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Peptides Aug 2023Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert...
Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. In contrast to this assumption, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to noradrenaline (NA) in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 micro-g/h NA without or with persistent intravenous administration of either 1.0 micro-g/h ANP or CNP for 14 days. Blood pressure (BP) was recorded under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NA was evaluated by heart weight/body weight (HW/BW) ratio and microscopic measurement of myocyte size of the left ventricle. Mean BP levels at the light and dark cycles rose by about 20 mmHg following NA infusion for 14 days, with slight increases in HW/BW ratio and ventricular myocyte size. Infusions of ANP and CNP had no significant effects on mean BP in NA-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NA. Cardiac hypertrophy induced by co-administration of NA and ANP was attenuated by treatment with prazosin or atenolol. In summary, both ANP and CNP potentiated cardiac hypertrophic effect of continuously infused NA in rats, suggesting a possible pro-hypertrophic action of natriuretic peptides on the heart.
Topics: Rats; Animals; Male; Rats, Wistar; Norepinephrine; Atrial Natriuretic Factor; Cardiomegaly; Blood Pressure; Natriuretic Peptide, C-Type; Natriuretic Peptide, Brain
PubMed: 37263541
DOI: 10.1016/j.peptides.2023.171035 -
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 -
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 -
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 -
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) Oct 2023Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the...
Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the phenylpropanoid methyleugenol (ME) in adult female mice exposed to a stress model induced by dexamethasone. The animals were randomly divided into groups containing eight animals and were pre-administered with dexamethasone (64 μg/kg subcutaneously). After 165 and 180 min, they were treated with ME (25, 50 and 100 mg/kg intraperitoneally) or imipramine (10 mg/kg intraperitoneally) after 45 min and 30 min, respectively; they were then submitted to tests which were filmed. The videos were analyzed blindly. In the tail suspension test, ME (50 mg/kg) increased latency and reduced immobility time. In the splash test, ME (50 mg/kg) decreased grooming latency and increased grooming time. In the open field, there was no statistical difference for the ME groups regarding the number of crosses, and ME (50 mg/kg) increased the number of rearing and time spent in the center. Regarding in silico studies, ME interacted with dopaminergic D1 and α1 adrenergic pathway receptors and with tryptophan hydroxylase inhibitor. In the in vivo evaluation of the pathways of action, the antidepressant potential of ME (50 mg/kg) was reversed by SCH23390 (4 mg/kg intraperitoneally) dopaminergic D1 receptor, Prazosin (1 mg/kg intraperitoneally) α1 adrenergic receptor, and PCPA (4 mg/kg intraperitoneally) tryptophan hydroxylase inhibitor. Our findings indicate that ME did not alter with the locomotor activity of the animals and shows antidepressant activity in female mice with the participation of the D1, α1 and serotonergic systems.
PubMed: 37895879
DOI: 10.3390/ph16101408 -
Vascular Pharmacology Aug 2023Sympathomimetic amines, including β-phenylethylamine (PEA), constrict animal blood vessels but their mechanism of action is not now thought to be through...
Sympathomimetic amines, including β-phenylethylamine (PEA), constrict animal blood vessels but their mechanism of action is not now thought to be through α-adrenoceptors and release of noradrenaline but via trace amine-associated receptors (TAARs). This information is not available for human blood vessels. Functional studies were therefore performed on human arteries and veins to establish whether they constrict to PEA and whether any constrictions are adrenoceptor-mediated. Isolated internal mammary artery or saphenous vein rings were set up in Kreb's-bicarbonate solution at 37 ± 0.5 °C gassed with O:CO (95:5) under class 2 containment. Isometric contractions were measured and cumulative concentration-response curves for PEA or the α-adrenoceptor agonist, phenylephrine were established. PEA showed concentration-related contractions. The maximum was significantly greater in arteries (1.53 ± 0.31 g, n = 9) than veins (0.55 ± 0.18 g, n = 10), but not when plotted as % of KCl contractions. PEA showed slowly developing contractions plateauing at 17,3 ± 3.7 min in mammary artery. The reference α-adrenoceptor agonist, phenylephrine, exhibited more rapid onset (peak 5.0 ± 1.2 min) but non-sustained contractions. In saphenous veins, PEA (62.8 ± 10.7%) and phenylephrine (61.4 ± 9.7%, n = 4) displayed the same maximum, but phenylephrine was more potent. The α-adrenoceptor antagonist, prazosin (1 μM), blocked phenylephrine contractions of mammary arteries but not PEA contractions in either vessel. PEA causes substantial vasoconstriction of human saphenous vein and mammary artery, which explains its vasopressor actions. This response, however, was not mediated via α-adrenoceptors, but likely due to TAARs. The classification of PEA as a sympathomimetic amine on human blood vessels is therefore no longer valid and requires revision.
Topics: Animals; Humans; Mammary Arteries; Vasoconstriction; Saphenous Vein; Phenylephrine; Norepinephrine; Receptors, Adrenergic
PubMed: 37399882
DOI: 10.1016/j.vph.2023.107191 -
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 -
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 -
International Journal of Molecular... Nov 2023In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (-) was designed....
In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (-) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds -. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α-adrenergic receptors (α-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α and α, was conducted. Selected compounds were tested for their activity towards two α-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds ( and ), which possess o-methoxyphenylpiperazine fragments, strong activity (IC < 100 nM) was observed. Some representatives ( and ), which contain alkyl linker, proved selectivity towards α-AR, while two compounds with 2-hydroxypropyl linker ( and ) to α-AR. Finally, hypotensive activity was examined in rats. The most active compound () proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.
Topics: Rats; Animals; Prazosin; Antihypertensive Agents; Radioligand Assay; Receptors, Adrenergic, alpha-1; Hypotension; Adrenergic alpha-1 Receptor Antagonists
PubMed: 38068933
DOI: 10.3390/ijms242316609