Role Of Adrenergic Receptors Research Articles

Noradrenaline and Seizures: A Perspective on the Role of Adrenergic Receptors in Limbic Seizures.

Noradrenergic fibers originating from the locus coeruleus densely innervate limbic structures, including the piriform cortex, which is the limbic structure with the lowest seizure threshold. Noradrenaline (NA) modulates limbic seizures while stimulating autophagy through β2- adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating β2-AR focally within the anterior piriform cortex affects limbic seizures. In this perspective, we analyzed a potential role for β2-AR as an anticonvulsant target within the anterior piriform cortex, area tempestas (AT). We developed this perspective based on current literature on the role of NA in limbic seizures and autophagy. The perspective is also grounded on preliminary data obtained by microinfusing within AT either a β2-AR agonist (salbutamol) or a β2-AR antagonist (butoxamine) 5 minutes before bicuculline. β2-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at β2-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for β2-AR as an anticonvulsant in AT. NA counteracts limbic seizures. This relies on various receptors in different brain areas. The anterior piriform cortex plays a key role in patients affected by limbic epilepsy. The anticonvulsant effects of NA through β2-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective where β2-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking β2-AR to autophagy and seizure modulation should be extensively investigated.

THE ROLE OF ADRENERGIC RECEPTORS IN THE ACTION OF ADRENALINE ON PLASMA LACTATE, GLUCOSE, LIVER, AND SKELETAL MUSCLE GLYCOGEN IN THE COMMON AFRICAN TOAD BUFO REGULARIS

In mammals, the roles of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia are well known. However, in amphibians, there is limited information on the relative contribution of liver and skeletal muscle glycogen in adrenaline-induced hyperglycaemia. This study investigated the effects of adrenaline on blood glucose, plasma lactate, liverand skeletal muscle glycogen and the role of adrenergic receptors in the common African toad, bufo regularis. One hundred and twenty-five adult common African toads (70-100g) of both sexes were randomly collected and used in the study.Blood samples were collected from truncus arteriosus to estimate glucose and lactate levels. Blood glucose was determined immediately by modified glucose oxidase method. Plasma lactate was determined by modification of the Barker-Summerson method. Liver and gastrocnemius muscle glycogen were determined using anthrone reagents method. Adrenaline caused significant increase in blood glucose, lactate levels and significant reduction in liver and muscle glycogen. When toads were pre-treated with propranolol or prazosin, adrenalines reduction in liver and muscle glycogen was significantly reduced while the increase in blood glucose and lactate levels was prevented. Combination of both blockers abolished the increase in blood glucose, lactate levels and blocked reduction in liver and muscle glycogen produced by adrenaline. The results of this study showed that adrenalinecaused liver and skeletal muscle glycogen breakdown, increase in plasma lactate levels which resulted in hyperglycaemia in the common African toad bufo regularis. The study also showed that both alpha- and beta-adrenergic receptors are involved in mediating the effects of adrenaline on blood glucose, plasma lactate, liver, and muscle glycogenolysis and gluconeogenesis.

Role of adrenergic receptors in shock.

Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)-hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Angiogenesis is essential during development or when tissue restoration and oxygenation is required. Limited or excessive formation of blood vessels is a hallmark of several pathologies, and many angiogenesis-related pathways are being studied to highlight potential targets for effective angiogenesis-stimulating or inhibiting therapeutic approaches. A few studies point to the adrenergic system as a significant regulator of angiogenesis, directly or indirectly. Functional adrenergic receptors are expressed on endothelial cells and affect their response to the adrenergic system. The latter can also upregulate the release of growth factors by mural cells of the vessel wall, blood cells or cancer cells, thus subsequently affecting endothelial cell functions and angiogenesis. In the present study we summarize up-to-date literature on the known effects of the adrenergic receptors on physiological and pathological angiogenesis.

The Role of Adrenergic Receptors, Muscarinic Receptors, Glucocorticoids, Reactive Oxygen Species in Stress‐Induced Cardiac Injury

Takotsubo syndrome (TS) is a rare but dangerous disease that can be fatal. The pathogenesis of TS is not well understood because there is no animal model of TS that would be as close as possible to TS. We hypothesized that adrenergic receptors, muscarinic receptors, glucocorticoids, reactive oxygen species (ROS) can be involved in the development of stress-induced cardiac injury (SICI). It was established that immobilization of rats induced the state which is similar TS in human: increased 99mTc-pyrophosphate (99mTc-PP) accumulation in the heart, QTc interval prolongation, contractility dysfunction of the heart, elevation of the serum creatine kinase MB level. Immobilization stress induced an increase in coronary blood flow. Blockade of β1-adrenergic receptor (AR) prevents 99mTc-PP accumulation in the myocardium. Blockade of β2-AR aggravates SICI. Stimulation of β2-AR increased cardiac tolerance to stress. Inhibition of β3-AR, α1-AR, mineralocorticoid receptor and angiotensin AT1 receptor had no effect on SICI. Blockade of peripheral muscarinic receptors or α2-AR aggravates SICI. Inhibition of glucocorticoid receptor attenuated but not abolished SICI. Pretreatment with the selective β1-AR antagonist atenolol attenuates stress-induced cardiac contractility dysfunction but not recover cardiac contractility completely. It was established that ROS are not involved in SICI. It was obtained indirect evidence that circulated in blood catecholamines play an important role in SICI. Consequently, the activation of β1-AR plays an important role in SICI. However, there are other receptors which are also involved in SICI.

The role of β-adrenergic receptors in stress-induced cardiac injury in a rat model of Takotsubo syndrome

Introduction. The pathophysiological mechanisms of cardiac injury in Takotsubo syndrome are currently poorly understood. The role of adrenergic receptor (AR) subtypes in the development of stress-induced myocardial injury (SIMI) remains unclear.Aim. To assess the role of β-ARs in the development of SIMI.Material and Methods. The study was performed using female Wistar rats (n = 84). Rats were subject to 24-hour immobilization in the supine position to simulate SIMI. 99mTc-pyrophosphate radiopharmaceutical was used to determine the degree of cardiac injury.Results. The study showed that β-AR blockade with propranolol reduced the degree of cardiac injury by 38.4%. Selective β1- AR antagonists, atenolol and nebivolol, led to 2.00- and 2.55-fold decreases in 99mTc pyrophosphate accumulation in the heart, respectively. Blockade of β2-ARs by a selective antagonist ICI-118.551 caused an increase in the degree of 99mTc-pyrophosphate accumulation in the heart by 34.6%. A selective β3-AR antagonist L-748337 did not affect 99mTc pyrophosphate accumulation in the heart.Conclusions. The study showed that β1-ARs are involved in the damaging effects of stress on the heart during immobilization stress. β2-AR had a cardioprotective effect in immobilization. β3-AP did not play a significant role in the stress-induced cardiac injury with a single exposure to the stressor.

Ganoderic acid A protects neural cells against NO stress injury in vitro via stimulating β adrenergic receptors.

Excessive nitric oxide (NO) causes extensive damage to the nervous system, and the adrenergic system is disordered in many neuropsychiatric diseases. However, the role of the adrenergic system in protection of the nervous system against sodium nitroprusside (SNP) injury remains unclear. In this study, we investigated the effect of ganoderic acid A (GA A) against SNP injury in neural cells and the role of adrenergic receptors in GA A neuroprotection. We found that SNP (0.125−2 mM) dose-dependently decreased the viability of both SH-SY5Y and PC12 cells and markedly increased NO contents. Pretreatment with GA A (10 μM) significantly attenuated SNP-induced cytotoxicity and NO increase in SH-SY5Y cells, but not in PC12 cells. Furthermore, pretreatment with GA A caused significantly higher adrenaline content in SH-SY5Y cells than in PC12 cells. In order to elucidate the mechanism of GA A-protecting SH-SY5Y cells, we added adrenaline, phentolamine, metoprolol, or ICI 118551 1 h before GA A was added to the culture medium. We found that addition of adrenaline (10 μM) significantly improved GA A protection in PC12 cells. The addition of β1-adrenergic receptor antagonist metoprolol (10 μM) or β2-adrenergic receptor antagonist ICI 118551 (0.1 μM) blocked the protective effect of GA A, whereas the addition of α-adrenergic receptor antagonist phentolamine (0.1 μM) did not affect GA A protection in SH-SY5Y cells. These results suggest that β-adrenergic receptors play an important role in the protection of GA A in SH-SY5Y cells against SNP injuries, and excessive adrenaline system activation caused great damage to the nervous system.

Amphetamine promotes cortical Up state: Role of adrenergic receptors.

Cortical neurons oscillate synchronously between the Up and Down state during slow-wave sleep and general anesthesia. Using local-field-potential recording in the rat prefrontal cortex (PFC), we have shown that systemic administration of methylphenidate promotes PFC Up states and reduces PFC slow oscillation, suggesting a depolarizing effect of the drug on PFC neurons. Here, we report that systemic injection of d-amphetamine produced similar effects. Our evidence further suggests that norepinephrine (NE) plays a major role in the effects of d-amphetamine since they were mimicked by the NE reuptake inhibitors tomoxetine and nisoxetine and completely blocked by the α1 receptor antagonist prazosin. The effects of d-amphetamine persisted, however, in the presence of α2 or β receptor blockade. Experiments with α1 subtype-selective antagonists further suggest that d-amphetamine's effects depend on activation of central, but not peripheral, α1A receptors. Unexpectedly, the putative α1 receptor agonist cirazoline failed to mimic the effects of d-amphetamine. Previous studies suggest that cirazoline is also an antagonist at α2 receptors. Furthermore, it is a partial, not full, agonist at α1B and α1D receptors. Whether or not these properties of cirazoline contribute to its failure to mimic d-amphetamine's effects remains to be determined. Methylphenidate and d-amphetamine are two most common medications for attention-deficit/hyperactivity disorder (ADHD). Both, however, are associated with adverse effects including abuse potential and psychotomimetic effects. Further understanding of their mechanisms of action will help develop safer treatments for ADHD and offer new insights into drug addiction and psychosis.

A Role for Adrenergic Receptors in the Uterotonic Effects of Ergometrine in Isolated Human Term Nonlaboring Myometrium

(Anesth Analg. 2017;124(5):1581–1588) Ergometrine has long been used as a prophylactic uterotonic agent to reduce the risk of postpartum hemorrhage. However, its exact mechanism of action remains unclear. Previous studies have linked it to the stimulation of adrenoreceptors on the inner layer of the myometrium, resulting in increased basal tone. Thus, in the present study, the authors test the effects of α-adrenoceptor antagonist ligands on the action of ergometrine on isolated human myometrial cells.

A Role for Adrenergic Receptors in the Uterotonic Effects of Ergometrine in Isolated Human Term Nonlaboring Myometrium

Ergometrine is a uterotonic agent that is recommended in the prevention and management of postpartum hemorrhage. Despite its long-standing use, the mechanism by which it acts in humans has never been elucidated fully. The objective of this study was to investigate the role of adrenoreceptors in ergometrine's mechanism of action in human myometrium. The study examined the hypothesis that α-adrenoreceptor antagonism would result in the reversal of the uterotonic effects of ergometrine. Myometrial samples were obtained from women undergoing elective cesarean delivery. The samples were then dissected into strips and mounted in organ bath chambers. After the generation of an ergometrine concentration-response curve (10 to 10 M), strips were treated with increasing concentrations of ergometrine (10 to 10 M) alone and ergometrine (10 to 10 M) in the presence of phentolamine (10 M), prazosin (10 M), propranolol (10 M), or yohimbine (10 M). The effects of adding ergometrine and the effect of drug combinations were analyzed using linear mixed effects models with measures of amplitude (g), frequency (contractions/10 min), and motility index (g×contractions/10 min). A total of 157 experiments were completed on samples obtained from 33 women. There was a significant increase in the motility index (adding 0.342 g × counts/10 min/μM; 95% confidence interval [CI], 0.253-0.431, P < .001), amplitude (0.078 g/μM; 95% CI, 0.0344-0.121, P = 5e-04), and frequency (0.051 counts/10 min/μM; 95% CI, 0.038-0.063, P < .001) in the presence of ergometrine. The α-adrenergic antagonist phentolamine and the more selective α1-adrenergic antagonist prazosin inhibited the ergometrine mediated increase in motility index, amplitude, and frequency (-1.63 g × counts/10 min/μM and -16.70 g × counts/10 min/μM for motility index, respectively). These results provide novel evidence for a role for α-adrenergic signaling mechanisms in the action of ergometrine on human myometrial smooth muscle in the in vitro setting. Information that sheds light on the mechanism of action of ergometrine may have implications for the development of further uterotonic agents.

English

The role of adrenergic receptors in nicotine-induced hyperglycaemia has not been well studied in amphibians. Thus, this study investigates the effects of alpha and beta adrenergic receptor blockers in nicotine-induced hyperglycaemia in the common African toad Bufo regularis. Toads fasted for 24 h were anaesthetized with sodium pentobarbitone (3 mg/100 g body weight) intraperitoneally (i.p) and given intravenous (i.v) injection of 0.7% amphibian saline, or nicotine (50 &micro;g/kg), nicotine(50 &micro;g/kg i.v) 30 min after pretreatment with prazosin (0.2 mg/kg i.v), propranolol (0.5 mg/kg i.v) or combination of both prazosin (0.2 mg/kg i.v) and propranolol (0.5 mg/kg, i.v). Thereafter, blood samples were also collected from truncus arteriosus for estimation of blood glucose level using the modified glucose oxidase method. Nicotine caused significant increase (P&lt;0.01) in the levels of blood glucose in the common African toad. Pre-treatment of the toads with prazosin (0.2 mg/kg i.v) or propranolol (0.5 mg/kg, i.v) significantly (p &lt; 0.01) reduced the hyperglycaemia induced by nicotine (50 &micro;g/kg i.v). However, the combination of prazosin (0.2 mg/kg i.v) and propranolol (0.5 mg/kg, i.v) abolished the hyperglycaemic effect of nicotine (50 &micro;g/kg i.v). The above results on glucose metabolism suggests involvement of both alpha and beta adrenoceptors in nicotine-induced hyperglycaemia in common African toad B. regularis. &nbsp; Key words: Nicotine, hyperglycaemia, prazosin, propranolol, common African toad Bufo regularis.

Adrenaline Rush: The Role of Adrenergic Receptors in Stimulant-Induced Behaviors

Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

The role of alpha and beta adrenergic receptors in cortisol-induced hyperglycaemia in the common African toad (Bufo regularis)

The role of adrenergic receptors in cortisol-induced hyperglycaemia is not well known. The present study investigated the effects of adrenergic receptor blockers in cortisol-induced hyperglycaemia in the common African toad (Bufo regularis). Each toad was fasted and anesthetized with sodium pentobarbitone (3 mg/100 g i.p). The animals (control) received intravenous (i.v) injection of 0.7% amphibian saline while animals (untreated) were given cortisol (20 µg/kg). In pre-treatment groups, animals received prazosin (0.2 mg/kg i.v), propranolol 0.5 mg/kg or combination of prazosin (0.2 mg/kg i.v) and propranolol (0.5 mg/kg i.v) before i.v injection of cortisol (20 µg/kg). Thereafter, blood samples were collected for estimation of blood glucose level using the modified glucose oxidase method. Cortisol caused significant increase in blood glucose level from 44.4±3.8 to 71.7±9.7 mg/dl. Pre-treatment of the toads with propranolol (0.5 mg/kg i.v) caused significant reduction (p≤ 0.01) in cortisol-induced hyperglycaemia while pre-treatment with prazosin (0.2 mg/kg i.v) produced no significant effect on hyperglycaemia induced by cortisol. The combination of both prazosin and propranolol completely abolished the effects of cortisol on blood glucose level. The results suggest that cortisol-induced hyperglycaemia in the toad (B. regularis) is mediated probably by both the α- and β-adrenergic receptors with the beta adrenergic receptors playing dominant role. Key words: Cortisol, hyperglycaemia, prazosin, propranolol, amphibian saline, common African toad.

The positive inotropic effect of the ethyl acetate fraction from Erythrina velutina leaves on the mammalian myocardium: the role of adrenergic receptors

We studied the effects of ethyl acetate fraction (EAcF) obtained from Erythrina velutina leaves on mammalian myocardium. The effect of EAcF on the contractility was studied using guinea-pig left atria mounted in a tissue bath (Tyrode's solution, 29°C, 95% CO2 , 5% O2 ) and electrically stimulated (1 Hz). Concentration-response curves of EAcF were obtained in the presence of propranolol (1 μm), nifedipine (1 μm) and in reserpinized animals (5 mg/kg). The involvement of l-type calcium current (ICa,L ) on the EAcF effect was observed in cardiomyocytes of mice assessed using patch-clamp technique. EAcF (550 μg/ml) had a positive inotropic effect, increasing the atrial force by 164% (EC50 = 157 ± 44 μg/ml, n = 6), but it was less potent than isoproterenol (EC50 = 0.0036 ± 0.0019 μg/ml, n = 8). The response evoked by EAcF was abolished by propranolol or nifedipine. Reserpine did not alter the inotropic response of EAcF. Furthermore, an enhancement of the ICa,L peak (31.2%) with EAcF was observed. Chemical analysis of EAcF revealed the presence of at least 10 different flavonoid glycoside derivatives. Two were identified as vicenin II and isorhoifolin. We conclude that EAcF increases the cardiac contractile force by increasing the l-type calcium current and activating the adrenergic receptor pathway.

Vascular and Extravascular Volume Expansion of Dobutamine and Norepinephrine in Normovolemic Sheep

In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. Series 1 (n = 6 per group): no drug (control), dobutamine (10 μg x kg(-1) x min), or norepinephrine (1.0 μg x kg(-1) x min(-1)) was begun 30 min before a 24-mL x kg(-1), 20-min, 0.9% NaCl bolus. The effect of drug and fluid on plasma volume (ΔPV), urinary output (UOP), and extravascular volume (ΔEVV) was determined. Series 2: Identical protocol but no fluid bolus. Series 1: the fluid bolus resulted in a peak and sustained ΔPV expansion. Norepinephrine (7.5 ± 0.9 mL x kg(-1)) and dobutamine (9.5 ± 1.1 mL x kg(-1)) significantly increased ΔPV compared with control (3.8 ± 1.1 mL x kg(-1)). Cumulative UOP was reduced by dobutamine (3.8 ± 1.4 mL x kg) compared with norepinephrine (25.1 ± 3.9 mL x kg(-1)) and control (16.9 ± 4.0 mL x kg(-1)). Norepinephrine increased ΔPV, while reducing ΔEVV after bolus. Series 2: ΔPV was unchanged in the control group. Dobutamine and norepinephrine increased ΔPV over time, 5.1 ± 0.5 and 4.0 ± 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of ΔEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. β-Adrenergic agonists enhance vascular volume expansion, whereas α-adrenergic agonists eliminate extravascular fluid.

Adrenergic Regulation of AMP-activated Protein Kinase in Brown Adipose Tissue in Vivo

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine-threonine kinase that senses cellular energy status, is activated by stress and neurohumoral stimuli. We investigated the mechanisms by which adrenergic signaling alters AMPK activation in vivo. Brown adipose tissue (BAT) is highly enriched in sympathetic innervation, which is critical for regulation of energy homeostasis. We performed unilateral denervation of BAT in wild type (WT) mice to abolish neural input. Six days post-denervation, UCP-1 protein levels and AMPK α2 protein and activity were reduced by 45%. In β(1,2,3)-adrenergic receptor knock-out mice, unilateral denervation led to a 25-45% decrease in AMPK activity, protein expression, and Thr(172) phosphorylation. In contrast, acute α- or β-adrenergic blockade in WT mice resulted in increased AMPK α Thr(172) phosphorylation and AMPK α1 and α2 activity in BAT. But short term blockade of α-adrenergic signaling in β(1,2,3)-adrenergic receptor knock-out mice resulted in decreased AMPK activity in BAT, which strongly correlated with enhanced phosphorylation of AMPK on Ser(485/491), a site associated with inhibition of AMPK activity. Both PKA and AKT inhibitors attenuated AMPK Ser(485/491) phosphorylation resulting from α-adrenergic blockade and prevented decreases in AMPK activity. In vitro mechanistic studies in BAT explants showed that the effects of α-adrenergic blockade appeared to be secondary to inhibition of oxygen consumption. In conclusion, adrenergic pathways regulate AMPK activity in vivo acutely via alterations in Thr(172) phosphorylation and chronically through changes in the α catalytic subunit protein levels. Furthermore, AMPK α Ser(485/491) phosphorylation may be a novel mechanism to inhibit AMPK activity in vivo and alter its biological effects.

Differential effects of β-adrenergic receptor blockade in the medial prefrontal cortex during aversive and incidental taste memory formation

The medial prefrontal cortex (mPFC) is a brain area crucial for memory, attention, and decision making. Specifically, the noradrenergic system in this cortex is involved in aversive learning, as well as in the retrieval of these memories. Some evidence suggests that this area has an important role during taste memory, particularly during conditioned taste aversion (CTA), a model of aversive memory. Despite some previous evidence, there is scarce information about the role of adrenergic receptors in the mPFC during formation of aversive taste memory and appetitive/incidental taste memory. The goal of this research was to evaluate the role of mPFC β-adrenergic receptors during CTA acquisition/consolidation or CTA retrieval, as well as during incidental taste memory formation using the model of latent inhibition of CTA. The results showed that infusions in the mPFC of the β-adrenergic antagonist propranolol before CTA acquisition impaired both short- and long-term aversive taste memory formation, and also that propranolol infusions before the memory test impaired CTA retrieval. However, propranolol infusions before pre-exposure to the taste during the latent inhibition procedure had no effect on incidental taste memory acquisition or consolidation. These data indicate that β-adrenergic receptors in the mPFC have different functions during taste memory formation: they have an important role during aversive taste association as well as during aversive retrieval but not during incidental taste memory formation.

Role of adrenergic receptors in the caffeine-induced increase in glucose uptake by the canine hindlimb

The present study was designed to investigate the effects of alpha and beta adrenergic receptor blockers on caffeine-induced increase in canine hindlimb glucose uptake. The study was carried out on fasted male anaesthetized dogs divided into five groups [5 dogs per group]. Each dog was given a bolus injection of normal saline, caffeine [6 mg/kg] caffeine after pretreatment with prazosin [0.2 mg/kg], caffeine after pretreatment with propranolol [0.5 mg/kg] or caffeine after pretreatment with a combination of prazosin [0.2 mg/kg] and propranolol [0.5 mg/kg]. The experiments were carried out under resting and exercising conditions of the hindlimb. Hindlimb glucose uptake [HGU] was calculated as the product of blood flow and arterio-venous glucose difference. Blood glucose was determined by the glucose oxidase method and blood flow to the hindlimb was determined by time-collection method. The results showed that pretreatment of the animal with either prazosin or propranolol significantly reduced caffeine-induced hyperglycemia, glucose extraction and hindlimb glucose uptake at rest. The two blockers also separately reduced caffeine-induced hyperglycemia during contraction of the hindlimb. Prazosin or propranolol did not however influence the effect of caffeine on glucose extraction and hindlimb glucose uptake during contraction of the hindlimb. It was therefore concluded that alpha and beta adrenergic receptors are involved in caffeine induced responses at rest and not during hindlimb contraction.

Role of adrenergic receptors in human coronary vasomotion

The oxygen delivered by the coronary blood flow at rest is almost maximally extracted (nearly 75%) by the heart. This implies a very limited oxygen extraction reserve of the myocardium....

G010 Regulation of voltage-dependent calcium channels by Nedd4-1

Calcium entry into excitable cells can be regulated by controlling both the activity of calcium channels and the amount of channels available at the plasma membrane. Little is known about their internalisation and degradation. One post-translational modification shown to be involved in membrane protein internalisation and subsequent degradation is the attachment of ubiquitin moieties by ubiquitin-ligases. Previously, it has been shown that cardiac ion channels such as Nav1.5 and KCNQ1 are down-regulated by ubiquitin-ligases of the Nedd4 family. These regulations involve the interaction between the PY motif of the target channels and the WW motif of the ubiquitin-ligases. Despite the absence of such PY motif in the cardiac voltage-gated calcium channel Cav1.2, we investigated whether this channel could by regulated in the same manner than other cardiac channels as previously described. We co-expressed, in HEK293 cells, L-type calcium channels and its two regulatory subunits Cavbeta and Cavalpha2delta1 together with ubiquitin-ligases, and examined by voltage-clamp whole-cell recordings the calcium current. We next determined by western blot and surface biotinylation assays the availability of the different subunits of calcium channels in total HEK293 lysates, and at the cell surface. Levels of ubiquitylation of the different subunits were assessed by pull-down GST-S5A and immunoprecipitation of Cav1.2 and its subunits. We found that co-expressing the ubiquitin-ligase Nedd4-1 significantly reduced Cav currents, and decreased Cavalpha and its subunit protein levels. This effect was Nedd4-1 specific since none of the other members of the Nedd4 family we tested produced a similar effect. We also found that the effect of Nedd4-1 was dependent on the co-expression of the Cavbeta subunit. No Nedd4-1-dependent increase in ubiquitylation of the Cavalpha protein was found; and unexpectedly, the two regulating subunits Cavbeta and Cavalpha2delta1 were detected to be deubiquitylated upon Nedd4-1 co-expression. Our data suggest that Nedd4-1 regulates the expression of Cav channels and its subunits by Nedd4-1 via an indirect mechanism constituting a new regulatory pathway to be determined. Further experiments will focus on the role of adrenergic receptors known to be ubiquitylated by Nedd4 and to bind to Cav1.2.