Effects of ticagrelor, empagliflozin and tamoxifen against experimentally-induced vascular reactivity defects in rats in vivo and in vitro

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

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Current Trends in the Pharmacotherapy of Cataracts

Pharmaceuticals ◽

10.3390/ph13010015 ◽

2020 ◽

Vol 13 (1) ◽

pp. 15 ◽

Cited By ~ 2

Author(s):

Segewkal H. Heruye ◽

Leonce N. Maffofou Nkenyi ◽

Neetu U. Singh ◽

Dariush Yalzadeh ◽

Kalu K. Ngele ◽

...

Keyword(s):

Low Income ◽

Ex Vivo ◽

Radical Scavenging ◽

Antioxidant Defense System ◽

Enzymatic Antioxidants ◽

Repair Mechanisms ◽

Blurry Vision ◽

Experimentally Induced

Cataracts, one of the leading causes of preventable blindness worldwide, refers to lens degradation that is characterized by clouding, with consequent blurry vision. As life expectancies improve, the number of people affected with cataracts is predicted to increase worldwide, especially in low-income nations with limited access to surgery. Although cataract surgery is considered safe, it is associated with some complications such as retinal detachment, warranting a search for cheap, pharmacological alternatives to the management of this ocular disease. The lens is richly endowed with a complex system of non-enzymatic and enzymatic antioxidants which scavenge reactive oxygen species to preserve lens proteins. Depletion and/or failure in this primary antioxidant defense system contributes to the damage observed in lenticular molecules and their repair mechanisms, ultimately causing cataracts. Several attempts have been made to counteract experimentally induced cataract using in vitro, ex vivo, and in vivo techniques. The majority of the anti-cataract compounds tested, including plant extracts and naturally-occurring compounds, lies in their antioxidant and/or free radical scavenging and/or anti-inflammatory propensity. In addition to providing an overview of the pathophysiology of cataracts, this review focuses on the role of various categories of natural and synthetic compounds on experimentally-induced cataracts.

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Peripheral vascular neuroeffector mechanisms in experimental cholestasis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.265.3.g579 ◽

1993 ◽

Vol 265 (3) ◽

pp. G579-G586 ◽

Cited By ~ 1

Author(s):

G. Jacob ◽

O. Said ◽

J. Finberg ◽

A. Bomzon

Keyword(s):

Electrical Stimulation ◽

Bile Duct ◽

Vascular Reactivity ◽

Bile Duct Ligation ◽

Norepinephrine Uptake ◽

Pithed Rats ◽

Duct Ligation ◽

Adrenoceptor Agonists

Jaundiced patients have systemic hypotension and are more susceptible to hemorrhagic shock than nonjaundiced individuals. We have hypothesized that the mechanism whereby these cardiovascular complications arise is linked to a disturbance of the vascular neuroeffector process in the cardiovascular system. With the use of 3-day bile duct-manipulated (sham-operated) and bile duct-ligated rats, we have evaluated alpha-adrenoceptor function and amine uptake using in vivo and in vitro techniques. Blunted pressor responsiveness to norepinephrine, electrical stimulation, and the alpha 1-adrenoceptor agonists, methoxamine and phenylephrine, was observed in the bile duct-ligated pithed rats. In contrast, normal responsiveness to BHT-933 and clonidine, the alpha 2-adrenoceptor agonists, was seen in these animals. The uptake 1 blocker, cocaine, caused potentiation of equal magnitudes of the pressor responsiveness to electrical stimulation and norepinephrine in the sham-operated and bile duct-ligated pithed rats. In aortic rings prepared from the bile duct-ligated rats, blunted in vitro vascular reactivity to norepinephrine and the same alpha 1-adrenoceptor agonists was seen. Bile duct ligation had no effect on norepinephrine uptake or its kinetics in stressed and unstressed arterial rings and portal veins. We have thus concluded that bile duct ligation induces a defect in the functional expression of cardiovascular alpha 1-adrenoceptors without any effects on the activity of alpha 2-adrenoceptors or norepinephrine uptake.

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Fludrocortisone and Hydrocortisone, Alone or in Combination, on In Vivo Hemodynamics and In Vitro Vascular Reactivity in Normal and Endotoxemic Rats

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000072 ◽

2014 ◽

Vol 63 (6) ◽

pp. 488-496 ◽

Cited By ~ 5

Author(s):

Bruno Laviolle ◽

Nicolas Nesseler ◽

Catherine Massart ◽

Eric Bellissant

Keyword(s):

Vascular Reactivity

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Vascular reactivity and endothelial NOS activity in rat thoracic aorta during and after hyperbaric oxygen exposure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00145.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1988-H1998 ◽

Cited By ~ 22

Author(s):

Jonas Hink ◽

Stephen R. Thom ◽

Ulf Simonsen ◽

Inger Rubin ◽

Erik Jansen

Keyword(s):

Catalytic Activity ◽

Polyethylene Glycol ◽

Hyperbaric Oxygen ◽

Vascular Reactivity ◽

Superoxide Production ◽

No Production ◽

Enos Activity ◽

No Bioavailability

Accumulating evidence suggests that hyperbaric oxygen (HBO) stimulates neuronal nitric oxide (NO) synthase (NOS) activity, but the influence on endothelial NOS (eNOS) activity and vascular NO bioavailability remains unclear. We used a bioassay employing rat aortic rings to evaluate vascular NO bioavailability. HBO exposure to 2.8 atm absolute (ATA) in vitro decreased ACh relaxation. This effect remained unchanged, despite treatment with SOD-polyethylene glycol and catalase-polyethylene glycol, suggesting that the reduction in endothelium-derived NO bioavailability was independent of superoxide production. In vitro HBO induced contraction of resting aortic rings with and without endothelium, and these contractions were reduced by the NOS inhibitor Nω-nitro-l-arginine. In addition, in vitro HBO attenuated the vascular contraction produced by norepinephrine, and this effect was reversed by Nω-nitro-l-arginine, but not by endothelial denudation. These findings indicate stimulation of extraendothelial NO production during HBO exposure. A radiochemical assay was used to assess NOS activity in rat aortic endothelial cells. Catalytic activity of eNOS in cell homogenates was not decreased by HBO, and in vivo HBO exposure to 2.8 ATA was without effect on eNOS activity and/or vascular NO bioavailability in vitro. We conclude that HBO reduces endothelium-derived NO bioavailability independent of superoxide production, and this effect seems to be unrelated to a decrease in eNOS catalytic activity. In addition, HBO increases the resting tone of rat aortic rings and attenuates the contractile response to norepinephrine by endothelium-independent mechanisms that involve extraendothelial NO production.

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Experimentally induced hip dislocation dislocation in vitro and in vivo

Acta Orthopaedica Scandinavica ◽

10.3109/17453678309154168 ◽

1983 ◽

Vol 54 (sup199) ◽

pp. 1-57 ◽

Cited By ~ 4

Author(s):

Stefan Asplund ◽

Åke Hjelmstedt

Keyword(s):

Hip Dislocation ◽

Experimentally Induced

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Effect of pioglitazone on vascular reactivity in vivo and in vitro

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.3.r660 ◽

1996 ◽

Vol 270 (3) ◽

pp. R660-R666 ◽

Cited By ~ 4

Author(s):

T. A. Kotchen ◽

H. Y. Zhang ◽

S. Reddy ◽

R. G. Hoffmann

Keyword(s):

Adipose Tissue ◽

Glucose Uptake ◽

Vascular Function ◽

Vascular Reactivity ◽

Sprague Dawley ◽

Vasoactive Agents ◽

Sprague Dawley Rats ◽

Pressor Responses

Pioglitazone (a thiazolidinedione derivative) increases insulin sensitivity and prevents hypertension in the Dahl-salt-sensitive (S) rat. The present study was undertaken to determine if pioglitazone modulates pressor responsiveness to vasoactive agents, both in vivo and in vitro. In vivo, pretreatment with pioglitazone inhibited (P < 0.02) pressor responses to both norepinephrine and angiotensin II in conscious Dahl-S, but not in Sprague-Dawley rats. In vitro, pioglitazone augmented the capacity of insulin to inhibit pressor responses of strips of thoracic aortas to norepinephrine, but not to angiotensin. Additionally, in vitro, incubation with insulin plus pioglitazone augmented acetylcholine-induced, but not nitroprusside-induced vasodilation. Pioglitazone pretreatment increased (P < 0.001) in vitro insulin-stimulated glucose uptake in adipose tissue, but not in thoracic aortas of Dahl-S. We hypothesize that pioglitazone attenuates hypertension by modulating the effects of insulin on vascular function, resulting in both blunted vasoconstriction and augmented acetylcholine-induced vasodilation. These alterations are not accounted for by an effect of pioglitazone on glucose uptake by vascular smooth muscle.

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Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis

Cellular and Molecular Immunology ◽

10.1038/s41423-020-00591-7 ◽

2021 ◽

Author(s):

Amir Boufenzer ◽

Kevin Carrasco ◽

Lucie Jolly ◽

Benjamin Brustolin ◽

Elisa Di-Pillo ◽

...

Keyword(s):

Vascular Reactivity ◽

Myeloid Cell ◽

Neutrophil Extracellular Trap ◽

Toll Like Receptor 4 ◽

Genetic Ablation ◽

Experimental Septic Shock ◽

Net Release

AbstractDuring sepsis, neutrophil activation induces endothelial cell (EC) dysfunction partly through neutrophil extracellular trap (NET) release. The triggering receptor expressed on myeloid cell-1 (TREM-1) is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4 (TLR4) engagement. Although the key role of TLR4 signaling in NETosis is known, the role of TREM-1 in this process has not yet been investigated. Here, we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure. In contrast, pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo. Moreover, isolated NETs were able to activate ECs and impair vascular reactivity, and these deleterious effects were dampened by TREM-1 inhibition. TREM-1 may, therefore, constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.

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Abstract 34: Statins Directly Activate Erk5 and Reduce Endothelial Dysfunction and Acute Allograft Rejection

Circulation Research ◽

10.1161/res.111.suppl_1.a34 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Yuichiro Takei ◽

Nhat-Tu Le ◽

Hakjoo Lee ◽

Kyung-Sun Heo ◽

Cheryl Hurley ◽

...

Keyword(s):

Allograft Rejection ◽

High Throughput Screening ◽

Transcriptional Activity ◽

Vascular Reactivity ◽

Pleiotropic Effects ◽

Protective Effects ◽

Acute Allograft Rejection

Rationale: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are principal therapeutic agents for the treatment of hypercholesteremia. Statins, however, appear to also exert cholesterol-independent pleiotropic effects, such as improvement of endothelial (EC) function, stabilization of fibrous plaques, and decrease vascular inflammation. It is now well established that statins are beneficial in the prevention of cardiovascular disease and also widely used for suppressing cardiac allograft rejection. Previously, we have reported anti-inflammatory effect of ERK5 kinase in ECs. Methods and Results: In this study, we screened small molecules that activate ERK5 using high throughput screening, and identified statins as strong activators of the transcriptional activity of ERK5. In particular, we have found that pitavastatin increases ERK5 transcriptional activity, KLF2 promoter activity, and eNOS mRNA expression in ECs. These effects are abolished by the depletion of ERK5, but not its direct upstream kinase, MEK5. In addition, pitavastatin directly and dose-dependently activates ERK5 kinase activity in an in vitro kinase reaction assay, suggesting that ERK5 is a direct target of this statin. To examine the functional role of EC ERK5 activation by the statin in vivo, we utilized inducible endothelial ERK5 knock out (EC-ERK5-KO) mice and evaluated the effect of pitavastatin on EC function and acute allograft rejection. Depletion of ERK5 in ECs resulted in significant EC inflammation and dysfunction in vivo. Although pitavastatin reduced leukocyte rolling and vascular reactivity in mesebteruc microvessels of diabetic mice and prolonged allograft survival in a full allomismatch combination model, these protective effects were lost in EC-ERK5-KO mice. Conclusion: These data suggest the crucial role of ERK5 in pleiotropic effects of statins on EC dysfunction and allograft rejection in vivo.

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