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American Journal of Physiology. Renal... Jan 2020Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition,...
Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.
Topics: Acute Kidney Injury; Animals; Apoptosis; Humans; Inflammation; Intestine, Small; Ischemia; Kidney; Mice; Norepinephrine; Paneth Cells; Tyrosine 3-Monooxygenase
PubMed: 31813250
DOI: 10.1152/ajprenal.00471.2019 -
Circulation Research Jul 2020Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from...
RATIONALE
Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined.
OBJECTIVE
To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE.
METHODS AND RESULTS
We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+β adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all ≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, =0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (=0.012), but this effect was not observed in the EE Andeans.
CONCLUSIONS
These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.
Topics: Acetylcholine; Adaptation, Physiological; Adrenergic Agents; Adult; Altitude; Altitude Sickness; Blood Pressure; Blood Vessels; Heart Rate; Humans; Male; Nitroprusside; Phentolamine; Polycythemia; Propranolol; Receptors, Adrenergic; Signal Transduction; Sympathetic Nervous System; Vasodilation; Vasodilator Agents
PubMed: 32268833
DOI: 10.1161/CIRCRESAHA.119.316053 -
Journal of Taibah University Medical... Apr 2023Inhibition of carbohydrate digestion enzymes (α-amylase and α-glucosidase) has been reported in studies as a therapeutic approach for the management or treatment of...
OBJECTIVES
Inhibition of carbohydrate digestion enzymes (α-amylase and α-glucosidase) has been reported in studies as a therapeutic approach for the management or treatment of type 2 diabetes mellitus, owing to its potential to decrease postprandial hyperglycemia. The anti-diabetic potential of (also known as garlic) against diabetes mellitus has been established. Therefore, in this study, we assessed the antidiabetic potential of using enzyme assays after which we explored computational modelling approach using the quantified GC-MS identities to unravel the key bioactive compounds responsible for the anti-diabetic potential.
METHODS
We used enzyme inhibition assays (α-amylase and α-glucosidase) to evaluate antidiabetic potential and subsequently performed gas chromatography-mass spectroscopy (GC-MS) to identify and quantify the bioactive compounds of the plant extract. The identified bioactive compounds were subjected to docking and pharmacokinetic assessment.
RESULTS
phenolic extract showed high dose-dependent inhibition of α-amylase and α-glucosidase (p < 0.05). Interestingly, the extract inhibited α-glucosidase with a half maximal inhibitory concentration of 53.75 μg/mL, a value higher than that obtained for the standard acarbose. Docking simulation revealed that morellinol and phentolamine were the best binders of α-glucosidase, with mean affinity values of -7.3 and -7.1 kcal/mol, respectively. These compounds had good affinity toward active site residues of the enzyme, and excellent drug-like and pharmacokinetic properties supporting clinical applications.
CONCLUSIONS
Our research reveals the potential of as a functional food for the management of type 2 diabetes, and suggests that morellinol and phentolamine may be the most active compounds responsible for this anti-diabetic prowess. Therefore these compounds require further clinical asessment to demonstrate their potential for drug development.
PubMed: 36817213
DOI: 10.1016/j.jtumed.2022.09.011 -
Insects Aug 2022The diamondback moth () is one of the most destructive lepidopteran pests of cruciferous vegetables, and insights into regulation of its physiological processes...
The diamondback moth () is one of the most destructive lepidopteran pests of cruciferous vegetables, and insights into regulation of its physiological processes contribute towards the development of new pesticides against it. Thus, we investigated the regulatory functions of its β-adrenergic-like octopamine receptor (PxOctβ3). The open reading frame (ORF) of was phylogenetically analyzed, and the levels of expression of the receptor mRNA were determined. This ORF was also cloned and expressed in HEK-293 cells. A series of octopamine receptor agonists and antagonists were tested against PxOctβ3. We showed that the receptor is a member of the Octβ3 protein family, and an analysis using quantitative PCR showed that it was expressed at all developmental stages of . Octopamine activated PxOctβ3, resulting in increased levels of intracellular cAMP. Furthermore, the agonists naphazoline, clonidine, 2-phenethylamine, and amitraz activated the PxOctβ3 receptor, and naphazoline was the most effective. Only metoclopramide and mianserin had significant antagonistic effects on PxOctβ3, whereas yohimbine, phentolamine, and chlorpromazine lacked obvious antagonistic effects. The injection of double-stranded RNA in an RNA interference assay indicated that PxOctβ3 regulates development in . This study demonstrated the pharmacological properties and functions of PxOctβ3 in , thus, providing a theoretical basis for the design of pesticides that target octopamine receptors.
PubMed: 36005359
DOI: 10.3390/insects13080735 -
Frontiers in Endocrinology 2022Essential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the...
AIMS
Essential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the role of α-adrenergic receptors (α-AR) in the cardiovascular reactivity to a norepinephrine (NE)-stress reactivity-mimicking NE-infusion in essential hypertensive individuals (HT) as compared to normotensive individuals (NT).
METHODS
24 male HT and 24 male NT participated in three experimental trials on three separate days with a 1-min infusion followed by a 15-min infusion. Trials varied in infusion-substances: placebo saline (Sal)-infusions (trial-1:Sal+Sal), NE-infusion without (trial-2:Sal+NE) or with non-selective α-AR blockade by phentolamine (PHE) (trial-3:PHE+NE). NE-infusion dosage (5g/ml/min) and duration were chosen to mimic duration and physiological effects of NE-release in reaction to established stress induction protocols. We repeatedly measured systolic (SBP) and diastolic blood pressure (DBP) as well as heart rate before, during, and after infusions.
RESULTS
SBP and DBP reactivity to the three infusion-trials differed between HT and NT ('s≤.014). HT exhibited greater BP reactivity to NE-infusion alone compared to NT (trial-2-vs-trial-1: 's≤.033). Group differences in DBP reactivity to NE disappeared with prior PHE blockade (trial-3: =.26), while SBP reactivity differences remained (trial-3: =.016). Heart rate reactivity to infusion-trials did not differ between HT and NT (=.73).
CONCLUSION
Our findings suggest a mediating role of α-AR in DBP hyperreactivity to NE-infusion in EHT. However, in SBP hyperreactivity to NE-infusion in EHT, the functioning of α-AR seems impaired suggesting that the SBP hyperreactivity in hypertension is not mediated by α-AR.
Topics: Adrenergic Agents; Blood Pressure; Essential Hypertension; Humans; Hypertension; Infusions, Intravenous; Male; Norepinephrine; Phentolamine
PubMed: 35937820
DOI: 10.3389/fendo.2022.824616 -
Journal of Dental Anesthesia and Pain... Feb 2021To evaluate changes in the effectiveness of phentolamine mesylate in combination with different local anesthetics (LAs) and vasoconstrictors. A prospective randomized...
BACKGROUND
To evaluate changes in the effectiveness of phentolamine mesylate in combination with different local anesthetics (LAs) and vasoconstrictors. A prospective randomized double-blind study was conducted with 90 patients divided into three groups, with each group being administered one of three different LAs: lidocaine 2% 1/80,000, articaine 4% 1/200,000, and bupivacaine 0.5% 1/200,000.
METHODS
We compared treatments administered to the mandible involving a LA blockade of the inferior alveolar nerve. Results were assessed by evaluating reduction in total duration of anesthesia, self-reported patient comfort using the visual analog pain scale, incidence rates of the most common adverse effects, overall patient satisfaction, and patient feedback.
RESULTS
The differences among the three groups were highly significant (P < 0.001); time under anesthesia was especially reduced for both the lip and tongue with bupivacaine. The following adverse effects were reported: pain at the site of the anesthetic injection (11.1%), headaches (6.7%), tachycardia (1.1%), and heavy bleeding after treatment (3.3%). The patients' feedback and satisfaction ratings were 100% and 98.9%, respectively.
CONCLUSIONS
Efficient reversal of LAs is useful in dentistry as it allows patients to return to normal life more readily and avoid common self-injuries sometimes caused by anesthesia. Phentolamine mesylate reduced the duration of anesthesia in the three studied groups, with the highest reduction reported in the bupivacaine group (from 460 min to 230 min for the lip and 270 min for the tongue [P < 0.001]).
PubMed: 33585684
DOI: 10.17245/jdapm.2021.21.1.49 -
JAMA Network Open Oct 2022Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Despite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown.
OBJECTIVE
To test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021.
INTERVENTIONS
A 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion.
MAIN OUTCOMES AND MEASURES
Blood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli.
RESULTS
Of the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects.
CONCLUSIONS AND RELEVANCE
These findings lay the foundations for clinical applications for kisspeptin in women with HSDD.
TRIAL REGISTRATION
ISRCTN trial registry identifier: ISRCTN17271094.
Topics: Female; Male; Humans; Adult; Libido; Kisspeptins; Phentolamine; Sexual Dysfunctions, Psychological; Hormones
PubMed: 36287566
DOI: 10.1001/jamanetworkopen.2022.36131 -
World Journal of Gastroenterology Nov 2014To investigate the effects and underlying mechanisms of resveratrol and genistein on contractile responses of rat gastrointestinal smooth muscle.
AIM
To investigate the effects and underlying mechanisms of resveratrol and genistein on contractile responses of rat gastrointestinal smooth muscle.
METHODS
Isolated strips of gastrointestinal smooth muscle from Spraque-Dawley rats were suspended in organ baths containing Kreb's solution, and the contractility of smooth muscles was measured before and after incubation with resveratrol and genistein, and the related mechanisms were studied by co-incubation with various inhibitors.
RESULTS
Resveratrol and genistein dose-dependently decreased the resting tension, and also reduced the mean contractile amplitude of gastrointestinal smooth muscle. Estrogen receptor blockades (ICI 182780 and tamoxifen) failed to alter the inhibitory effects induced by resveratrol and genistein. However, their effects were attenuated by inhibitions of α-adrenergic receptor (phentolamine), nitric oxide synthase (levorotatory-NG-nitroarginine), ATP-sensitive potassium channels (glibenclamide), and cyclic adenosine monophosphate (SQ22536). In high K(+)/Ca(2+)-free Kreb's solution containing 0.01 mmol/L egtazic acid, resveratrol and genistein reduced the contractile responses of CaCl2, and shifted its cumulative concentration-response curves rightward.
CONCLUSION
Resveratrol and genistein relax gastrointestinal smooth muscle via α-adrenergic receptors, nitric oxide and cyclic adenosine monophosphate pathways, ATP-sensitive potassium channels, and inhibition of L-type Ca(2+) channels.
Topics: Animals; Calcium Channels, L-Type; Cyclic AMP; Dose-Response Relationship, Drug; Duodenum; Female; Gastric Mucosa; Gastrointestinal Motility; Genistein; In Vitro Techniques; KATP Channels; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Phytoestrogens; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Resveratrol; Signal Transduction; Stilbenes; Stomach
PubMed: 25386082
DOI: 10.3748/wjg.v20.i41.15335 -
American Journal of Physiology. Heart... Jan 2023Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular...
Increasing evidence indicates that cerebrovascular compliance contributes to the dynamic regulation of cerebral blood flow but the mechanisms regulating cerebrovascular compliance in humans are unknown. This retrospective study investigated the impact of neural, endothelial, and myogenic mechanisms on the regulation of vascular compliance in the cerebral vascular bed compared with the forearm vascular bed. An index of vascular compliance () was assessed using a Windkessel model applied to blood pressure waveforms (finger photoplethysmography) and corresponding middle cerebral artery blood velocity or brachial artery blood velocity waveforms (Doppler ultrasound). Data were analyzed during a 5-min baseline period (10 waveforms) under control conditions and during distinct sympathetic blockade (, phentolamine; 10 adults), cholinergic blockade (, glycopyrrolate; 9 adults), and myogenic blockade (, nicardipine; 14 adults). In e, phentolamine increased similarly in the cerebral vascular bed (131 ± 135%) and forearm vascular bed (93 ± 75%; = 0.45). In , glycopyrrolate increased cerebrovascular (72 ± 61%) and forearm vascular (74 ± 64%) to a similar extent ( = 0.88). In , nicardipine increased but to a greater extent in the cerebral vascular bed (88 ± 88%) than forearm vascular bed (20 ± 45%; = 0.01). Therefore, adrenergic, cholinergic, and myogenic mechanisms contribute to the regulation of cerebrovascular and forearm vascular compliance. However, myogenic mechanisms appear to exert more specific control over vascular compliance in the brain relative to the forearm. Vascular compliance represents an important determinant in the dynamics and regulation of blood flow through a vascular bed. However, the mechanisms that regulate vascular compliance remain poorly understood. This study examined the impact of neural, endothelial, and myogenic mechanisms on cerebrovascular compliance compared with forearm vascular compliance. Distinct pharmacological blockade of α-adrenergic, endothelial muscarinic, and myogenic inputs altered cerebrovascular and forearm vascular compliance. These results further our understanding of vascular control and blood flow regulation in the brain.
Topics: Adult; Humans; Forearm; Phentolamine; Nicardipine; Glycopyrrolate; Retrospective Studies; Blood Pressure; Cerebrovascular Circulation; Adrenergic Agents; Cholinergic Agents; Regional Blood Flow
PubMed: 36459447
DOI: 10.1152/ajpheart.00377.2022 -
PloS One 2014During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells...
OBJECTIVE
During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells (EPCs) mobilization was enhanced with an increase of sympathetic nerve activity and norepinephrine (NE) secretion, yet the cellular and molecular mechanisms involved in the effects of NE on EPCs has less been investigated.
METHODS AND RESULTS
EPCs from BMs, peripheral circulation and spleens, the VEGF concentration in BM, skeletal muscle, peripheral circulation and spleen and angiogenesis in ischemic gastrocnemius were quantified in mice with hindlimbs ischemia. Systemic treatment of NE significantly increased EPCs number in BM, peripheral circulation and spleen, VEGF concentration in BM and skeletal muscle and angiogenesis in ischemic gastrocnemius in mice with hind limb ischemia, but did not affair VEGF concentration in peripheral circulation and spleen. EPCs isolated from healthy adults were cultured with NE in vitro to evaluate proliferation potential, migration capacity and phosphorylations of Akt and eNOS signal moleculars. Treatment of NE induced a significant increase in number of EPCs in the S-phase in a dose-dependent manner, as well as migrative activity of EPCs in vitro (p<0.05). The co-treatment of Phentolamine, I127, LY294002 and L-NAME with NE blocked the effects of NE on EPCs proliferation and migration. Treatment with NE significantly increased phosphorylation of Akt and eNOS of EPCs. Addition of phentolamine and I127 attenuated the activation of Akt/eNOS pathway, but metoprolol could not. Pretreatment of mice with either Phentolamine or I127 significantly attenuated the effects of NE on EPCs in vivo, VEGF concentration in BM, skeletal muscle and angiogenesis in ischemic gastrocnemius, but Metoprolol did not.
CONCLUSION
These results unravel that sympathetic nervous system regulate EPCs mobilization and their pro-angiogenic capacity via α adrenoceptor, β 2 adrenoceptor and meanwhile Akt/eNOS signaling pathway.
Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Adrenergic beta-2 Receptor Antagonists; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelial Progenitor Cells; Hindlimb; Humans; Ischemia; Male; Metoprolol; Mice, Inbred C57BL; Muscle, Skeletal; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Norepinephrine; Phentolamine; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Vascular Endothelial Growth Factor A
PubMed: 25007164
DOI: 10.1371/journal.pone.0101774