Adrenoceptor Antagonist Research Articles

Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

Heightened SAM- and HPA-axis activity during acute stress impairs decision-making: A systematic review on underlying neuropharmacological mechanisms

Individuals might be exposed to intense acute stress while having to make decisions with far-reaching consequences. Acute stress impairs processes required for decision-making by activating different biological stress cascades that in turn affect the brain. By knowing which stress system, brain areas, and receptors are responsible for compromised decision-making processes, we can effectively find potential pharmaceutics that can prevent the deteriorating effects of acute stress. We used a systematic review procedure and found 44 articles providing information on this topic. Decision-making processes could be subdivided into 4 domains (cognitive, motivational, affective, and predictability) and could be referenced to specific brain areas, while mostly being impaired by molecules associated with the sympathetic-adrenal-medullar and hypothalamic-pituitary-adrenal axes. Potential drugs to alleviate these effects included α1 and β adrenoceptor antagonists, α2 adrenoceptor agonists, and corticotropin releasing factor receptor1/2 antagonists, while consistent stress-like effects were found with yohimbine, an α2 adrenoceptor antagonist. We suggest possible avenues for future research.

Structure-Based Drug Design of ADRA2A Antagonists Derived from Yohimbine.

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.

Effect of NaV1.7 blockers on post-ganglionic sympathetic nerve function

NaV1.7, also known as the sodium voltage-gated channel alpha subunit 9 (SCN9A), plays a critical role in action potential induction and conduction in pain-causing nociceptors. Accordingly, NaV1.7 blockers may be effective non-opioids analgesics. SCN9A is also expressed in autonomic neurons, but its functional role in the autonomic system is less established. We employed three highly selective NaV1.7 inhibitors to investigate the role of NaV1.7 in action potential conduction in postganglionic sympathetic nerves and in sympathetic adrenergic contractions of blood vessels. Our single neuron rt-PCR analysis revealed that nearly all neurons (32/39) isolated from guinea pig stellate ganglia expressed NaV1.7 mRNA. Genentech Pharmaceuticals provided a highly selective NaV1.7 blocker, GNE8493, which exhibits a selectivity ranging from 500 to 5000-fold for NaV1.7 over all other NaV subtypes. SiteOne Pharmaceuticals contributed another mechanistically distinct and highly selective NaV1.7 blocker, ST2262, with a selectivity of 1000-fold for human NaV1.7 over other NaV subtypes (as reported in Sci Rep. 10:14791, 2020). Unfortunately, ST2262 has little affnity for rodent and guinea pig NaV1.7. We quantified the effect of GNE8493 on postganglionic compound actional potentials (CAP) within the sympathetic trunk of superior cervical ganglia (SCG). GNE8493 inhibited the CAP in the postganglionic neurons of SCG by ~ 70% (n=5, p<0.01). With such a significant impact of the NaV1.7 blocker on post-ganglionic actional potential conduction, we were prompted to explore its potential physiological relevance. Our study involved the isolated pulmonary arteries from anonymous human lung donors (obtained from IIAM) and isolated pulmonary arteries and the abdominal aorta from guinea pigs. We measured smooth muscle tension using standard tissue bath techniques. Stimulation of intrinsic nerves was achieved through electrical field stimulation (EFS) at 12V, 1msec, and 10Hz for 30 seconds, resulting in rapid contractions in all tissues. These contractions were completely prevented by the nonselective NaV1 blocker tetrodotoxin and by the alpha adrenoceptor antagonist prazosin. The contractions were quantified as a percentage of the maximum adrenergic contraction achievable, induced by the addition of 100 μM phenylephrine at the end of the experiment. In guinea pigs, GNE8493 completely blocked sympathetic contractions of the isolated pulmonary arteries (IC50 of -log (M) 5.8) and abdominal aorta (IC50 of -log (M) 6.4 ± 0.3). In human pulmonary arteries, GNE8493 (1 μM) and ST2262 inhibited the sympathetic contractions 94% and 87%, respectively (p<0.01, n=6). These findings support the hypothesis that pharmacological inhibition of NaV1.7 using selective inhibitors has the potential to reduce sympathetic function in specific vascular beds. R35HL155671 - BJU F32HL170490 - JSK. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Correction to "The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with K A Values Distinct From Their Equilibrium Dissociation Constants as β 2-Adrenoceptor Antagonists: Evidence for Functional Affinity".

Correction to "The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with K A Values Distinct From Their Equilibrium Dissociation Constants as β 2-Adrenoceptor Antagonists: Evidence for Functional Affinity".

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α1D/1A-adrenoceptor antagonist and homology modelling

α1-Adrenergic receptor (AR) blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs. We previously reported that phenylpiperazine analogues with amide and propane linker were moderate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α1D/1A-subtype selectivity. Herein, we replaced propane moiety with 2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups. Of these new compounds, quinoline surrogate 17 exhibited extremely weak antagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α1A/1B and α1D/1B selectivity. Intriguingly, the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17, supporting ligand regulates the receptor in a highly stereospecific manner. Finally, the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex with α1A and the subtype receptor selectivity for R-17 was also rationalized in this study. Taken together, our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS, and provided a basis for discovery of α1D/1A-selective ligands.

Clinical Use of Adrenergic Receptor Ligands in Acute Care Settings.

In this chapter, we review how ligands, both agonists and antagonists, for the major classes of adrenoreceptors, are utilized in acute care clinical settings. Adrenergic ligands exert their effects by interacting with the three major classes of adrenoceptors. Adrenoceptor agonists and antagonists have important applications, ranging from treatment of hypotension to asthma, and have proven to be extremely useful in a variety of clinical settings of acute care from the operating room to the critical care environment. Continued research interpreting the mechanisms of adrenoreceptors may help the discovery of new drugs with more desirable clinical profiles.

The β-Blocker Carvedilol and Related Aryloxypropanolamines Promote ERK1/2 Phosphorylation in HEK293 Cells with K A Values Distinct From Their Equilibrium Dissociation Constants as β 2-Adrenoceptor Antagonists: Evidence for Functional Affinity.

The determination of affinity by using functional assays is important in drug discovery because it provides a more relevant estimate of the strength of interaction of a ligand to its cognate receptor than radioligand binding. However, empirical evidence for so-called, "functional affinity" is limited. Herein, we determined whether the affinity of carvedilol, a β-adrenoceptor antagonist used to treat heart failure that also promotes extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, differed between these two pharmacological activities. Four structurally related β-adrenoceptor antagonists (alprenolol, carazolol, pindolol, propranolol) that also activated ERK1/2 were included as comparators to enhance our understanding of how these drugs work in the clinical setting. In HEK293 cells stably expressing the human β 2-adrenoceptor carvedilol and related aryloxypropanolamines were partial agonists of ERK1/2 phosphorylation with potencies ([A]50s) that were lower than their equilibrium dissociation constants (K Bs) as β 2-adrenoceptor antagonists. As the [A]50 of a partial agonist is a good approximation of its K B, then these data indicated that the affinities of carvedilol and related ligands for these two activities were distinct. Moreover, there was a significant negative rank order correlation between the [A]50 of each ligand to activate ERK1/2 and their intrinsic activities (i.e., as intrinsic activity for ERK1/2 phosphorylation increased, so did affinity). Genome editing revealed that the transducer that coupled the β 2-adrenoceptor to ERK1/2 phosphorylation in response to carvedilol and other β 2-adrenoceptor antagonists was Gαs. Collectively, these data support the concept of "functional affinity" and indicate that the ability of the β 2-adrenoceptor to recruit Gαs may influence the affinity of the activating ligand. SIGNIFICANCE STATEMENT: In HEK293 cells overexpressing the human β2-adrenoceptor carvedilol and four related aryloxypropanolamines behaved as β2-adrenoceptor antagonists and partial agonists of ERK1/2 phosphorylation with rank orders of affinity that were distinct. These data imply that carvedilol and other β-blockers can stabilize the β2-adrenoceptor in different affinity conformations that are revealed when functionally distinct responses are measured. This is the basis for the pharmacological concept of "functional affinity."

Nicorandil and carvedilol mitigates motor deficits in experimental autoimmune encephalomyelitis-induced multiple sclerosis: Role of TLR4/TRAF6/MAPK/NF-κB signalling cascade

Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (KATP) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of KATP channel opener (nicorandil) as well as α and β adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice. Mice was treated with nicorandil (6 mg/kg/day; p.o.) and carvedilol (10 mg/kg/day; p.o.) for 14 days. Nicorandil and carvedilol showed improvement in clinical scoring, behaviour and motor coordination as established by histopathological investigation and immunohistochemical detection of MBP. Furthermore, both treatments downregulated the protein expression of TLR4/ MYD88/TRAF6 signalling cascade with downstream inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis leading to reduction of neuroinflammatory status, as witnessed by reduction of NF-κB, TNF-α, IL-1β and IL-6 contents. Moreover, nicorandil and carvedilol attenuated oxidative damage by increasing Nrf2 content and SOD activity together with reduction of MDA content. In addition, an immunomodulating effect via inhibiting the gene expression of CD4, TGF-β, and IL-17 as well as TGF-β, IL-17, and IL-23 contents along with anti-apoptotic effect by decreasing Bax protein expression and Caspase-3 content and increasing Bcl-2 protein expression was observed with nicorandil and carvedilol treatments. In conclusion, nicorandil and carvedilol exerted a neuroprotective activity against EAE induced neuronal loss via inhibition of TLR4/MYD88/TRAF6/JNK/p38-MAPK axis besides antioxidant and anti-apoptotic effects.

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model.

Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 μg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.

THE EFFICACY AND SAFETY OF SILODOSIN FOR THE TREATMENT OF BENIGN HYPERPLASIA PROSTATE: A SYSTEMATIC REVIEW

Background: BPH is a prevalent and costly condition affecting the quality of life for older men. adrenoceptor antagonists provide effective relief for bothersome symptoms but do not prevent the need for surgery or acute urinary obstruction. Silodosin, newer adrenoceptor antagonist, offers comparable symptom relief to tamulosin Aim: This systematic review evaluates the efficacy and safety of silodosin for the treatment of benign prostatic hyperplasia (BPH) and its suitability for daily clinical practice.. Methods: This systematic review examined the use of silodosin in men with benign prostatic hyperplasia (BPH). Multiple databases were searched for relevant literature. (PubMed and Cochrane Library) Results: This systematic review included four randomized trials involving 2504 patients with benign prostatic hyperplasia. The analysis showed that silodosin demonstrated significant improvements in International Prostate Symptom Score, specifically in storage and voiding symptoms, compared to placebo. Conclusion: Silodosin shows efficacy and safety for treating benign prostatic hyperplasia (BPH), but the higher incidence of retrograde ejaculation warrants further high-quality, long-term studies, including direct comparisons with tamsulosin.

Social defeat stress enhances the rewarding effects of cocaine through α1A adrenoceptors in the medial prefrontal cortex of mice

Various stressors potentiate the rewarding effects of cocaine and contribute to cocaine cravings. However, it remains unclear whether psychosocial stress enhances the rewarding effects of cocaine. Accordingly, this study employed a cocaine-conditioned place preference (CPP) paradigm combined with social defeat (SD) exposure to investigate the effects of acute SD stress on cocaine reward in male mice. We found that SD stress immediately before the posttest significantly increased cocaine CPP, and systemic blockade of α1 adrenoceptors, but not β adrenoceptors, suppressed this increase. Fiber photometry recordings with GRABNE1m sensors revealed increased noradrenaline (NA) levels in the medial prefrontal cortex (mPFC) in test mice in response to attacks by aggressor mice during SD. Moreover, the SD stress-induced enhancement of CPP was effectively suppressed by intra-mPFC infusion of an α1 adrenoceptor antagonist. In vitro whole-cell recordings demonstrated that silodosin, an α1A, but not α1B or α1D, adrenoceptor antagonist, inhibited NA-induced depolarizing currents and facilitation of excitatory synaptic transmissions. Consistently, intra-mPFC silodosin infusion significantly suppressed the SD stress-induced CPP enhancement. Conversely, intra-mPFC infusion of α1A adrenoceptor agonist augmented cocaine CPP in the absence of stress exposure. Additionally, intranasal silodosin administration attenuated the SD stress-induced enhancement of CPP, and chemogenetic inhibition of mPFC excitatory neurons also suppressed the SD stress-induced CPP enhancement. Together, these findings suggest that NA stimulation of α1A adrenoceptors and the subsequent activation of mPFC pyramidal cells may contribute to SD stress-induced amplification of the rewarding effects of cocaine, and intranasal silodosin administration may hold therapeutic potential for mitigating stress-associated cocaine craving.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Selective inhibition of neurogenic, but not agonist-induced contractions by phospholipase A2 inhibitors points to presynaptic phospholipase A2 functions in contractile neurotransmission to human prostate smooth muscle.

Phospholipases A2 (PLA2 ) may be involved in α1 -adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1 -adrenergic contractions of the prostate, is still unknown. While α1 -adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2 . Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1 -adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls. Frequency-dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3and 1 µM) neither affected EFS-induced contractions, nor contractions by α1 -adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM). Our findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1 -adrenergic agonists occur PLA2 -independent. Lacking sensitivity to montelukast excludes an involvement of PLA2 -derived leukotrienes in promotion of contractile neurotransmission.

Effects of RS17053 on α1 -adrenoceptors in rat vas deferens and aorta.

RS17053 is classed as an α1A -adrenoceptor selective antagonist. We have examined its profile of action at all subtypes of α1 -adrenoceptor. Noradrenaline (NA) evoked contractions of rat vas deferens involve α1D -adrenoceptors in phasic contractions and α1A -adrenoceptors in tonic contractions. Contractions of rat aorta to NA involve α1D - and α1B -adrenoceptors. RS17053 (10-5 M) shifted NA potency and virtually abolished tonic contractions to NA, with little or limited effect on phasic contractions. The α1D -adrenoceptor antagonist BMY7378 (3 × 10-7 M) significantly inhibited the remaining phasic component of the contractions, and the α1A -adrenoceptor antagonist RS100329 (10-7 M) inhibited further the residual tonic contraction. Hence, RS17053 shows high selectivity for α1A -adrenoceptors over α1D -adrenoceptors in rat vas deferens. However, RS17053 (10-5 M) produced a large shift in the potency of NA in rat aorta, with a pKB of 6.82. Large shifts of NA potency in rat aorta involve α1B -adrenoceptor blockade. Results in rat vas deferens demonstrate low potency of RS17053 at α1D -adrenoceptors, but results from rat aorta can only be explained as demonstrating α1B -adrenoceptor antagonism by RS17053. RS17053 may be a useful pharmacological tool when reclassified as a mainly α1A - and to a lesser extent α1B -adrenoceptor antagonist with little effect at α1D -adrenoceptors.

Postoperative analgesic effect of hyaluronidase versus dexamethasone as additives to bupivacaine in transversus abdominis plane block for inguinal hernia repair: prospective, randomized, and double-blinded controlled study

Background Inguinal hernia repair is associated with severe postoperative pain. Transversus abdominus plain block has been proved to provide effective analgesia for somatic lower abdominal pain. Several adjuvants have been added to local anesthetic to improve the quality of analgesia. This study compares the additive effect of hyaluronidase versus dexamethasone to improve the quality of analgesia of transversus abdominus plain block for inguinal hernia repair. Patients and methods This prospective, randomized, controlled, and double-blind study was carried out in Sohag University Hospital between November 2020 and February 2021. Seventy-five participants scheduled for inguinal hernia repair were included and randomly assigned into control, hyaluronidase, and dexamethasone groups. Exclusion criteria were neurological, psychiatric, neuromuscular, cardiovascular, pulmonary, renal, hepatic disease, alcoholism or drug abuse, pregnancy or lactating women, and patients receiving adrenoceptor agonist or antagonist therapy or chronic analgesic therapy, patients with morbid obesity, coagulopathy, and known allergy to study medications, and sepsis surgical scar at the site to be operated upon and those who refuse. We targeted from this study to assess time to first analgesia, consumption of morphine, and visual analog scale at rest and during physical activity. Also, we targeted to assess heart rate, noninvasive blood pressure, SpO2%, and adverse effects (nausea and vomiting, respiratory depression). Results Our study showed comparable analgesic efficacy for hyaluronidase versus dexamethasone with longer time to the first request of analgesia, less morphine consumption, and less side effects compared with these two groups to the control group. Conclusion Adding hyaluronidase or dexamethasone to bupivacaine not only prolonged the duration of analgesia and decreased the consumption of opioids but also decreased the incidence of adverse effects.

Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using noradrenaline receptor antagonists in female C57BL/6JRj mice

RationaleNoradrenergic dysfunction is associated with disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) quantifies changes in attention and impulsivity.ObjectiveTo use NA receptor antagonists to examine the roles of NA on attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval (vITI) schedules.MethodsTwo cohorts of 36 female C57BL/6JRj mice were examined separately in the rCPT vSD and vITI schedules. Both cohorts received antagonists of the following adrenoceptors: α1 (doxazosin, DOX: 1.0, 3.0, 10.0 mg/kg), α2 (yohimbine, YOH: 0.1, 0.3, 1.0 mg/kg), and β1/2 (propranolol, PRO: 1.0, 3.0, 10.0 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity.ResultsDOX showed similar effects in both schedules, improving discriminability and accuracy, and reducing responding and impulsivity, and DOX also reduced locomotor activity. YOH showed prominent effects in the vSD schedule to increase responding and impulsivity, while impairing discriminability and accuracy. YOH did not affect locomotor activity. PRO increased responding and impulsivity, decreased accuracy, but did not affect discriminability or locomotor activity.ConclusionAntagonism of α2 or β1/2 adrenoceptors caused similar increases in responding and impulsivity and worsened attentional performance, while α1 adrenoceptor antagonism showed the opposite effects. Our results suggest that endogenous NA exerts bidirectional control of most behaviours in the rCPT. The parallel vSD and vITI studies showed a substantial overlap in effects, but also some differences that indicate differing sensitivity towards noradrenergic manipulations.

Synthesis, biological evaluation, and molecular modeling of ORM-10921 and its analogs as α2C -adrenoceptor antagonists.

The α2C -adrenoceptor (α2C -AR) is regarded as one of the potential targets for antipsychotics. A few of structurally diverse α2C -AR antagonists have been reported, among which ORM-10921, containing one rigid tetracyclic framework with two neighboring chiral centers, has exhibited remarkable antipsychotic-like effects and pro-cognitive properties in different animal models. Yet the binding mode of ORM-10921 remains elusive. In this study, all of its four stereoisomers and a set of its analogs were synthesized and in vitro evaluated for their α2C -AR antagonist activities. The molecular docking study and hydration site analysis gave a rational explanation for the biological results, which might provide helpful insights into the binding mode and future optimization.

C42 OR 1896 EXERTS POSITIVE INOTROPIC EFFECTS IN ISOLATED HUMAN RIGHT ATRIAL MUSCLE

Abstract Levosimendan is approved for use as an intravenous agent to treat temporarily patients with severe systolic heart failure. It is thought, but hitherto never tested in isolated human cardiac tissue, that the main metabolite of levosimendan, called OR 1896, might cause the positive inotropic effect of levosimendan in patients. For comparison, we studied mouse atrial preparations. OR alone (up to 10 µM) failed to increase force of contraction in mouse atrial preparations while in the presence of the phosphodiesterase (PDE) IV–inhibitor rolipram (0.1 µM) profound positive inotropic effects and positive chronotropic effects of OR 1895 were recorded in mouse atrial preparations. In contrast to mouse atrium, we noticed that OR 1896 alone (0.01 µM to 10 µM cumulatively applied) exerted time– and concentration–dependent positive inotropic effects 1 µM increase by 72 ± 14.7%, p<0.05, n=7) and shortened the time of relaxation (by 7 .3 %, p<0.05, n=7) in isolated electrically paced human right atrial muscle preparations (obtained during cardiac surgery), that started at 0.1 µM and plateaued at 1 µM OR 1896. The positive inotropic effect of OR 1896 was antagonized by 10 µM propranolol. The positive inotropic effect of OR 1896 in mouse atrial preparations and human right atrial preparations was less effective than that of 1 µM isoprenaline (human atrium by 154 %). The positive inotropic effect of OR 1896 was diminished by pre–incubation of the samples with the PDE III inhibitor cilostamide (10 µM). EMD 57033 (10 µM), a calcium sensitizer, increased force of contraction further in the additional presence of 1 µM OR 1896. Our data suggest that OR 1896 is indeed a positive inotropic agent in the human heart and that OR 1896 acts mainly as a PDE III – inhibitor because the effect of OR 1896 was attenuated by a β–adrenoceptor antagonist and thus OR 1896 is unlikely to act as a calcium sensitizer in the human heart.