sensitive, G protein-coupled membrane receptors (MT1 as well MT2), which are present in both the pancreatic tissue and islets of rats and humans, as well as in rat insulinoma cells (INS1). Via the Gi-protein-adenylatecyclase-3′,5′-cyclic adenosine monophosphate (cAMP) and, possibly, the guanylatecyclase-cGMP pathways, melatonin decreases insulin secretion, whereas, by activating the Gq-protein-phospholipase C-IP3 pathway, it has the opposite effect. For further analysis of the interactions between melatonin and insulin, diabetic rats were investigated with respect to melatonin synthesis in the pineal gland and plasma insulin levels. In this context, recent investigations have proven that type 2 diabetic rats and humans display decreased melatonin levels, whereas type 1 diabetic IDDM rats or those with diabetes induced by streptozotocin (STZ) of the present study show increased plasma melatonin levels and elevated AA-NAT-mRNA. Furthermore, the mRNA of pineal insulin receptors and β1-adrenoceptors, including the clock genes Per1 and Bmal1 and the clock-controlled output gene Dbp, increases in both young and middle-aged STZ rats. The results therefore indicate that the decreased insulin levels in STZ-induced type 1 diabetes are associated with higher melatonin plasma levels. In good agreement with earlier investigations, it was shown that the elevated insulin levels observed in type 2 diabetes, are associated with decreased melatonin levels. The results thus prove that a melatonin–insulin antagonism exists. Astonishingly, notwithstanding the drastic metabolic disturbances in STZ-diabetic rats, the diurnal rhythms of the parameters investigated are maintained. [ABSTRACT FROM AUTHOR]

Mirtazapine is a racemic antidepressant with a multireceptor profile. Previous studies have shown that the enantiomers of mirtazapine have different pharmacologic effects in the brain of laboratory animals. In the present study, we used positron emission tomography (PET) and autoradiography to study effects of ( R)- and ( S)-[11C]mirtazapine in the human brain. Detailed brain imaging by PET using three methods of kinetic data analysis showed no reliable differences between regional binding potentials of ( R)- and ( S)-[11C]mirtazapine in healthy subjects. Autoradiographic studies carried out in whole hemispheres of human brain tissue showed, however, that ( R)- and ( S)-mirtazapine differ markedly as inhibitors of [3H]clonidine binding at α2-adrenoceptors. The multireceptor binding profiles of mirtazapine enantiomers, along with individual differences between subjects, may preclude PET neuroimaging from demonstrating reliable differences between the regional distribution and binding of ( R)- and ( S)-[11C]mirtazapine in the living human brain. [ABSTRACT FROM AUTHOR]