Α2-antagonist Yohimbine Research Articles

Targeting α1- and α2-adrenergic receptors as a countermeasure for fentanyl-induced locomotor and ventilatory depression

This study assessed the ability of α1 and α2-adrenergic drugs to decrease fentanyl-induced locomotor and ventilatory depression. Rats were given saline or fentanyl, followed by: (1) naltrexone, (2) naloxone, (3) nalmefene, (4) α1 agonist phenylephrine, (5) α1 antagonist prazosin, (6) α1D antagonist BMY-7378, (7) α2 agonist clonidine, (8) α2 antagonist yohimbine or (9) vehicle. All µ-opioid antagonists dose-dependently reversed fentanyl-induced locomotor and ventilatory depression. While the α1 drugs did not alter the effects of fentanyl, clonidine dose-dependently decreased locomotion and respiration with and without fentanyl. Conversely, yohimbine given at a low dose (0.3–1 mg/kg) stimulated ventilation when given alone and higher doses (>1 mg/kg) partially reversed (∼50 %) fentanyl-induced ventilatory depression, but not locomotor depression. High doses of yohimbine in combination with a suboptimal dose of naltrexone reversed fentanyl-induced ventilatory depression, suggestive of additivity. Yohimbine may serve as an effective adjunctive countermeasure agent combined with naltrexone to rescue fentanyl-induced ventilatory depression.

Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors

Empathy involves integrated affective and cognitive processes to share the emotional state of others. This evolutionarily conserved ability has also been identified in nonhuman primates and rodents. Our previous work demonstrated that social interaction with a cagemate rat in pain induces mechanical pain hypersensitivity in cagemate observer (CO) rats. Moreover, we also demonstrated that the medial prefrontal cortex (mPFC) and the locus coeruleus-norepinephrine (LC-NE) system are involved in this process. The LC sends noradrenergic innervations throughout the brain, and its innervation of the prefrontal cortex plays important roles in working memory and attention. The present study seeks to study the roles of the LC-to-mPFC pathway in pain empathy in rats. Selective ablation of the noradrenergic innervations of the mPFC through bilateral injections of the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-β-hydroxylase into the mPFC diminished mechanical pain hypersensitivity in CO rats. Bilateral intra-mPFC applications of the adrenergic α1 receptor antagonist prazosin and the β receptor antagonist propranolol, but not the adrenergic α2 antagonist yohimbine, eliminated mechanical pain hypersensitivity in CO rats. In contrast, intra-mPFC applications of prazosin, yohimbine or propranolol did not affect the mechanical pain sensitivity of rats per se. Our results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and β receptors.

NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats.

In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 μg/μl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

Toxicity of agents used for opioid withdrawal: a case-based approach.

Toxicity of agents used for opioid withdrawal: a case-based approach.

Synergic stimulation of serotonin 5-HT1A receptor and α2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives

Neuropathic pain affects millions of people causing disability and impairing quality of life. Commonly used analgesics are generally characterized by limited therapeutic outcomes. The serotonin 5‐HT1A receptor and the α2 adrenergic receptors are involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since their stimulation may modulate the nervous signaling altered by neuropathies, the purpose of the present research is the study of the combined activation of 5‐HT1A and α2 receptors by rationally designed imidazoline ligands ((S)-(-)-1 and 2–5) in a rat model of neuropathic pain (chronic constriction injury - CCI). On day 14 after nerve damage, the acute administration per os (p.o.) of low doses of (S)-(-)-1 (0.1–1mg/kg) was able to significantly increase the pain threshold to mechanical noxious stimuli for more than 1h. (S)-(-)-1 efficacy was confirmed by the decrease of spontaneous pain evaluated as hind limb weight bearing alterations. The clinically-used compound gabapentin (100mg/kg p.o.) induced a pain relieving effect similar to (S)-(-)-1 administered at 100 fold lower dose. In the same model, the selected analogues, compounds 2–5 (1mg/kg p.o.) were effective 30min after administration. In particular, 5 fully reverted the CCI-induced hypersensitivity. The pain relieving activity of 5 was significantly prevented by the selective 5-HT1A receptor antagonist WAY 100635 (1mg/kg intraperitoneally, i.p.) and, at a lesser extent, by the α2 antagonist yohimbine (3mg/kg i.p.). A novel pharmacodynamic approach to the treatment of neuropathic pain is presented.

Enhanced anti-immobility effects of Sanggenon G isolated from the root bark of Morus alba combined with the α2-antagonist yohimbine in the rat forced swim test.

In this study, we aimed to determine whether Sanggenon G, an active compound isolated from the root bark of Morus alba, exhibited enhanced anti-immobility activity with the addition of the α2-antagonist yohimbine in rats subjected to forced swim test (FST)-induced depression. Fluoxetine (a selective serotonin reuptake inhibitor) treatment in rats reduced the immobility time, and pretreatment with yohimbine significantly enhanced the antidepressant-like behavior of fluoxetine at 5, 10 and 20mg/kg. Similarly, Sanggenon G significantly decreased the immobility time, reducing immobility by a maximum of 43.9% when treated at a dose of 20mg/kg. Furthermore, pretreatment with yohimbine significantly enhanced the antidepressant-like behavior of Sanggenon G at 5 and 10mg/kg. Our findings suggest that the antidepressant-like effect of Sanggenon G could be facilitated by concomitant use of the α2-antagonist. Further studies are needed to evaluate the potential of Sanggenon G as an alternative therapeutic approach for the treatment of depression.

The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism

AimsIn this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. MethodsRat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. ResultsThe α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K+−stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K+-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. SignificanceThis study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors.

Synthesis of five and six-membered heterocycles bearing an arylpiperazinylalkyl side chain as orally active antinociceptive agents

A number of heterocycles bearing an arylpiperazinylalkyl side chain and structurally related to the previously described lead ET1 (4-amino-6-methyl-2-[3-(4-p-tolylpiperazin-1-yl)propyl]-5-vinylpyridazin-3(2H)-one) was synthesized and tested for their antinociceptive activity in Writhing Test. Many compounds, tested at doses of 20–40mg/kg po were able to reduce the number of abdominal constrictions by more than 47% and, in same cases, the potency is comparable to lead ET1 as for 5e, 24a, 27b and 27c. The analgesia induced by the active compounds was completely prevented by pretreatment with α2-antagonist yohimbine, confirming the involvement of the adrenergic system in the mechanism of action for these new compounds.

The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats

Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs.

Noradrenergic modulation of risk/reward decision making.

Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 μg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension.

Non‐quantal release of acetylcholine in rat atrial myocardium is inhibited by noradrenaline

In the mammalian myocardium, ACh, which is the main neurotransmitter of cardiac parasympathetic postganglionic fibres, can be released via both quantal (vesicular) and non-quantal (non-vesicular) mechanisms of secretion. Non-quantal release is continuous and independent of vagus activity and exocytosis of ACh-containing vesicles. During the incubation of myocardium in the presence of acetylcholinesterase (AChE) inhibitors, non-quantal ACh release leads to accumulation of ACh in the myocardium and cholinergic effects, which are proportional to the intensity of non-quantal secretion. The aim of the present study was to reveal whether non-quantal release of ACh can be modulated by another major cardioregulator, noradrenaline, or whether it represents uncontrolled leakage of ACh from cholinergic fibres. Cholinergic changes of electrical activity induced by the AChE inhibitor paraoxon (5 × 10(-6) M) in isolated rat right atrial preparations were determined by means of a standard microlectrode technique and used as a measure of the intensity of non-quantal release. Noradrenaline (10(-7) and 10(-6) M) substantially suppressed, but did not abolish, effects of paraoxon via stimulation of α-adrenoceptors, because all experiments were conducted in the presence of the β-blocker propranolol (5 × 10(-6) M). A blocker of ganglionic transmission, hexamethonium bromide (10(-4) M), failed to alter the inhibitory effect of noradrenaline, indicating that only non-quantal ACh release is suppressed by this neurotransmitter. The effects of noradrenaline could be reduced by the α2-antagonist yohimbine (10(-6) M). However, both the α1-agonist phenylephrine (10(-6) M) and the α2-agonist clonidine (10(-6) M) significantly inhibited the cholinergic effects of paraoxon, indicating the possible involvement of both α-adrenoceptor subtypes in mediation of the adrenergic inhibition of non-quantal ACh release. Thus, cardiac non-quantal ACh release can be negatively regulated by noradrenaline, providing another facet of sympathetic-parasympathetic interaction in the heart.

α2-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells

α2-Adrenergic agonists simulate norepinephrine (NE) action on α2 receptors of sympathetic neurons to mediate feedback inhibition of NE release. These agents are used as valuable adjuncts for management of hypertension and for anesthesia. Their action, equivalent to NE on α2 adrenergic receptors, raises the question whether α2 agonists may also target NE transporters (NETs), another major control mechanism for noradrenergic neurotransmission. We thus investigated the effect of α2 agonists on transport of the NE analog, 131I-metaiodobenzylguanidine (MIBG). Results from this investigation showed that xylazine and dexmedetomidine dose-dependently blocked [3H]nisoxetine binding in neuron-like SK-N-SH cells. Furthermore, the agents acutely suppressed cellular MIBG uptake in a dose-dependent manner. This effect was uninfluenced by the α2 antagonist yohimbine, but was completely reversed by drug removal. There was no change in membrane NET density by the agents. Moreover, saturation analysis showed that xylazine and dexmedetomidine significantly increased Km without affecting Vmax, indicating competitive inhibition of MIBG transport. Thus, the α2 adrenergic agonists xylazine and dexmedetomidine, acutely suppress NET function through competitive inhibition of substrate transport, likely by direct interaction on a region that over-laps with the nisoxetine binding site.

Yohimbine Increases Impulsivity Through Activation of cAMP Response Element Binding in the Orbitofrontal Cortex

Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance-dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients. Yohimbine's effects were assessed in rats using the five-choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein-a transcription factor implicated in the stress response-in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB. Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbine's effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine. These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations.

Noradrenergic and GABAB Receptor Activation Differentially Modulate Inputs to the Premotor Nucleus RA in Zebra Finches

Neuromodulators can rapidly modify neural circuits, altering behavior. Songbirds provide an excellent system for studying the role of neuromodulation in modifying circuits that underlie behavior because song learning and production are mediated by a discrete set of interconnected nuclei. We examined the neuromodulatory effects of noradrenergic and GABA B receptor activation on synaptic inputs to the premotor robust nucleus of the arcopallium (RA) in zebra finches using whole cell voltage-clamp recording in vitro. In adults, norepinephrine strongly reduced input from the lateral magnocellular nucleus of the anterior nidopallium (LMAN) but only slightly reduced the input from nucleus HVC (proper name), the excitatory input from axon collaterals of other RA neurons, and input from GABAergic interneurons. The effect of norepinephrine was mimicked by the alpha2 adrenoceptor agonist UK14,304 and blocked by the alpha2 antagonist yohimbine. Conversely, the GABA B receptor agonist baclofen strongly decreased HVC, collateral, and GABAergic inputs to RA neurons while causing little reduction in the LMAN input. In juveniles undergoing song learning, norepinephrine reduced the LMAN input, caused only a small reduction in the HVC input, and greatly reduced the collateral and GABAergic inputs. Baclofen caused similar results in juvenile and adult birds, reducing HVC, collateral, and GABAergic inputs significantly more than the LMAN input. Significant increases in paired-pulse ratio accompanied all reductions in synaptic transmission, suggesting a presynaptic locus. The reduction in the LMAN input by norepinephrine may be important for mediating changes in song elicited by different social contexts and is well-placed to play a role in song learning.

Noradrenergic Agonists and Antagonists Influence Migration of Cortical Spreading Depression in Rat—a Possible Mechanism of Migraine Prophylaxis and Prevention of Postischemic Neuronal Damage

Cortical spreading depression (CSD) is thought to be a neuronal mechanism that expands the penumbra zone after focal brain ischemia and that causes migraine aura. Both adrenergic agonists and antagonists significantly influence the size of the penumbra zone and decline the frequency of migraine. To study whether these compounds act by influencing CSD, we applied different drugs topically to an area of the exposed cortex of anesthetized adult rats and observed the migration of CSD-related DC potential deflections across the treated area. The adrenergic agonist norepinephrine (1 mmol/L) and the alpha(2)-agonist clonidine (0.56 mmol/L) blocked reversibly the migration of CSD. The beta-blocker propranolol (250 micromol/L to 1 mmol/L) dose-dependently diminished migration velocity or even blocked migration of CSD. The CSD blockade by the alpha(2)-antagonist yohimbine (1.75 mmol/L) was because of its action on inhibitory 5-HT(1A) receptors. None of the substances in the concentrations used had influence on regional cerebral blood flow or on systemic arterial blood pressure. The data suggest that the interference of these compounds with CSD may contribute to their beneficial therapeutic effect. The effect of beta-receptor antagonists in human migraine needs further exploration, since these drugs also work in migraine without aura.

Supraclinical concentrations of dexmedetomidine evoke norepinephrine release from rat cerebrocortical slicesPossible involvement of the orexin-1 receptor

Dexmedetomidine is a highly selective α2-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to increase norepinephrine release from cardiac stores. In addition, some report using microdialysis shows that intrathecal clonidine increased norepinephrine release from the dorsal horn in mid-thoracic spinal cord but dexmedetomidine did not. Thus, in the present study we have studied effects of dexmedetomidine on norepinephrine release from rat cerebrocortical slices and compared this with clonidine. We have also used a selective α2-antagonist yohimbine and an orexin-1 receptor antagonist SB-334867 to examine whether the effects of dexmedetomidine on norepinephrine release are mediated via α2-adrenergic or orexin (OX) receptors. In addition, concentrations of orexin A in the evoked sample were also measured. Dexmedetomidine significantly increased norepinephrine release (basal = 100%) from rat cerebrocortical slices in a concentration-dependent manner with Emax 377.3 ± 8.6% and pEC50 6.12 ± 0.07, whereas clonidine significantly reduced the release with Emax 62.1 ± 6.8% and pEC50 4.55 ± 0.25. Yohimbine (10−5 M) did not affect the concentration–response curve of dexmedetomidine for norepinephrine release. However, SB-334867 concentration-dependently antagonized dexmedetomidine-evoked norepinephrine release with Imax 91.0 ± 9.4% and pIC50 5.99 ± 0.18. Orexin A concentrations did not differ between the samples. Thus, supraclinical concentrations of dexmedetomidine increase norepinephrine release from rat cerebrocortical slices, and this release may be mediated via OX1 but not α2-adrenoceptors.

Sympatho-modulatory therapies in perioperative medicine

With increasing life expectancy and improved surgical technology an ever-larger number of elderly patients with cardiovascular disease, or significant cardiovascular risk factors will undergo major surgery. More than 5% of an unselected surgical population undergoing non-cardiac surgery will suffer from perioperative cardiovascular complications including myocardial infarction and cardiac death. The incidence of adverse cardiac events may even reach 30% in high-risk patients undergoing vascular surgery causing a substantial financial burden of perioperative health care costs. 59 Thus, all therapeutic measures should be undertaken to reach the challenging goal of a lower incidence of perioperative cardiovascular complications. Gaining control over sympathetic nervous system activity, that is blunting the adrenergic response to the surgical trauma, traditionally represents an important aspect of anaesthetic practice. 21 Anaesthesiology has been regarded as the ‘practice of autonomic nervous system medicine’. While variable and moderate changes in sympathetic nervous system activity function as a servo-control mechanism and are even required to maintain and optimize cardiac performance, undue liberation of excitotoxic substances such as catecholamines and inflammatory cytokines, particularly during emergence from anaesthesia and the painful postoperative period, facilitates the occurrence of cardiovascular complications. 83 84 At this point, the life-supporting adrenergic drive (‘fight-or-flight-response’) turns into a potentially hazardous life-threatening maladaptation. In support of this concept, the beneficial effects of antiadrenergic treatment regimens in perioperative medicine have been confirmed, in observational studies, metaanalyses 55 1 66 and randomized controlled clinical trials. 43 54 59 63 80 84 However, the seemingly established concept of ‘sympatholysis’ as an effective cardioprotective treatment modality needs considerable refinement in the light of the many new experimental and clinical findings. The parlance of ‘sympatholytic’ protection erroneously equates annihilation of any type of adrenergic stimulation with cardioprotection and should be replaced by ‘sympathomodulatory’protection. The present review summarizes findings from large-scale heart failure trials and discusses basic and clinical aspects of individual sympatho-modulatory therapies, as currently used in perioperative medicine, including b-adrenergic antagonism, a2-agonism, and regional anaesthetic techniques. For limitation of space, reviews will often be cited where further references to the primary literature may be found.

Differential role of adrenoceptors in control of plasma glucose and fatty acids in carp, Cyprinus carpio (L.).

Carp were cannulated in the dorsal aorta, and after 2 days of recovery they were infused with 1) norepinephrine, 2) yohimbine (alpha(2)-antagonist) plus norepinephrine, 3) clonidine (alpha(2)-agonist), and 4) isoproterenol (nonselective beta-agonist). Norepinephrine lowered the plasma free fatty acid (FFA) level and raised the plasma glucose level for several hours. Norepinephrine in combination with the alpha(2)-antagonist yohimbine resulted in retardation of the FFA decrease, indicating the involvement of alpha(2)-adrenoceptors. Infusion with the partial alpha(2)-agonist clonidine had a smaller effect. Infusion with isoproterenol caused a marked increase of glucose levels, and unexpectedly a decline of plasma FFA levels, indicating a direct involvement of beta-adrenoceptors. Combination of isoproterenol with either atenolol (beta(1)-antagonist) or ICI-118,551 (beta(2)-antagonist) showed that both beta(1)- and beta(2)-adrenoceptors were involved in the glucose release by isoproterenol. Remarkably, the decline of FFA levels was augmented in the presence of ICI-118,551, whereas with atenolol present plasma FFA levels were increased by isoproterenol. Thus it is concluded that in carp both beta(1)- and beta(2)-adrenoceptors mediate glucose release, whereas lipolysis is controlled by inhibitory beta(1)-adrenoceptors and stimulatory beta(2)-adrenoceptors, as well as by inhibitory alpha(2)-adrenoceptors.

Cardiovascular effects of catecholamines injected into the DBB of rats, influence of urethane anaesthesia and local colchicine

In a previous publication it was shown that 1 μg colchicine injected into the diagonal band of Broca (DBB) produced a significant decrease in femoral artery blood pressure (and/or volume) measured in urethane-anaesthetised rats. In order to test if the central catecholamines were involved in this effect, guide cannulae were implanted in the DBB and a catheter in the femoral artery. On-line pressure recordings were taken before during and after α1, α2 and β adrenoreceptor agonists and antagonists were injected into the region of the DBB of non-anaesthetised and urethane anaesthetised male Wistar rats with and without injection of colchicine. Arterial pressure was significantly increased in the non-anaesthetised rats (114.6±2.6 n=11 vs. 149.3±3.3 mmHg n=12, p<0.01) yet significantly reduced (82.0±3.9 n=11 vs. 63.8±4.5 mmHg n=12, p<0.01) in the urethane treated rats by the α2 agonist clonidine. The α2 antagonist yohimbine blocked these effects in both preparations. In contrast, the β adrenoreceptor agonist isoprenaline produced a significant decrease in arterial pressure in both preparations (107.7±3.9 n=11 vs. 85.9±4.0 mmHg n=12, p<0.01) (102.6±6.7 n=11 vs. 81.7±3.4 mmHg n=12, p<0.01) and this effect was blocked by the β antagonist propranolol. Colchicine injected into the DBB abolished the effects of the α2 agonist and antagonist in the non-anaesthetised but not the anaesthetised rats. The responses to the β agonist and antagonist were not greatly affected by the colchicine in the non-anaesthetised rats whereas in the anaesthetised rat β agonist injection tended to totally depress arterial pressure. These results suggest that the sympathetic nervous system in the DBB plays a significant role in the central control of arterial pressure and that the α2 component is significantly affected by the state of anaesthesia.