Effects of endothelin receptor blockade on hypervasoreactivity in streptozotocin-diabetic rats: vessel-specific involvement of thromboxane A2

2006 ◽  
Vol 84 (8-9) ◽  
pp. 823-833 ◽  
Author(s):  
Emi Arikawa ◽  
Claudia Cheung ◽  
Inna Sekirov ◽  
Mary L. Battell ◽  
Violet G. Yuen ◽  
...  
Keyword(s):  
Vascular Function ◽  
Acute Effect ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Receptor Blockade ◽  
Endothelin Receptor ◽  
Contractile Responses ◽  
In Vitro Incubation ◽  
Synthase Inhibitor

Increased vasoconstrictor response to norepinephrine (NE) and endothelin (ET)-1 in arteries from diabetic animals is ameliorated by chronic endothelin receptor blockade with bosentan and was absent in endothelium-denuded arteries, suggesting the involvement of ET-1 and an endothelium-derived contracting factor such as thromboxane A2 (TxA2). To examine this possibility, we determined the effects of acute blockade of ET receptors or inhibition of TxA2 synthesis on the vascular function of superior mesenteric arteries (SMA) and renal arteries (RA) isolated from nondiabetic and 11-week streptozotocin (STZ) diabetic rats chronically treated with either bosentan or vehicle. Both in vitro incubation with bosentan and a selective ETA receptor blocker, BQ123, eradicated the increase in NE contractile responses in diabetic SMA. Additionally, in vitro incubation with the thromboxane synthase inhibitor, dazmegrel, abrogated the exaggerated NE and ET-1 contractile responses in diabetic SMA. Conversely, in RA, no significant acute effect of bosentan, BQ123, nor dazmegrel on vascular responses to NE was observed. Dazmegrel incubation attenuated the maximum contractile responses to ET-1 in diabetic RA; however, these responses in diabetic RA remained significantly greater than those of other groups. Diabetic RA but not SMA exhibited an enhanced contractile response to the TxA2 analogue U46619, which was corrected by chronic bosentan treatment. Immunohistochemical analyses in diabetic SMA revealed an increase in ETA receptor level that was normalized by chronic bosentan treatment. These data indicate that an interaction between ET-1 and TxA2 may be involved in mediating the exaggerated vasoconstrictor responses in diabetic arteries. Furthermore, the underlying mechanisms appear to be vessel specific.

scholarly journals The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

2021 ◽  
Vol 22 (15) ◽  
pp. 7774
Author(s):  
Sevil Korkmaz-Icöz ◽  
Cenk Kocer ◽  
Alex A. Sayour ◽  
Patricia Kraft ◽  
Mona I. Benker ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Reperfusion Injury ◽  
Vascular Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Bypass ◽  
Diabetic Rats ◽  
Organ Bath ◽  
Sodium Glucose Cotransporter

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

Vascular responses to agonists in rat mesenteric artery from diabetic rats

1987 ◽  
Vol 65 (7) ◽  
pp. 1484-1490 ◽  
Author(s):  
Devendra K. Agrawal ◽  
John H. McNeill
Keyword(s):  
Diabetic Rats ◽  
Isometric Tension ◽  
Mesenteric Arteries ◽  
Diabetic Rat ◽  
Prostaglandin E ◽  
Contractile Responses ◽  
Alpha Adrenoceptor ◽  
Diabetic Model ◽  
Rat Mesenteric Artery ◽  
Adrenoceptor Agonists

The effect of diabetes on vascular smooth muscle function was investigated in the muscular arteries from spontaneously and chemically induced diabetic rats. Isolated ring segments of superior mesenteric arteries from BB diabetic and streptozotocin (STZ)-diabetic rats (12 weeks after onset of diabetes) were used for isometric tension studies. Contractile responses to alpha-adrenoceptor agonists (norepinephrine, methoxamine, phenylephrine, B-HT 920, guanabenz, SKF 89748-A), serotonin, and K+ were significantly higher in STZ-diabetic rat arteries as compared with the controls. In spontaneously diabetic rat arteries only the contractile responses to the putatively selective alpha2-adrenoceptor agonists, K+ and prostaglandin E1, were significantly increased. pD2 values of the agonists in both groups of diabetic arteries were not significantly different from the respective controls. Nifedipine inhibited all contractile responses in a dose-dependent fashion. The responses to K+ and alpha2-adrenoceptor agonists were attenuated to a greater extent by nifedipine in both groups of diabetic blood vessels. The calcium channel activator, BAY K 8644, produced a twofold increase in force of contraction in streptozotocin-diabetic and spontaneously diabetic rat arteries as compared with the responses in their respective controls. These results suggest caution in extrapolating all the findings from the streptozotocin-induced diabetic model to the spontaneously diabetic model. However, increased activity of calcium channels in vascular muscle cells in both groups of diabetics may be responsible, at least in part, for the increased vascular contractility in diabetes mellitus.

scholarly journals Aging Affects KV7 Channels and Perivascular Adipose Tissue-Mediated Vascular Tone

2021 ◽  
Vol 12 ◽  
Author(s):  
Yibin Wang ◽  
Fatima Yildiz ◽  
Andrey Struve ◽  
Mario Kassmann ◽  
Lajos Markó ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Vascular Function ◽  
Vascular Tone ◽  
Mesenteric Arteries ◽  
Aging Effects ◽  
Perivascular Adipose Tissue ◽  
Kcnq Channels ◽  
Age Related ◽  
Cardiovascular Morbidity And Mortality

Aging is an independent risk factor for hypertension, cardiovascular morbidity, and mortality. However, detailed mechanisms linking aging to cardiovascular disease are unclear. We studied the aging effects on the role of perivascular adipose tissue and downstream vasoconstriction targets, voltage-dependent KV7 channels, and their pharmacological modulators (flupirtine, retigabine, QO58, and QO58-lysine) in a murine model. We assessed vascular function of young and old mesenteric arteries in vitro using wire myography and membrane potential measurements with sharp electrodes. We also performed bulk RNA sequencing and quantitative reverse transcription-polymerase chain reaction tests in mesenteric arteries and perivascular adipose tissue to elucidate molecular underpinnings of age-related phenotypes. Results revealed impaired perivascular adipose tissue-mediated control of vascular tone particularly via KV7.3–5 channels with increased age through metabolic and inflammatory processes and release of perivascular adipose tissue-derived relaxation factors. Moreover, QO58 was identified as novel pharmacological vasodilator to activate XE991-sensitive KCNQ channels in old mesenteric arteries. Our data suggest that targeting inflammation and metabolism in perivascular adipose tissue could represent novel approaches to restore vascular function during aging. Furthermore, KV7.3–5 channels represent a promising target in cardiovascular aging.

Vascular responses to sodium nitroprusside in the human fetal-placental circulation

1995 ◽  
Vol 7 (6) ◽  
pp. 1557 ◽  
Author(s):  
MA Read ◽  
WB Giles ◽  
IM Leitch ◽  
AL Boura ◽  
WA Walters
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Function ◽  
No Production ◽  
Low Oxygen ◽  
Experimental Conditions ◽  
Arterial Perfusion ◽  
Basal Tone ◽  
Intra Uterine Growth Retardation ◽  
Synthase Inhibitor

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.

Abstract P267: Arbidol, A Targeted Covid-19 Therapy, Inhibited Contractile Responses To Phenylephrine In Mesenteric Arteries And Aortas Of Hypertensive Rats

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Olufunke O Arishe ◽  
Stephanie Wilczynski ◽  
Anna Thamasett ◽  
Clinton R Webb
Keyword(s):  
Lipid Membranes ◽  
Vascular Reactivity ◽  
Viral Infections ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Adrenergic Stimulation ◽  
Hypertensive Rats ◽  
Contractile Responses ◽  
Viral Attachment

Background: Hypertension is the most prevalent comorbidity of COVID-19 infection. This infection is caused by the severe acute respiratory syndrome coronavirus SARS-CoV-2. SARS-CoV-2 is a single-stranded RNA and could activate the endosomal Toll-like receptor 7 (TLR7), indicating a vital role of the receptor in its therapeutic target. Studies have reported that the lysosomotropic drug chloroquine has antihypertensive effects through its action on inhibiting the endosomal TLRs. Arbidol is a potential broad-spectrum antiviral used in the treatment of many viral infections including influenza. Arbidol prevents viral infection by interacting with aromatic acids; arbidol also binds to lipid membranes, altering the configuration of the cytoplasm or endosome. Wang et al., in 2020 reported that arbidol effectively inhibited the coronavirus SARS-CoV-2 in vitro by impeding viral attachment and release from the endolysosomes. Hypothesis: We hypothesized that arbidol would improve vascular reactivity in hypertension. Methods: We studied the effects of arbidol on the contractility of mesenteric resistance arteries (MRA) and aortas of male Wistar rats (20 weeks old, n=4) and spontaneously hypertensive rats (SHR) (20 weeks old, n=4) on a myograph by incubating the arterial rings with 10μM arbidol (Sigma, USA.) or vehicle (DMSO) for 30 mins. Statistical analysis was performed using nonlinear regression, and one- and two-way ANOVAs. Results: Arbidol (10 μM) impaired the contractile responses of MRA and aorta from normotensive and hypertensive rats to phenylephrine (PE). MRA Wistar: (pEC50 6.11 ± 0.15 vs 3.42 ± 0.38), SHR: (5.89 ± 0.19 vs 3.56 ± 0.19) and aorta Wistar: (pEC 50 7.49 ± 0.19 vs 5.97 ± 0.14), SHR (pEC50 7.14 ± 0.31 vs 4.41 ± 0.15). The arbidol-induced impaired contraction to PE was greater in the SHR aorta compared with the Wistar aorta. After washing out the drug, the arterial rings contracted to 120mM KCl at the same magnitude as the initial contraction to 120mM KCl. Conclusions: Our data demonstrate that arbidol impairs vascular contractile responses to α-adrenergic stimulation, with a greater response in the hypertensive rats. This indicates antihypertensive effects potentially through the regulation of TLR signaling.

Role of extracellular Ca2+ in the selective enhancement of contractile responses of arteries from diabetic rats to noradrenaline

1994 ◽  
Vol 72 (12) ◽  
pp. 1544-1551 ◽  
Author(s):  
Worku Abebe ◽  
Kim Howard Harris ◽  
Kathleen M. MacLeod
Keyword(s):  
Matched Control ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Percentage Change ◽  
Contractile Responses ◽  
Similar Percentage ◽  
Selective Enhancement ◽  
Channel Agonist

Maximum contractile responses of diabetic aortas incubated in the absence of extracellular Ca2+ to increasing Ca2+ (0.01–10 mM) in the presence of 1 μM noradrenaline, but not 40 mM KCl, were significantly increased compared with those of age-matched control rats. Maximum contractile responses of both aortas and mesenteric arteries from diabetic rats to noradrenaline, but not KCl, in the presence of extracellular Ca2+ (2.5 mM) were also significantly enhanced. The Ca2+ channel antagonists verapamil and nifedipine and the Ca2+ channel agonist BAY K8644 produced a similar percentage change in the magnitude of the noradrenaline response in arteries from both control and diabetic rats. These data confirm the selective nature of the enhancement of contractile responses of arteries from diabetic rats to noradrenaline and suggest that this may be mediated in part through enhanced noradrenaline-induced influx of extracellular Ca2+ through channels sensitive to the Ca2+ channel ligands. However, this does not appear to be the only explanation for the enhanced contractile responses of diabetic arteries to noradrenaline, since in the presence of maximum concentrations of nifedipine (3 μM) and verapamil (10μM), responses of diabetic arteries to noradrenaline were still greater than those of control arteries.Key words: diabetes, arteries, contractility, noradrenaline, extracellular Ca2+.

scholarly journals Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure

2006 ◽  
Vol 188 (3) ◽  
pp. 435-442 ◽  
Author(s):  
P W F Hadoke ◽  
R S Lindsay ◽  
J R Seckl ◽  
B R Walker ◽  
C J Kenyon
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Adult Female ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Female Rats ◽  
Control Group ◽  
Pregnant Rats ◽  
Vascular Contractility

Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 μg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12–16 weeks) of Dex-treated mothers (148.0 ± 3.6 mmHg, n=10) compared with the control group (138.0 ± 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 ± 3.6 mmHg) than in controls (135.3 ± 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

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