Comparison of Adrenergic and Purinergic Receptor Contributions to Vasomotor Responses in Mesenteric Arteries of C57BL/6J Mice and Wistar Rats

2020 ◽  
Vol 58 (1) ◽  
pp. 1-15
Author(s):  
Astha Mittal ◽  
Peter D. Park ◽  
Ray Mitchell ◽  
Hanwei Fang ◽  
Pooneh Bagher
Keyword(s):  
Wistar Rats ◽  
Purinergic Receptor ◽  
Electrical Field Stimulation ◽  
Mesenteric Arteries ◽  
Platinum Electrodes ◽  
Third Order ◽  
Organ Systems ◽  
Perivascular Nerves ◽  
Selection For ◽  
Arteriolar Tone

<b><i>Introduction:</i></b> The sympathetic nervous system can modulate arteriolar tone through release of adenosine triphosphate and norepinephrine, which bind to purinergic and adrenergic receptors (ARs), respectively. The expression pattern of these receptors, as well as the composition of neurotransmitters released from perivascular nerves (PVNs), can vary both in organ systems within and across species, such as mice and rats. <b><i>Objective:</i></b> This study explores the function of α<sub>1A</sub> subtypes in mouse and rat third-order mesenteric arteries and investigates PVN-mediated vasoconstriction to identify which neurotransmitters are released from sympathetic PVNs. <b><i>Methods:</i></b> Third-order mesenteric arteries from male C57BL/6J mice and Wistar rats were isolated and mounted on a wire myograph for functional assessment. Arteries were exposed to phenylephrine (PE) and then incubated with either α<sub>1A</sub> antagonist RS100329 (RS) or α<sub>1D</sub> antagonist BMY7378, before reexposure to PE. Electrical field stimulation was performed by passing current through platinum electrodes positioned adjacent to arteries in the absence and presence of a nonspecific alpha AR blocker phentolamine and/or P2X<sub>1</sub>-specific purinergic receptor blocker NF449. <b><i>Results:</i></b> Inhibition of α<sub>1</sub> ARs by RS revealed that PE-induced vasoconstriction is primarily mediated through α<sub>1A</sub> and that the contribution of the α<sub>1A</sub> AR is greater in rats than in mice. In the mouse model, sympathetic nerve-mediated vasoconstriction is mediated by both ARs and purinergic receptors, whereas in rats, vasoconstriction appeared to only be mediated by ARs and a nonpurinergic neurotransmitter. Further, neither model demonstrated that α<sub>1D</sub> ARs play a significant role in PE-mediated vasoconstriction. <b><i>Conclusions:</i></b> The mesenteric arteries of male C57BL/6J mice and Wistar rats have subtle differences in the signaling mechanisms used to mediate vasoconstriction. As signaling pathways in humans under physiological and pathophysiological conditions become better defined, the current study may inform animal model selection for preclinical studies.

scholarly journals P2X1 receptors mediate sympathetic postjunctional Ca2+ transients in mesenteric small arteries

2006 ◽  
Vol 291 (6) ◽  
pp. H3106-H3113 ◽  
Author(s):  
Christine Lamont ◽  
C. Vial ◽  
R. J. Evans ◽  
W. G. Wier
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Electrical Field Stimulation ◽  
Muscle Cells ◽  
Sympathetic Nerves ◽  
Mesenteric Arteries ◽  
P2x Receptor ◽  
Small Arteries ◽  
Perivascular Nerves ◽  
Intracellular Ca

Brief, spatially localized Ca2+ transients occur in the smooth muscle adjacent to perivascular nerves of small arteries during neurogenic contractions. We named these “junctional Ca2+ transients” (jCaTs) and postulated that they arose from Ca2+ entering smooth muscle cells through P2X1 receptors activated by neurally released ATP. Nevertheless, the lack of potent, subtype-selective P2X-receptor antagonists made determining the exact molecular identity of the channels difficult. Here we used small, pressurized mesenteric arteries from P2X1-receptor-deficient mice (KO) to test the hypothesis that jCaTs arise from Ca2+ entering the smooth muscle cell via P2X1 receptors. In wild-type (WT) arteries, confocal microscopy of fluo-4 fluorescence during electrical field stimulation (EFS) of perivascular sympathetic nerves revealed jCaTs in the smooth muscle cells adjacent to the perivascular nerves, similar to those reported previously in rat arteries, and α-latrotoxin (2.5 nM) markedly increased the frequency of “spontaneous” jCaTs. In the KO arteries, however, neither EFS nor α-latrotoxin elicited any jCaTs. A potent P2X-receptor agonist, α,β-methylene ATP (10.0 μM), elicited strong contractions and increased intracellular Ca2+ concentration in WT arteries but elicited neither in KO arteries. A biphasic vasoconstriction in response to EFS was observed in WT arteries. In KO arteries, however, the initial rapid, transient component of the biphasic vasoconstriction was absent. The data support the hypothesis that jCaTs represent Ca2+ that enters the smooth muscle cells through P2X1 receptors activated by neurally released ATP and that this Ca2+ is involved in the initial rapid component of the sympathetic neurogenic contraction.

scholarly journals A Blunted Sympathetic Function and an Enhanced Nitrergic Activity Contribute to Reduce Mesenteric Resistance in Hyperthyroidism

2021 ◽  
Vol 22 (2) ◽  
pp. 570
Author(s):  
Laia Cros-Brunsó ◽  
Laura Camacho-Rodríguez ◽  
Ángel Martínez-González ◽  
Pablo Llévenes ◽  
Mercedes Salaices ◽  
...  
Keyword(s):  
Citrate Synthase ◽  
Purinergic Receptor ◽  
Body Weight Gain ◽  
Electrical Field Stimulation ◽  
Alpha Adrenoceptor ◽  
Adrenoceptor Antagonist ◽  
Sympathetic Function ◽  
Vasoconstrictor Response ◽  
Relevant Role ◽  
Male Wistar Rats

We aimed to determine whether an experimental model of hyperthyroidism could alter the function of sympathetic and nitrergic components of mesenteric innervation. For this purpose, male Wistar rats were divided into (1) control rats (CT) and (2) rats infused with L-Thyroxine (HT). Body weight gain and adipose tissue accumulation were lower in HT rats, while systolic blood pressure and citrate synthase activity in the soleus muscle were increased by HT. In segments from the superior mesenteric artery, the application of an electrical field stimulation (EFS) induced a vasoconstrictor response, which was lower in arteries from HT animals. The alpha-adrenoceptor antagonist phentolamine diminished EFS-induced vasoconstriction to a lower extent in HT arteries, while the purinergic receptor antagonist suramin reduced contractile response to EFS only in segments from CT. In line with this, noradrenaline release, tyrosine hydroxylase expression and activation and dopamine β hydroxylase expression were diminished in HT. The unspecific nitric oxide synthase (NOS) inhibitor L-NAME increased EFS-induced vasoconstriction more markedly in segments from HT rats. NO release was enhanced in HT, probably due to an enhancement in neuronal NOS activity, in which a hyperactivation of both PKC and PI3K-AKT signaling pathways might play a relevant role. In conclusion, perivascular mesenteric innervation might contribute to reduce the vascular resistance observed in hyperthyroidism.

scholarly journals Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

2018 ◽  
Vol 19 (12) ◽  
pp. 3942 ◽  
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Jiangning Yang ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Mesenteric Arteries ◽  
Vascular Contraction ◽  
Gk Rats ◽  
Vasoconstrictor Response

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

Dexamethasone decreases neuronal nitric oxide release in mesenteric arteries from hypertensive rats through decreased protein kinase C activation

2009 ◽  
Vol 117 (8) ◽  
pp. 305-312 ◽  
Author(s):  
Rosa Aras-López ◽  
Fabiano E. Xavier ◽  
Mercedes Ferrer ◽  
Gloria Balfagón
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Glucocorticoid Receptors ◽  
Electrical Field Stimulation ◽  
Mesenteric Arteries ◽  
Hypertensive Rats ◽  
Pkc Inhibitor ◽  
Kinase C ◽  
No Release ◽  
Wistar Kyoto

Neuronal NO plays a functional role in many vascular tissues, including MAs (mesenteric arteries). Glucocorticoids alter NO release from endothelium and the CNS (central nervous system), but no results from peripheral innervation have been reported. In the present study we investigated the effects of dexamethasone on EFS (electrical field stimulation)-induced NO release in MAs from WKY (Wistar–Kyoto) rats and SHRs (spontaneously hypertensive rats) and the role of PKC (protein kinase C) in this response. In endothelium-denuded MAs, L-NAME (NG-nitro-L-arginine methyl ester) increased the contractile response to EFS only in segments from SHRs. EFS-induced contraction was reduced by 1 μmol/l dexamethasone in segments from SHRs, but not WKY rats, and this effect was abolished in the presence of dexamethasone. EFS induced a tetrodotoxin-resistant NO release in WKY rat MAs, which remained unchanged by 1 μmol/l dexamethasone. In SHR MAs, dexamethasone decreased basal and EFS-induced neuronal NO release, and this decrease was prevented by the glucocorticoid receptor antagonist mifepristone. Dexamethasone did not affect nNOS [neuronal NOS (NO synthase)] expression in either strain. In SHR MAs, incubation with calphostin C (a non-selective PKC inhibitor), Gö6983 (a classic PKC δ and ζ inhibitor), LY379196 (a PKCβ inhibitor) or PKCζ-PI (PKCζ pseudosubstrate inhibitor) decreased both basal and EFS-induced neuronal NO release. Additionally, PKC activity was reduced by dexamethasone. The PKC inhibitor-induced reduction in NO release was unaffected by dexamethasone. In conclusion, results obtained in the present study indicate that PKC activity positively modulates the neuronal NO release in MAs from SHRs. They also reveal that by PKC inhibition, through activation of glucocorticoid receptors, dexamethasone reduces neuronal NO release in these arteries.

scholarly journals A Bayesian Model for Prediction of Rheumatoid Arthritis from Risk Factors

2020 ◽  
Author(s):  
Leon Lufkin ◽  
Marko Budišić ◽  
Sumona Mondal ◽  
Shantanu Sur
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Predictive Model ◽  
Characteristic Curve ◽  
Strong Association ◽  
Autoimmune Disorder ◽  
Mixed Data ◽  
Validation Dataset ◽  
Third Order ◽  
Organ Systems

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that typically manifests as destructive joint inflammation but also affects multiple other organ systems. The pathogenesis of RA is complex where a variety of factors including comorbidities, demographic, and socioeconomic variables are known to influence the incidence and progress of the disease. In this work, we aimed to predict RA from a set of 11 well-known risk factors and their interactions using Bayesian logistic regression. We considered up to third-order interactions between the risk factors and implemented factor analysis of mixed data (FAMD) to account for both the continuous and categorical natures of these variables. The predictive model was further optimized over the area under the receiver operating characteristic curve (AUC) using a genetic algorithm (GA). We use data from the National Health and Nutrition Examination Survey (NHANES). Our optimal predictive model has a smoothed AUC of 0.826 (95% CI: 0.801 −0.850) on a validation dataset and 0.805 (95% CI: 0.781 −0.829) on a holdout test dataset. Our model identified multiple second- and third-order interactions that demonstrate a strong association with RA, implying the potential role of risk factor interactions in the disease mechanism. Interestingly, we find that the inclusion of higher-order interactions in the model only marginally improves overall predictive ability. Our findings on the contribution of RA risk factors and their interaction on disease prediction could be useful in developing strategies for early diagnosis of RA, thus opening potential avenues for improved patient outcomes and reduced healthcare burden to society.

scholarly journals Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly

2020 ◽  
Vol 40 (5) ◽  
pp. 1207-1219 ◽  
Author(s):  
Jennifer van der Horst ◽  
Rian W. Manville ◽  
Katie Hayes ◽  
Morten B. Thomsen ◽  
Geoffrey W. Abbott ◽  
...  
Keyword(s):  
Preventive Intervention ◽  
Ex Vivo ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Benzoquinone Imine ◽  
Kv7 Channels ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Perivascular Nerves ◽  
Life Threatening

Objective: Intravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation. Conclusions: Direct and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.

Orthotropic patterns of Pasternak foundation in smart vibration analysis of magnetostrictive nanoplate

2015 ◽  
Vol 230 (4) ◽  
pp. 559-572 ◽  
Author(s):  
A Ghorbanpour Arani ◽  
Z Khoddami Maraghi ◽  
H Khani Arani
Keyword(s):  
Automotive Industry ◽  
Deformation Theory ◽  
Dimensional Space ◽  
Differential Quadrature Method ◽  
Shear Deformation Theory ◽  
Stability Factor ◽  
Pasternak Foundation ◽  
Third Order ◽  
Motion Equations ◽  
Selection For

In this research, free vibration of rectangular nanoplate made of magnetostrictive materials is studied while it is focused on elastic medium as an efficient stability factor. For this purpose, Pasternak foundation is developed by considering orthotropy angle where the effect of Pasternak shear modulus is investigated in different directions. Since the nanoplate is subjected to the coil, a feedback control system follows the effects of uniform magnetic field on vibration characteristics of magnetostrictive nanoplate. So, Reddy’s third-order shear deformation theory along with Eringen’s nonlocal continuum model are utilized in order to derive motion equations at nanoscale using Hamilton’s principle. Five coupled motion equations solved by differential quadrature method in two-dimensional space by considering different boundary conditions. Results indicate that with appropriative selection for orthotropy angle, normal, and shear Pasternak foundation modulus, it is possible to achieve optimal and desire values to more stability of magnetostrictive nanoplate. These findings can be used in automotive industry, communications equipment in nano- and microstructures.

scholarly journals A Bayesian Model to Analyze the Association of Rheumatoid Arthritis With Risk Factors and Their Interactions

2021 ◽  
Vol 9 ◽  
Author(s):  
Leon Lufkin ◽  
Marko Budišić ◽  
Sumona Mondal ◽  
Shantanu Sur
Keyword(s):  
Rheumatoid Arthritis ◽  
Risk Factors ◽  
Characteristic Curve ◽  
Strong Association ◽  
Mixed Data ◽  
Validation Dataset ◽  
Individual Risk ◽  
Third Order ◽  
Cross Sectional ◽  
Organ Systems

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that commonly manifests as destructive joint inflammation but also affects multiple other organ systems. The pathogenesis of RA is complex where a variety of factors including comorbidities, demographic, and socioeconomic variables are known to associate with RA and influence the progress of the disease. In this work, we used a Bayesian logistic regression model to quantitatively assess how these factors influence the risk of RA, individually and through their interactions. Using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), a set of 11 well-known RA risk factors such as age, gender, ethnicity, body mass index (BMI), and depression were selected to predict RA. We considered up to third-order interactions between the risk factors and implemented factor analysis of mixed data (FAMD) to account for both the continuous and categorical natures of these variables. The model was further optimized over the area under the receiver operating characteristic curve (AUC) using a genetic algorithm (GA) with the optimal predictive model having a smoothed AUC of 0.826 (95% CI: 0.801–0.850) on a validation dataset and 0.805 (95% CI: 0.781–0.829) on a holdout test dataset. Apart from corroborating the influence of individual risk factors on RA, our model identified a strong association of RA with multiple second- and third-order interactions, many of which involve age or BMI as one of the factors. This observation suggests a potential role of risk-factor interactions in RA disease mechanism. Furthermore, our findings on the contribution of RA risk factors and their interactions to disease prediction could be useful in developing strategies for early diagnosis of RA.

scholarly journals Vasomotor action of androgens in the mesenteric artery of hypertensive rats. Role of perivascular innervation

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246254
Author(s):  
Lucía Isidoro-García ◽  
Diva M. Villalpando ◽  
Mercedes Ferrer
Keyword(s):  
Mesenteric Artery ◽  
Electrical Field Stimulation ◽  
Mesenteric Arteries ◽  
Hypertensive Rats ◽  
No Donor ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Vasomotor Function ◽  
Wistar Kyoto ◽  
And Function

Androgens may exert cardiovascular protective actions by regulating the release and function of different vascular factors. In addition, testosterone (TES) and its 5-reduced metabolites, 5α- and 5β-dihydrotestosterone (5α- and 5β-DHT) induce vasorelaxant and hypotensive effects. Furthermore, hypertension has been reported to alter the release and function of the neurotransmitters nitric oxide (NO), calcitonin gene-related peptide (CGRP) and noradrenaline (NA). Since the mesenteric arteries possess a dense perivascular innervation and significantly regulate total peripheral vascular resistance, the objective of this study was to analyze the effect of TES, 5α- and 5β-DHT on the neurogenic release and vasomotor function of NO, CGRP and NA. For this purpose, the superior mesenteric artery from male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats was used to analyze: (i) the effect of androgens (10 nM, incubated for 30 min) on the neurogenic release of NO, CGRP and NA and (ii) the vasoconstrictor-response to NA and the vasodilator responses to the NO donor, sodium nitroprusside (SNP) and exogenous CGRP. The results showed that TES, 5α- or 5β-DHT did not modify the release of NO, CGRP or NA induced by electrical field stimulation (EFS) in the arteries of SHR; however, in the arteries of WKY rats androgens only caused an increase in EFS-induced NO release. Moreover, TES, and especially 5β-DHT, increased the vasodilator response induced by SNP and CGRP in the arteries of SHR. These findings could be contributing to the hypotensive/antihypertensive efficacy of 5β-DHT previously described in conscious SHR and WKY rats, pointing to 5β- DHT as a potential drug for the treatment of hypertension.

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