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Oxidative Medicine and Cellular... 2020Norepinephrine (NE) is the naturally occurring adrenergic agonist that is released in response to hypotension, and it is routinely administered in clinical settings to...
Norepinephrine (NE) is the naturally occurring adrenergic agonist that is released in response to hypotension, and it is routinely administered in clinical settings to treat moderate to severe hypotension that may occur during general anesthesia and shock states. Although NE has incontestable beneficial effects on blood pressure maintenance during hypotensive conditions, deleterious effects of NE on endothelial cell function may occur. In particular, the role of reactive oxygen species (ROS) and NADPH oxidase (Nox) on the deleterious effects of NE on endothelial cell function have not been fully elucidated. Therefore, we investigated the effects of NE on ROS production in rat lung microvascular endothelial cells (RLMEC) and its contribution to cell death. RLMEC were treated with NE (5 ng/mL) for 24 hours and ROS production was assessed by CellROX and DCFDA fluorescence. Nox activity was assessed by NADPH-stimulated ROS production in isolated membranes and phosphorylation of p47phox; cell death was assessed by flow cytometry and DNA fragmentation. Caspase activation was assessed by fluorescent microscopy. Nox1, Nox2, and Nox4 mRNA expression was assessed by real-time PCR. NE increased ROS production, Nox activity, p47phox phosphorylation, Nox2 and Nox4 mRNA content, caspase-3 activation, and RLMEC death. Phentolamine, an -adrenoreceptor antagonist, inhibited NE-induced ROS production and Nox activity and partly inhibited cell death while -blockade had no effect. Apocynin and PEGSOD inhibited NE-induced caspase-3 activation and cell death while direct inhibition of caspase-3 abrogated NE-induced cell death. PEG-CAT inhibited NE-induced cell death but not caspase-3 activation. Collectively, these results indicate that NE induces RLMEC death via activation of Nox by -adrenergic signaling and caspase-3-dependent pathways. NE has deleterious effects on RLMECs that may be important to its long-term therapeutic use.
Topics: Acetophenones; Adrenergic alpha-1 Receptor Antagonists; Animals; Caspase 3; Caspase Inhibitors; Cell Death; Endothelial Cells; Lung; NADPH Oxidase 1; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; Norepinephrine; Phentolamine; Polyethylene Glycols; Rats; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase
PubMed: 32104529
DOI: 10.1155/2020/2563764 -
BMC Ophthalmology Oct 2022Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD.
METHODS
In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed.
RESULTS
Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia.
CONCLUSION
PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD.
TRIAL REGISTRATION
The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.
Topics: Adult; Contrast Sensitivity; Female; Glare; Humans; Hyperemia; Male; Middle Aged; Night Blindness; Night Vision; Ophthalmic Solutions; Phentolamine; Vision Disorders
PubMed: 36209072
DOI: 10.1186/s12886-022-02621-6 -
Pakistan Journal of Medical Sciences 2020To discuss the clinical efficacy of phentolamine in the treatment of feeding intolerance in premature infants with low birth weight.
OBJECTIVE
To discuss the clinical efficacy of phentolamine in the treatment of feeding intolerance in premature infants with low birth weight.
METHODS
Seventy-one low-birth-weight infants with feeding intolerance were randomly divided into the phentolamine group and the erythromycin group (38 patients and 33 patients, respectively). The infants were given basic treatment, such as gastric lavage, temporary fasting, nutritional support and abdominal massage. The phentolamine group was intravenously pumped with phentolamine as the basis of basic treatment, while the erythromycin group was given erythromycin as the basis of basic treatment. The time for gastrointestinal symptoms to disappear, the time the basic standard was reached, the time parenteral nutrition was used, the total time enteral feeding was implemented, the length of stay, and the increase in physical indexes according to the corrected gestational age of 40 weeks of the two groups were compared.
RESULTS
There was no significant difference between the phentolamine group and the erythromycin group in vomiting disappearance time or the increase in physical indicators at the corrected gestational age of 40 weeks (P>0.05), while the abdominal distension disappearance time, the time of restoration to birth weight, the time to reach the basic standard, the total time of parenteral nutrition, the total time of enteral feeding, and the length of stay in the phentolamine group were shorter than those in the erythromycin group, with significant differences (P<0.05).
CONCLUSION
Phentolamine has a significant effect on alleviating symptoms and shortening the treatment time while treating feeding intolerance in premature infants with low birth weight, without adverse events, so it is worthy of clinical promotion.
PubMed: 33235592
DOI: 10.12669/pjms.36.7.2633 -
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 -
American Journal of Physiology.... Apr 2023Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic...
Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during ) incremental intra-arterial infusion of phenylephrine to assess α-adrenergic receptor responsiveness and ) combined intra-arterial infusion of β-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-β-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; 3 ± 18%; < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; = 0.041) doses. Blockade of β-adrenergic receptors alone had no effect on resting FVC ( = 0.500) and combined α-β-blockade induced a similar vasodilatory response at SL and HA ( = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA ( = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-β-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-β-blockade: +19 ± 23%; = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-β-blockade: -23 ± 11%; = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.
Topics: Male; Humans; Adrenergic Agents; Vasoconstriction; Vasoconstrictor Agents; Phenylephrine; Regional Blood Flow; Muscle, Skeletal; Hypoxia
PubMed: 36717165
DOI: 10.1152/ajpregu.00230.2022 -
PeerJ 2021Sleep is a recuperative process, and its dysregulation has cognitive, metabolic, and immunological effects that are largely deleterious to human health. Epidemiological...
Sleep is a recuperative process, and its dysregulation has cognitive, metabolic, and immunological effects that are largely deleterious to human health. Epidemiological and empirical studies have suggested that sleep fragmentation (SF) as result of obstructive sleep apnea (OSA) and other sleep abnormalities leads to pronounced inflammatory responses, which are influenced by the sympathetic nervous system (SNS). However, the underlying molecular mechanisms contributing to SNS regulation of SF-induced inflammation are not fully understood. To assess the effects of the SNS upon inflammatory responses to SF, C57BL/6j female mice were placed in automated SF chambers with horizontally moving bars across the bottom of each cage at specified intervals to disrupt sleep. Mice were first subjected to either control (no bar movement), acute sleep fragmentation (ASF), or chronic sleep fragmentation (CSF) on a 12:12-h light/dark schedule. ASF involved a bar sweep every 120 s for 24 h, whereas CSF involved a bar sweep every 120 s for 12 h (during 12 L; resting period) over a period of 4 weeks. After exposure to these conditions, mice received an intraperitoneal injection of either phentolamine (5 mg/kg BW; an α-adrenergic receptor blocker), propranolol (5 mg/kg BW; a β-adrenergic receptor blocker), or vehicle (saline). Serum corticosterone concentration, brain and peripheral cytokine (IL1β, TNFα, and TGFβ) mRNA expression, and body mass were assessed. ASF and CSF significantly elevated serum corticosterone concentrations as well as cytokine mRNA expression levels compared with controls, and mice subjected to CSF had decreased body mass relative to controls. Mice subjected to CSF and treated with phentolamine or propranolol had a greater propensity for a decrease in cytokine gene expression compared with ASF, but effects were tissue-specific. Taken together, these results suggest that both α- and β-adrenergic receptors contribute to the SNS mediation of inflammatory responses, and adrenergic antagonists may effectively mitigate tissue-specific SF-mediated inflammation.
PubMed: 34221721
DOI: 10.7717/peerj.11616 -
Frontiers in Physiology 2020Oviposition is an important reproductive behavior that is triggered by mating in insects, and biogenic amines might be involved in its regulation. The effects of...
Oviposition is an important reproductive behavior that is triggered by mating in insects, and biogenic amines might be involved in its regulation. The effects of biogenic amines on oviposition have only been studied in a few insect species, and the findings to date have not been conclusive. In addition, there are few studies on the effects of biogenic amines on oviposition of the diamondback moth, L. Here, we tested how mating and biogenic amines regulate oviposition of by injecting amines and amine receptor antagonists into virgin and mated females and counting the number of eggs laid afterward. Biogenic amines of octopamine and tyramine could induce virgin adults of to lay eggs, while dopamine and serotonin had no such effect on oviposition. Furthermore, the octopamine antagonists mianserin, epinastine, and phentolamine inhibited oviposition by mated females. The tyramine antagonist yohimbine, dopamine antagonist SCH23390, and serotonin antagonist ketanserin did not block oviposition by mated females, and octopamine and tyramine-inducing oviposition by virgin females could be inhibited by the octopamine antagonists mianserin and epinastine instead of the tyramine antagonist yohimbine. We conclude that octopamine and its receptors are involved in mating-triggered oviposition in , while tyramine acts as a subsidiary. Further, the inducing effect of tyramine on oviposition is achieved via octopamine receptors instead of tyramine receptors. This experiment is helpful to further understand the role of biogenic amines in mating regulation and to provide a new strategy for controlling .
PubMed: 32528307
DOI: 10.3389/fphys.2020.00475 -
Pharmacology & Therapeutics Aug 2016The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against... (Review)
Review
The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.
Topics: Animals; Biomarkers; Clinical Studies as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Pulmonary; Lisuride; Phenotype; Phentolamine; Protein-Tyrosine Kinases; Vasoactive Intestinal Peptide
PubMed: 27133570
DOI: 10.1016/j.pharmthera.2016.04.012 -
Frontiers in Physiology 2017Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine...
Octopamine and tyramine, both biogenic amines, are bioactive chemicals important in diverse physiological processes in invertebrates. In insects, octopamine and tyramine operate analogously to epinephrine and norepinephrine in the vertebrates. Octopamine and tyramine bind to G-protein coupled receptors (GPCRs) leading to changes in second messenger levels and thereby modifying the function in target tissues and insect behavior. In this paper, we report the cDNA sequences of two GPCRs, RhoprOctβ2-R, and RhoprTyr1-R, have been cloned and functionally characterized from . Octopamine and tyramine each activate RhoprOctβ2-R and RhoprTyr1-R in a dose-dependent manner. Octopamine is one order of magnitude more potent than tyramine in activating RhoprOctβ2-R. Tyramine is two orders of magnitude more potent than octopamine in activating RhoprTyr1-R. Phentolamine and gramine significantly antagonize RhoprOctβ2-R, whereas yohimbine and phenoxybenzamine are effective blockers of RhoprTyr1-R. The transcripts of both receptors are enriched in the central nervous system (CNS) and are expressed throughout the adult female reproductive system. It has been shown in other insects that Octβ2-R is essential for processes such as ovulation and fertilization. We previously reported that octopamine and tyramine modulate oviducts and bursa contractions in . Our data confirm the importance of octopamine and tyramine signaling in the reproductive system of .
PubMed: 29018364
DOI: 10.3389/fphys.2017.00744 -
Translational Andrology and Urology Aug 2019To evaluate the cost-effectiveness of alternate erectile dysfunction (ED) management options after failed first line phosphodiesterase-5-inhibitors (PDE5-I).
BACKGROUND
To evaluate the cost-effectiveness of alternate erectile dysfunction (ED) management options after failed first line phosphodiesterase-5-inhibitors (PDE5-I).
METHODS
An empiric, repetitive decision tree analysis model was constructed using literature review and expert clinical judgement. This assessed the expected costs and quality adjusted life years (QALYs) of decision alternatives over a 10-year period. The model incorporated interventions including alternate PDE5-Is, intracorporal injections (ICI) with alprostadil or trimix (alprostadil, phentolamine, and papaverine), and inflatable penile prosthesis placement (IPP) and included respective risks of failure, subsequent interventions, and other complications (including priapism risk). Average model QALY estimates obtained from the literature were as follows: ED =0.56, successful alternate PDE5-I =0.70, successful ICI =0.70, and successful IPP =0.78. Cost data were calculated from a high-volume academic center and published manufacturer data.
RESULTS
Over the 10-year period, IPP placement was the most cost-effective management option per preserved QALY (QALY =7.82, cost =$22,009/10 years) as compared to ICI alprostadil (QALY =8.51, cost =$62,890/10 years), ICI trimix (QALY =8.47, cost =$48,617/10 years) and alternate PDE5-I (QALY =7.73, $52,883/10 years).
CONCLUSIONS
Using expert opinion and published utility, cost, and complication data in a decision analysis, we demonstrated that IPP placement is the most cost-effective ED intervention following failed initial PDE5-I over a 10-year period as compared to alternate treatment options. Such cost-effectiveness outcomes may be used in ED management counseling.
PubMed: 31555563
DOI: 10.21037/tau.2019.03.10