Analyses of the Mode of Action of an Alpha-Adrenoceptor Blocker in Substantia Gelatinosa Neurons in Rats

To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.

Chemokine receptor antagonists with α1-adrenergic receptor blocker activity

Objectives Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C–C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α1-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α1-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles. Methods The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α1b-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1–BX471, BX513, BI639667; CCR2–RS504393, INCB3284; CCR3–SB328437; and CCR4–AZD2098, and C021; CCR5–Maraviroc; CCR10-BI6901. The pan-α1-adrenoceptor antagonist prazosin was used as control. Results Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α1b-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α1-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α1-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine. Conclusions Our data suggest that CCR antagonists should be screened for cross-reactivity with α1-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.

5-HT1A Serotonergic, α-Adrenergic and Opioidergic Receptors Mediate the Analgesic Efficacy of Vortioxetine in Mice

Vortioxetine is a multimodal antidepressant drug that affects several brain neurochemicals and has the potential to induce various pharmacological effects on the central nervous system. Therefore, we investigated the centrally mediated analgesic efficacy of this drug and the mechanisms underlying this effect. Analgesic activity of vortioxetine (5, 10 and 20 mg/kg, p.o.) was examined by tail-clip, tail-immersion and hot-plate tests. Motor performance of animals was evaluated using Rota-rod device. Time course measurements (30–180 min) showed that vortioxetine (10 and 20 mg/kg) administrations significantly increased the response latency, percent maximum possible effect and area under the curve values in all of the nociceptive tests. These data pointed out the analgesic effect of vortioxetine on central pathways carrying acute thermal and mechanical nociceptive stimuli. Vortioxetine did not alter the motor coordination of mice indicating that the analgesic activity of this drug was specific. In mechanistic studies, pre-treatments with p-chlorophenylalanine (serotonin-synthesis inhibitor), NAN-190 (serotonin 5-HT1A receptor antagonist), α-methyl-para-tyrosine (catecholamine-synthesis inhibitor), phentolamine (non-selective α-adrenoceptor blocker), and naloxone (non-selective opioid receptor blocker) antagonised the vortioxetine-induced analgesia. Obtained findings indicated that vortioxetine-induced analgesia is mediated by 5-HT1A serotonergic, α-adrenergic and opioidergic receptors, and contributions of central serotonergic and catecholaminergic neurotransmissions are critical for this effect.

Static And Dynamic Pupillometric Changes With Silodosin; Selective α1 Adrenoceptor Blocker

Backround: Intraoperative floopy iris syndrome is a variant of the small pupil syndrome that has been observed during cataract surgery in some patients currently or previously treated with the α1 adrenergic blockers. It is important for cataract surgeons to predict the probable complications, preoperatively. The aim of our study is to evaluate the static and dynamic pupil characteristics of patients treated with silodosin –a selective α1 adrenergic blocker- for Benign Prostate Hypertrophy (BPH) and to compare these values with healthy subjects using an automatic quantitative pupillometry system.Methods: A total of 74 BPH patients treated with silodosin for six months (group 1) and 30 healthy subjects (group 2) were enrolled in this prospective multidisciplinary cross-sectional study. Static and dynamic pupillometric measurements were obtained under optimized conditions and the results were compared between the two groups.Results: Seventy four male patients with a mean age of 63,35±7,21 (46-77) years with BPH treated with silodosin and 30 normal male subjects with a mean age of 63,07±4,73 (52-71) years were analyzed. There were statistically significant differences between the groups with regard to scotopic pupil diameter (PD), high photopic PD, and low photopic PD (p<0.001, for each one). Patient group has statistically significant higher values of amplitude and velocity of pupil contraction and lower values of duration of pupil contraction and latency, duration and velocity of pupil dilation.Conclusion: Static and dynamic pupil characteristics of subjects treated with silodosin for BPH is different from healthy eyes. In addition, our results may have shed light on understanding the risk for IFIS before cataract surgery and thus surgeons can be on the alert and take precautions.

Effects of Propranolol on Growth, Lipids and Energy Metabolism and Oxidative Stress Response of Phaeodactylum tricornutum

Present demographic trends suggest a rise in the contributions of human pharmaceuticals into coastal ecosystems, underpinning an increasing demand to evaluate the ecotoxicological effects and implications of drug residues in marine risk assessments. Propranolol, a non-selective β-adrenoceptor blocker, is used worldwide to treat high blood pressure conditions and other related cardiovascular conditions. Although diatoms lack β-adrenoceptors, this microalgal group presents receptor-like kinases and proteins with a functional analogy to the animal receptors and that can be targeted by propranolol. In the present work, the authors evaluated the effect of this non-selective β-adrenoceptor blocker in diatom cells using P. tricornutum as a model organism, to evaluate the potential effect of this compound in cell physiology (growth, lipids and energy metabolism and oxidative stress) and its potential relevance for marine ecosystems. Propranolol exposure leads to a significant reduction in diatom cell growth, more evident in the highest concentrations tested. This is likely due to the observed impairment of the main primary photochemistry processes and the enhancement of the mitochondrial respiratory activity. More specifically, propranolol decreased the energy transduction from photosystem II (PSII) to the electron transport chain, leading to an increase in oxidative stress levels. Cells exposed to propranolol also exhibited high-dissipated energy flux, indicating that this excessive energy is efficiently diverted, to some extent, from the photosystems, acting to prevent irreversible photoinhibition. As energy production is impaired at the PSII donor side, preventing energy production through the electron transport chain, diatoms appear to be consuming storage lipids as an energy backup system, to maintain essential cellular functions. This consumption will be attained by an increase in respiratory activity. Considering the primary oxygen production and consumption pathways, propranolol showed a significant reduction of the autotrophic O2 production and an increase in the heterotrophic mitochondrial respiration. Both mechanisms can have negative effects on marine trophic webs, due to a decrease in the energetic input from marine primary producers and a simultaneous oxygen production decrease for heterotrophic species. In ecotoxicological terms, bio-optical and fatty acid data appear as highly efficient tools for ecotoxicity assessment, with an overall high degree of classification when these traits are used to build a toxicological profile, instead of individually assessed.

INVESTIGATION OF THE NEUROPROTECTIVE EFFECT OF LINAGLIPTIN AND CELIPROLOL IN RESERPINE-INDUCED OROFACIAL DYSKINESIA AND ROTENONE-INDUCED NEURODEGENERATION IN RATS

Objective: Linagliptin, an anti-diabetic agent, proven to play an important role in regulating neuronal plasticity and reduce apoptosis and neuroinflammation by activating downstream AMPK/Sirt 1 pathway, which protects mitochondrial function and suppresses intracellular ROS accumulation and shows antioxidant action. Celiprolol, a β-1selective adrenoceptor blocker used as an anti-hypertensive agent, possesses a direct scavenging activity on oxygen radicals with antioxidant properties. The current study was designed to investigate the combined neuroprotective effect of linagliptin and celiprolol. Methods: Wistar rats of either sex were divided into different groups (n = 6). Eight groups each for Reserpine induced orofacial dyskinesia model and Rotenone induced neurodegeneration model to mimic Parkinson’s like conditions and treated or not with different doses of linagliptin and celiprolol. 24 h after the last dose, animals were subjected to behavioral, biochemical and histopathological evaluations. The data were analyzed by ANOVA and Bonferroni multiple comparison test. Results: Reserpine treatment increased VCMs, tongue protrusion and decreased locomotor activity. Rotenone treatment decreases the motor activity and exploratory ability of the animals. Reserpine as well as rotenone treatments decrease catalase, GSH, SOD and increase the LPO levels as compared to sham group animals. Reserpine and rotenone also showed the presence of ghost cells and vacuolated cytoplasm. Linagliptin and celiprolol alone as well as in combination normalized the behavioral, biochemical and histopathological complications. Conclusion: Linagliptin and Celiprolol showed neuroprotection by antioxidant activity as well as improved reserpine and rotenone-induced behavioral deficits. Both drugs have tenacious potential and can be used clinically with some further investigations.

β-1 adrenoceptors and AT1 receptors may not be involved in catecholamine-induced lethal arrhythmias

An excessive amount of catecholamines produce arrhythmias, but the exact mechanisms of this action are not fully understood. For this purpose, Sprague–Dawley rats were treated with or without atenolol, a β1-adrenoceptor blocker (20 mg/kg per day), for 15 days followed by injections of epinephrine for cumulative doses of 4 to 128 μg/kg. Another group of animals were pretreated with losartan, an angiotensin receptor (AT1) blocker (20 mg/kg per day), for comparison. Control animals received saline. Varying degrees of ventricular arrhythmias were seen upon increasing the dose of epinephrine, but the incidence and duration of the rhythm abnormalities as well as the number of episodes and severity of arrhythmias were not affected by treating the animals with atenolol or losartan. The levels of both epinephrine and norepinephrine were increased in the atenolol-treated rats but were unchanged in the losartan-treated animals after the last injection of epinephrine; the severity of arrhythmias did not correlate with the circulating catecholamine levels. These results indicate that both β1-adrenoceptors and AT1 receptors may not be involved in the pathogenesis of catecholamine-induced arrhythmias and support the view that other mechanisms, such as the oxidation products of catecholamines, may play a crucial role in the occurrence of lethal arrhythmias.