Opioids Cause Sex-Specific Vascular Changes via Cofilin-Extracellular Signal-Regulated Kinase Signaling: Female Mice Present Higher Risk of Developing Morphine-Induced Vascular Dysfunction than Male Mice

2021 ◽  
pp. 1-11
Author(s):  
Soyoung Cheon ◽  
Jeremy C. Tomcho ◽  
Jonnelle M. Edwards ◽  
Nicole R. Bearss ◽  
Emily Waigi ◽  
...  
Keyword(s):  
Vascular Dysfunction ◽  
Actin Dynamics ◽  
Male Mice ◽  
Resistance Arteries ◽  
Opioid Use ◽  
Female Mice ◽  
Extracellular Signal ◽  
Increased Risk ◽  
Vascular Age ◽  
Pulmonary Arterial

Recent studies have shown that chronic use of prescription or illicit opioids leads to an increased risk of cardiovascular events and pulmonary arterial hypertension. Indices of vascular age and arterial stiffness are also shown to be increased in opioid-dependent patients, with the effects being more marked in women. There are currently no studies investigating sex-specific vascular dysfunction in opioid use, and the mechanisms leading to opioid-induced vascular damage remain unknown. We hypothesized that exposure to exogenous opioids causes sex-specific vascular remodeling that will be more pronounced in female. Acknowledging the emerging roles of cofilins and extracellular signal-regulated kinases (ERKs) in mediating actin dynamics, we investigated the effects of morphine on these molecules. Twenty-four hour exposure to morphine increased inactivated cofilin and activated ERKs in resistance arteries from female mice, which may promote stress fiber over-assembly. We also performed continuous intraluminal infusion of morphine in pressurized resistance arteries from male and female mice using culture pressure myographs. We observed that morphine reduced the vascular diameter in resistance arteries from female, but not male mice. These results have significant implications for the previously unexplored role of exogenous opioids as a modifiable cardiovascular risk factor, especially in women.

Abstract MP59: Soluble Protein Oligomers Induce Endoplasmic Reticulum Stress In Mesenteric Resistance Arteries From Male And Female Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Emily W Waigi ◽  
Thaddaeus R Castaneda ◽  
Nicole R Bearss ◽  
Jonnelle M Edwards ◽  
David R Giovannucci ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular System ◽  
Vascular Dysfunction ◽  
Amyloid Β ◽  
Positive Control ◽  
Resistance Arteries ◽  
Male And Female ◽  
Female Mice ◽  
Antibody Staining

Amyloid β proteins, including toxic soluble oligomers (SPOs) are not only found in the brain duringAlzheimer’s, but also in the peripheral vascular system. The precise mechanism linking increasedcirculating levels of SPOs and vascular dysfunction remains unknown. We hypothesized that SPOslead to endoplasmic reticulum (ER) stress, further release of SPOs and vascular injury. Mesentericresistance arteries (MRAs) from 14 weeks old, male and female C57BL/6 mice were used forvascular function. Agonists were acetylcholine and phenylephrine (1nM-10mM). In acuteconditions, SPOs (0.1μM) caused pathologically exacerbated endothelium-dependent vasodilationcompared to vehicle (F12 media) [Male: EC50: SPOs: -7.0 ± 0.1 (n=4), vs. Vehicle -6.6 ± 0.1 (n=7)p=0.03; Female: EC50: SPOs: -7.3 ± 0.06 (n=5) vs. Vehicle -6.7 ± 0.1 (n=6), p=0.001]. Thisphenotype was similar to the positive control tunicamycin (5mg/ml) [Male: EC50: Tunicamycin: -7.3(n=4), vs. Vehicle -6.6 (n=7) p=0.2; Female: EC50: Tunicamycin: -7.7 (n=4) vs. Vehicle -6.8 (n=5)p=0.04]. To determine whether SPO’s cause ER stress, arteries were treated with ER stressinhibitor 4-Phenylbutyric acid (2mM). The ER stress inhibitor prevented the exacerbatedvasodilation induced by SPOs showing SPOs trigger ER stress in acute conditions independent ofsex. To determine whether SPOs are a consequence of ER stress, arteries were incubated withtunicamycin in the presence of the SPO inhibitor K01-162 (10mM). Interestingly, K01-162 did notprevent the tunicamycin-induced exacerbated vasodilation in arteries from male mice. However,this response was decreased in arteries from female mice showing that inducing ER stress leadsto the release of SPOs, escalating a feed-forward mechanism of further SPO release. There wereno changes in vascular contraction with tunicamycin or SPOs irrespective of sex. ER stress wasconfirmed with anti-KDEL antibody staining, specific for ER resident chaperones Grp78/94 andvisualized with multiphoton fluorescent confocal microscopy. These results demonstrate that SPO’sexacerbate endothelium-dependent vasodilation acutely and may contribute to brain and peripheralvascular edema and loss of autoregulation observed during cardiovascular and Alzheimer’sdisease.

scholarly journals Adulthood Deficiency of the Insulin-like Growth Factor-1 Receptor in Hippocampal Neurons Impairs Cell Structure and Spatial Learning and Memory in Male and Not Female Mice

2021 ◽  
Author(s):  
Cellas A Hayes ◽  
Erik L Hodges ◽  
Jessica P Marshall ◽  
Sreemathi Logan ◽  
Julie A Farley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Hippocampal Neurons ◽  
Spatial Learning And Memory ◽  
Insulin Like Growth Factor ◽  
Male Mice ◽  
Female Mice ◽  
Learning Impairments ◽  
Increased Risk

Reductions in insulin-like growth factor-1 (IGF-1) are associated with cognitive impairment and increased risk of neurodegenerative disease in advanced age. In mouse models, reduced IGF-1 early-in-life leads to memory impairments and synaptic dysfunction; however, these models are limited by systemic reductions in IGF-1. We hypothesized that IGF-1 continues to promote hippocampal neuron structure and function after development, and as such, the loss of IGF-1 signaling in adult neurons would lead to impaired spatial learning and memory. To test this, the IGF-1 receptor (IGF-1R) was genetically targeted in hippocampal neurons of adult male and female mice. Male mice deficient in neuronal IGF-1R exhibited spatial learning impairments as evidenced by increased pathlength and errors in the radial arm water maze. No differences in learning and memory were observed in female mice. Golgi-Cox staining revealed a reduced number of dendritic boutons of neurons the CA1 region of the hippocampus in male mice. Decreased MAPK and increased ROCK activity were also observed in these tissues. In vitro studies revealed that impaired neurite outgrowth due to inhibited IGF-1R signaling could be rescued by pharmacological inhibitors of ROCK. However, ROCK inhibition in neuronal IGF-1R deficient mice did not fully rescue learning impairments or bouton numbers. Together, our study highlights that IGF-1 continues to support spatial learning and memory and neuronal structure in adulthood.

Four-Corner Arthrodesis versus Proximal Row Carpectomy: Risk Factors and Complications Associated with Prolonged Postoperative Opioid Use

2020 ◽  
Author(s):  
Neill Y. Li ◽  
Alexander S. Kuczmarski ◽  
Andrew M. Hresko ◽  
Avi D. Goodman ◽  
Joseph A. Gil ◽  
...  
Keyword(s):  
Risk Factors ◽  
International Classification Of Diseases ◽  
Opioid Use ◽  
Proximal Row Carpectomy ◽  
Use Patterns ◽  
Patient Demographics ◽  
Implant Complications ◽  
Increased Risk ◽  
Classification Of Diseases

Abstract Introduction This article compares opioid use patterns following four-corner arthrodesis (FCA) and proximal row carpectomy (PRC) and identifies risk factors and complications associated with prolonged opioid consumption. Materials and Methods The PearlDiver Research Program was used to identify patients undergoing primary FCA (Current Procedural Terminology [CPT] codes 25820, 25825) or PRC (CPT 25215) from 2007 to 2017. Patient demographics, comorbidities, perioperative opioid use, and postoperative complications were assessed. Opioids were identified through generic drug codes while complications were defined by International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification codes. Multivariable logistic regressions were performed with p < 0.05 considered statistically significant. Results A total of 888 patients underwent FCA and 835 underwent PRC. Three months postoperatively, more FCA patients (18.0%) continued to use opioids than PRC patients (14.7%) (p = 0.033). Preoperative opioid use was the strongest risk factor for prolonged opioid use for both FCA (odds ratio [OR]: 4.91; p < 0.001) and PRC (OR: 6.33; p < 0.001). Prolonged opioid use was associated with an increased risk of implant complications (OR: 4.96; p < 0.001) and conversion to total wrist arthrodesis (OR: 3.55; p < 0.001) following FCA. Conclusion Prolonged postoperative opioid use is more frequent in patients undergoing FCA than PRC. Understanding the prevalence, risk factors, and complications associated with prolonged postoperative opioid use after these procedures may help physicians counsel patients and implement opioid minimization strategies preoperatively.

scholarly journals Predictors of Chronic Opioid Use: A Population-level Analysis of North Carolina Cancer Survivors Using Multi-Payer Claims

2021 ◽  
Author(s):  
Devon K Check ◽  
Christopher D Bagett ◽  
KyungSu Kim ◽  
Andrew W Roberts ◽  
Megan C Roberts ◽  
...  
Keyword(s):  
North Carolina ◽  
Substance Use ◽  
Cancer Survivors ◽  
Low Income ◽  
Opioid Therapy ◽  
Adjusted Relative Risk ◽  
Opioid Use ◽  
Chronic Opioid Therapy ◽  
Increased Risk ◽  
Chronic Opioid Use

Abstract Background No population-based studies have examined chronic opioid use among cancer survivors who are diverse with respect to diagnosis, age group, and insurance status. Methods We conducted a retrospective cohort study using North Carolina (NC) cancer registry data linked with claims from public and private insurance (2006–2016). We included adults with non-metastatic cancer who had no prior chronic opioid use (N = 38,366). We used modified Poisson regression to assess the adjusted relative risk of chronic opioid use in survivorship (&gt;90-day continuous supply of opioids in the 13–24 months following diagnosis) associated with patient characteristics. Results Only 3.0% of cancer survivors in our cohort used opioids chronically in survivorship. Predictors included younger age (adjusted risk ratio [aRR], 50–59 vs 60–69 = 1.23, 95% confidence interval [CI] = 1.05–1.43), baseline depression (aRR = 1.22, 95% CI = 1.06–1.41) or substance use (aRR = 1.43, 95% CI = 1.15–1.78) and Medicaid (aRR vs Private = 1.93, 95% CI = 1.56–2.40). Survivors who used opioids intermittently (vs not at all) before diagnosis were twice as likely to use opioids chronically in early survivorship (aRR = 2.62, 95% CI = 2.28–3.02). Those who used opioids chronically (vs intermittently or not at all) during active treatment had a nearly 17-fold increased likelihood of chronic use in survivorship (aRR = 16.65, 95 CI = 14.30–19.40). Conclusions Younger and low-income survivors, those with baseline depression or substance use, and those who require chronic opioid therapy during treatment are at increased risk for chronic opioid use in survivorship. Our findings point to opportunities improve assessment of psychosocial histories and to engage patients in shared decision-making around long-term pain management, when chronic opioid therapy is required during treatment.

scholarly journals Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation

2021 ◽  
Vol 22 (5) ◽  
pp. 2291
Author(s):  
Paul Marczynski ◽  
Myriam Meineck ◽  
Ning Xia ◽  
Huige Li ◽  
Daniel Kraus ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lupus Erythematosus ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Intima Media Thickness ◽  
Leukocytic Infiltration ◽  
Increased Risk ◽  
Altered Immune Status ◽  
Inflammatory Autoimmune Disease ◽  
Excellent Tool

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6−/− MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. Results: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. Conclusion: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

scholarly journals Online Opioid Stewardship Training for Long-Term Care Staff

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 533-533
Author(s):  
Linda Edelman ◽  
Troy Andersen ◽  
Cherie Brunker ◽  
Nicholas Cox ◽  
Jorie Butler ◽  
...  
Keyword(s):  
Staff Training ◽  
Long Term Care ◽  
Treatment Strategies ◽  
Care Staff ◽  
Video Content ◽  
Opioid Use ◽  
Term Care ◽  
Increased Risk ◽  
Pain Management Strategy

Abstract Opioids are often the first-line chronic pain management strategy for long-term care (LTC) residents who are also at increased risk for opioid-related adverse events. Therefore, there is a need to train LTC providers and staff about appropriate opioid use and alternative treatment strategies. Our interdisciplinary team worked with LTC partners to identify staff educational needs around opioid stewardship. Based on this need’s assessment, we developed eight modules about opioid use and risks for older adults, including those with dementia, recommendations for de-prescribing including other pharmacological and non-pharmacological alternatives, SBIRT, and motivational interviewing to determine “what matters”. Each 20-minute module contains didactic and video content that is appropriate for group staff training or individuals and provides rural LTC facilities access to needed training in their home communities. Within the first month of launching online, the program received over 1100 hits and LTC partners are incorporating modules into clinical staff training schedules.

scholarly journals Preconceptional Resveratrol Supplementation Partially Counteracts Age-Related Reproductive Complications in C57BL/6J Female Mice

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1934
Author(s):  
Marta Ziętek ◽  
Katarzyna Barłowska ◽  
Barbara Wijas ◽  
Ewa Szablisty ◽  
Atanas G. Atanasov ◽  
...  
Keyword(s):  
Drinking Water ◽  
Animal Models ◽  
Mating Success ◽  
Pregnancy Outcomes ◽  
Pregnancy Complications ◽  
Polyphenolic Compound ◽  
Female Mice ◽  
Age Related ◽  
Increased Risk ◽  
Anti Oxidant

Aging is associated with a drastic decline in fertility/fecundity and with an increased risk of pregnancy complications. Resveratrol (RES), a natural polyphenolic compound, has shown anti-oxidant and anti-inflammatory activities in both human and animal models, thus representing a potential therapeutic and prophylactic anti-aging supplement. Here, we investigated whether preconceptional resveratrol supplementation improved reproductive outcomes in mid-aged (8-month-old) and old (12-month-old) C57BL/6J female mice. Female siblings were cohoused and assigned to either RES or vehicle supplementation to drinking water for 10 consecutive weeks. Subsequently, females were mated with non-supplemented males and their pregnancy outcomes were monitored. RES improved mating success in old, but not in mid-aged females, and prevented the occurrence of delivery complications in the latter. These results indicate that preconceptional RES supplementation could partially improve age-related reproductive complications, but it was not sufficient to restore fecundity in female mice at a very advanced age.

scholarly journals Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

2019 ◽  
Vol 317 (4) ◽  
pp. F890-F905 ◽  
Author(s):  
Autumn N. Harris ◽  
Hyun-Wook Lee ◽  
Lijuan Fang ◽  
Jill W. Verlander ◽  
I. David Weiner
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Collecting Duct ◽  
Ammonia Excretion ◽  
Volume Density ◽  
Male Mice ◽  
Ammonia Metabolism ◽  
Female Mice ◽  
Predominant Component ◽  
Acid Load ◽  
Acid Loading

Renal ammonia excretion is a critical component of acid-base homeostasis, and changes in ammonia excretion are the predominant component of increased net acid excretion in response to metabolic acidosis. We recently reported substantial sex-dependent differences in basal ammonia metabolism that correlate with sex-dependent differences in renal structure and expression of key proteins involved in ammonia metabolism. The purpose of the present study was to investigate the effect of sex on the renal ammonia response to an exogenous acid load. We studied 4-mo-old C57BL/6 mice. Ammonia excretion, which was less in male mice under basal conditions, increased in response to acid loading to a greater extent in male mice, such that maximal ammonia excretion did not differ between the sexes. Fundamental structural sex differences in the nonacid-loaded kidney persisted after acid loading, with less cortical proximal tubule volume density in the female kidney than in the male kidney, whereas collecting duct volume density was greater in the female kidney. To further investigate sex-dependent differences in the response to acid loading, we examined the expression of proteins involved in ammonia metabolism. The change in expression of phosphoenolpyruvate carboxykinase and Rh family B glycoprotein with acid loading was greater in male mice than in female mice, whereas Na+-K+-2Cl– cotransporter and inner stripe of the outer medulla intercalated cell Rh family C glycoprotein expression were significantly greater in female mice than in male mice. There was no significant sex difference in glutamine synthetase, Na+/H+ exchanger isoform 3, or electrogenic Na+-bicarbonate cotransporter 1 variant A protein expression in response to acid loading. We conclude that substantial sex-dependent differences in the renal ammonia response to acid loading enable a similar maximum ammonia excretion response.

THE EFFECTS OF SPECIES, STRAIN AND SEX IN THYMOLYTIC TESTS OF BETAMETHASONE, DEXAMETHASONE AND OTHER STEROIDS

1962 ◽  
Vol 25 (1) ◽  
pp. 77-85 ◽  
Author(s):  
R. M. ATKINSON ◽  
M. A. PRATT ◽  
E. G. TOMICH
Keyword(s):  
Route Of Administration ◽  
Relative Potency ◽  
Male Mice ◽  
Female Mice ◽  
Betamethasone And Dexamethasone

SUMMARY Cortisol, prednisolone phosphate and the free alcohols and 21-phosphates of betamethasone and dexamethasone have been compared for thymolytic activity by the oral and subcutaneous routes in both sexes of two strains of rats and two strains of mice. The relative potency of betamethasone and dexamethasone differed with the route of administration and the sex, strain and species of animal employed. In female mice of the A2G strain, betamethasone was as potent as dexamethasone; in male mice of this strain, and in both sexes of GFF mice, WAG rats and PVG rats, betamethasone was much less potent than dexamethasone.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

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