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Purinergic Signalling Feb 2024Stimulation of sympathetic nerves in the vas deferens yields biphasic contractions consisting of a rapid transient component resulting from activation of P2X1 receptors...
Stimulation of sympathetic nerves in the vas deferens yields biphasic contractions consisting of a rapid transient component resulting from activation of P2X1 receptors by ATP and a secondary sustained component mediated by activation of α-adrenoceptors by noradrenaline. Noradrenaline can also potentiate the ATP-dependent contractions of the vas deferens, but the mechanisms underlying this effect are unclear. The purpose of the present study was to investigate the mechanisms underlying potentiation of transient contractions of the vas deferens induced by activation of α-adrenoceptors. Contractions of the mouse vas deferens were induced by electric field stimulation (EFS). Delivery of brief (1s duration) pulses (4 Hz) yielded transient contractions that were inhibited tetrodotoxin (100 nM) and guanethidine (10 µM). α,β-meATP (10 µM), a P2X1R desensitising agent, reduced the amplitude of these responses by 65% and prazosin (100 nM), an α-adrenoceptor antagonist, decreased mean contraction amplitude by 69%. Stimulation of α-adrenoceptors with phenylephrine (3 µM) enhanced EFS and ATP-induced contractions and these effects were mimicked by the phorbol ester PDBu (1 µM), which activates PKC. The PKC inhibitor GF109203X (1 µM) prevented the stimulatory effects of PDBu on ATP-induced contractions of the vas deferens but only reduced the stimulatory effects of phenylephrine by 40%. PDBu increased the amplitude of ATP-induced currents recorded from freshly isolated vas deferens myocytes and HEK-293 cells expressing human P2X1Rs by 93%. This study indicates that: (1) potentiation of ATP-evoked contractions of the mouse vas deferens by α-adrenoceptor activation were not fully blocked by the PKC inhibitor GF109203X and (2) that the stimulatory effect of PKC on ATP-induced contractions of the vas deferens is associated with enhanced P2X1R currents in vas deferens myocytes.
PubMed: 38374492
DOI: 10.1007/s11302-024-09993-y -
Frontiers in Cell and Developmental... 2023Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this...
Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Although both drugs reduced capillary pruning, a combination of experiments based on imaging, proteomics, electron microscopy and functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage.
PubMed: 38020883
DOI: 10.3389/fcell.2023.1256127 -
Child and Adolescent Psychiatric... Apr 2024Trauma exposure significantly impacts sleep in children. Nightmares are common. Evidence-based therapies are superior to medications but may not always be available in... (Review)
Review
Trauma exposure significantly impacts sleep in children. Nightmares are common. Evidence-based therapies are superior to medications but may not always be available in acute settings. No FDA-approved medications exist for the treatment of trauma-related sleep disturbances in youth. The evidence-base for the use of medications is largely based on case reports, retrospective chart reviews, clinical opinion, and adult studies. This evidence is reviewed for a number of medications, including prazosin, trazodone, alpha-2 agonists, quetiapine, and others.
Topics: Adult; Child; Humans; Adolescent; Retrospective Studies; Transients and Migrants; Stress Disorders, Post-Traumatic; Sleep; Prazosin; Sleep Wake Disorders
PubMed: 38395505
DOI: 10.1016/j.chc.2023.08.001 -
Hernia : the Journal of Hernias and... Dec 2023The rate of post-operative urinary retention (POUR) in inguinal hernia repairs (IHR) is estimated to be approximately 5.9% to 38% worldwide. Currently, there are minimal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The rate of post-operative urinary retention (POUR) in inguinal hernia repairs (IHR) is estimated to be approximately 5.9% to 38% worldwide. Currently, there are minimal studies on the prophylaxis of POUR after IHR. Pre-operative administration of alpha-blockers such as (but not limited to) Tamsulosin, Prazosin and Alfuzosin has shown promising results in the prevention of POUR in patients undergoing IHR. This study aims to determine the effectiveness of prophylactic alpha-blockade in the prevention of POUR after IHR.
METHODS
This study reports the findings of a systematic review and meta-analysis. Randomised controlled trials (RCTs) using prophylactic alpha-blockade for the prevention of POUR after open and/or laparoscopic IHR in patients aged more than 18 years in all sex groups were included. Multiple databases were searched from inception to October 2021 using the PRISMA flow diagram. Data were extracted and analysed to include eligibility criteria, comparator, intervention, study and participant characteristics. Studies excluded were non-RCT studies and patients with known urinary tract disorders such as benign prostate hypertrophy, urinary incontinence and cancer of the bladder or prostate. Subgroup analyses were also conducted. All effect measures of each data were odds ratio with 95% confidence interval. All studies were pooled using the dichotomous random effects Mantel-Haenszel statistical mode and I was used to assess heterogeneity. Publication bias was detected using the Cochrane risk-of-bias tool for randomised trials (RoB-2) involving two independent reviewers.
RESULTS
A total of eight RCTs were identified which provided adequate numeric data for incorporation into the meta-analysis. Overall, administration of pre-operative alpha-blocker prior to IHR did not prevent POUR (95% CI 1.20 (0.96-1.49), I: 34%). Subgroup analysis comparing pre-operative use of prophylactic alpha-blocker in open versus laparoscopic IHR has shown statistically significant reduction of POUR prevention in the laparoscopic group (95% CI 0.66 (0.47-0.92)), I: 43%). The older age group benefited from pre-operative alpha-blocker use with reduced incidence of POUR post-IHR (95% CI 0.14 (0.08, 0.23), I: 0%)). Gender did not affect the difference of incidence of POUR post-IHR despite pre-operative alpha-blockers (95% CI 0.62 (0.27, 1.44)), I: 53%)).
CONCLUSION
Overall, this meta-analysis has shown that administration of prophylactic alpha-blockers did not prevent POUR. However, there was statistically significant reduction of POUR in patients undergoing laparoscopic IHR as compared to open, as well as in older patients (age more than 60 years) after administration of pre-operative alpha-blocker. Hence, the use of pre-operative alpha-blocker especially in older patients should be considered and more RCTs should be undertaken.
Topics: Male; Humans; Aged; Urinary Retention; Hernia, Inguinal; Herniorrhaphy; Postoperative Complications; Tamsulosin
PubMed: 36952050
DOI: 10.1007/s10029-023-02764-5 -
Protein Science : a Publication of the... Nov 2023G protein-coupled receptors (GPCRs) are medically important membrane proteins that sample inactive, intermediate, and active conformational states characterized by...
G protein-coupled receptors (GPCRs) are medically important membrane proteins that sample inactive, intermediate, and active conformational states characterized by relatively slow interconversions (~μs-ms). On a faster timescale (~ps-ns), the conformational landscape of GPCRs is governed by the rapid dynamics of amino acid side chains. Such dynamics are essential for protein functions such as ligand recognition and allostery. Unfortunately, technical challenges have almost entirely precluded the study of side-chain dynamics for GPCRs. Here, we investigate the rapid side-chain dynamics of a thermostabilized α -adrenergic receptor (α -AR) as probed by methyl relaxation. We determined order parameters for Ile, Leu, and Val methyl groups in the presence of inverse agonists that bind orthosterically (prazosin, tamsulosin) or allosterically (conopeptide ρ-TIA). Despite the differences in the ligands, the receptor's overall side-chain dynamics are very similar, including those of the apo form. However, ρ-TIA increases the flexibility of Ile176 and possibly of Ile214 , adjacent to Pro215 of the highly conserved P I F motif crucial for receptor activation, suggesting differences in the mechanisms for orthosteric and allosteric receptor inactivation. Overall, increased Ile side-chain rigidity was found for residues closer to the center of the membrane bilayer, correlating with denser packing and lower protein surface exposure. In contrast to two microbial membrane proteins, in α -AR Leu exhibited higher flexibility than Ile side chains on average, correlating with the presence of Leu in less densely packed areas and with higher protein-surface exposure than Ile. Our findings demonstrate the feasibility of studying receptor-wide side-chain dynamics in GPCRs to gain functional insights.
Topics: Drug Inverse Agonism; Magnetic Resonance Spectroscopy; Receptors, G-Protein-Coupled; Membrane Proteins; Ligands
PubMed: 37805830
DOI: 10.1002/pro.4801 -
Pharmaceuticals (Basel, Switzerland) May 2024Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as "Calavera" or "calaverita", in the Huasteca Potosina (central region of Mexico). This plant...
Bateman ex Lindl. (Orchidaceae) is an orchid endemic to Mexico, known as "Calavera" or "calaverita", in the Huasteca Potosina (central region of Mexico). This plant species is used for the folk treatment of mental disorders and urological kidney disorders, according to the ethnomedicinal information obtained in this study. Ethanolic extracts of leaves (HE) and pseudobulb (PE) were obtained by microwave-assisted extraction (MAE). Gas Chromatography coupled with Mass Spectrometry (GC-MS) was used to carry out the chemical characterization of HE and PE. The pharmacological effects (antioxidant, diuretic, anxiolytic, locomotor, hypnotic, and sedative) of HE and PE were evaluated. The possible mechanism of action of the anxiolytic-like activity induced by HE was assessed using inhibitors of the GABAergic, adrenergic, and serotonergic systems. The possible mechanism of the diuretic action of HE was assessed using prostaglandin inhibitory antagonists and nitric oxide synthase (NOS) blockers. HE at 50 and 100 mg/kg exerted anxiolytic-like activity without inducing hypnosis or sedation. Flumazenil, prazosin, and ketanserin inhibited the anxiolytic-like activity shown by HE, which suggests the participation of GABA, α-adrenergic receptors, and 5-HT receptors, respectively. The diuretic effect was reversed by the non-selective NOS inhibitor L-NAME, which caused the reduction in nitric oxide (NO). These results demonstrate that the ethanolic extract of leaves exhibited anxiolytic-like activity and diuretic effects without inducing hypnosis or sedation. This work validates the medicinal uses of this orchid species.
PubMed: 38794158
DOI: 10.3390/ph17050588 -
Journal of Chemical Neuroanatomy Nov 2023The locus coeruleus (LC) is the major source for norepinephrine (NE) in the brain and projects to areas involved in learning and memory, reward, arousal, attention, and...
The locus coeruleus (LC) is the major source for norepinephrine (NE) in the brain and projects to areas involved in learning and memory, reward, arousal, attention, and autonomic functions related to stress. There are three types of adrenergic receptors that respond to NE: alpha1-, alpha2-, and beta-adrenergic receptors. Previous behavioral studies have shown the alpha1-adrenergic receptor (α1AR) to be present in the LC, however, with conflicting results. For example, it was shown that α1ARs in the LC are involved in some of the motivational effects of stimulation of the medial forebrain bundle, which was reduced by α1AR antagonist terazosin. Another study showed that during novelty-induced behavioral activation, the α1AR antagonist prazosin reduced c-fos expression in brain regions known to contain motoric α1ARs, except for the LC, where c-fos expression was enhanced. Despite new research delineating more specific connectivity of the neurons in the LC, and some roles of the adrenergic receptors, the α1ARs have not been localized at the subcellular level. Therefore, in order to gain a greater understanding of the aforementioned studies, we used immunohistochemistry at the electron microscopic (EM) level to determine which neuronal or glial elements in the LC express the α1AR. We hypothesized, based on previous work in the ventral periaqueductal gray area, that the α1AR would be found mainly presynaptically in axon terminals, and possibly in glial elements. Single labeling immunohistochemistry at the EM revealed that about 40% of labeled elements that contained the α1AR were glial elements, while approximately 50% of the labeled neuronal elements were axon terminals or small unmyelinated axons in the LC. Double labeling immunohistochemistry found the α1AR expressed in GFAP-labeled astrocytes, in both GABAergic and glutamatergic axon terminals, and in a portion of the α1AR dendrites, colocalized with tyrosine hydroxylase (TH, a marker for noradrenergic neurons). This study sheds light on the neuroanatomical framework underlying the effects of NE and pharmaceuticals acting directly or indirectly on α1ARs in the LC.
Topics: Rats; Mice; Animals; Locus Coeruleus; Rats, Sprague-Dawley; Presynaptic Terminals; Axons; Norepinephrine; Receptors, Adrenergic
PubMed: 37777094
DOI: 10.1016/j.jchemneu.2023.102343 -
The Korean Journal of Physiology &... Jul 2023α-adrenoceptors link via the G-protein Gq/G to both Ca entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study...
α-adrenoceptors link via the G-protein Gq/G to both Ca entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α-adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α-adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α-adrenoceptor mediated as they are competitively blocked by prazosin. The α-adrenoceptor antagonist RS100329 had low potency in rat aorta. The α-adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α-adrenoceptors and high concentrations blocking α-adrenoceptors. The Rho kinase inhibitor fasudil (10 μM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α-adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α-adrenoceptor are involved in contractions to NA, fasudil (3 μM) significantly reduced both early and late components to the NA contraction, the early component involving α- and α-adrenoceptors, and the late component involving α- and α-adrenoceptors. This suggests that fasudil inhibits α-adrenoceptor mediated responses. It is concluded that α- and α-adrenoceptors interact in rat aorta and α-, α- and α-adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α-adrenoceptor.
PubMed: 37386830
DOI: 10.4196/kjpp.2023.27.4.325 -
The Korean Journal of Pain Jan 2024Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of...
BACKGROUND
Sitagliptin is an antidiabetic drug that inhibits dipeptidyl peptidase-4 enzyme. This study aimed to investigate the antinociceptive and anti-inflammatory effects of sitagliptin in formalin and carrageenan tests and determine the possible mechanism(s) of its antinociceptive activity.
METHODS
Male Swiss mice (25-30 g) and male Wistar rats (180-220 g) were used for formalin and carrageenan tests, respectively. In the formalin test, paw licking time and in the carrageenan test, paw thickness were considered as indexes of pain behavior and inflammation respectively. Three doses of sitagliptin (2.5, 5, and 10 mg/kg) were used in these tests. Also, several antagonists and enzyme inhibitors were used to evaluate the role of adrenergic, serotonergic, dopaminergic, and opioid receptors as well as the NO/cGMP/K pathway in the antinociceptive effect of sitagliptin (5 mg/kg).
RESULTS
Sitagliptin showed significant antinociceptive and anti-inflammatory effects in the formalin and carrageenan tests respectively. In the carrageenan test, all three doses of sitagliptin significantly ( < 0.001) reduced paw thickness. Pretreatment with yohimbine, prazosin, propranolol, naloxone, and cyproheptadine could not reverse the antinociceptive effect of sitagliptin (5 mg/Kg), which indicates that adrenergic, opioid, and serotonin receptors (5HT) are not involved in the antinociceptive effects. L-NAME, methylene blue, glibenclamide, ondansetron, and sulpiride were able to reverse this effect.
CONCLUSIONS
NO/cGMP/K, 5HT and D pathways play an important role in the antinociceptive effect of sitagliptin. Additionally significant anti-inflammatory effects observed in the carrageenan test might contribute in reduction of pain response in the second phase of the formalin test.
PubMed: 38123184
DOI: 10.3344/kjp.23262 -
Beilstein Journal of Organic Chemistry 20242-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the...
2-Chloro-4-sulfonylquinazolines undergo functional group swap when treated with an azide nucleophile: 1) the azide replaces the sulfonyl group at the C4 position; 2) the intrinsic azide-tetrazole tautomeric equilibrium directs the nucleofugal sulfinate from the first step to replace chloride at the C2 position. This transformation is effective with quinazolines bearing electron-rich substituents. Therefore, the title transformations are demonstrated on the 6,7-dimethoxyquinazoline core, which is present in pharmaceutically active substances. The methodology application is showcased by transforming the obtained 4-azido-6,7-dimethoxy-2-sulfonylquinazolines into the α-adrenoceptor blockers terazosin and prazosin by further C2-selective SAr reaction and azide reduction.
PubMed: 38590535
DOI: 10.3762/bjoc.20.61