Endothelial Function In Mesenteric Arteries Research Articles

Functional Role of STIM-1 and Orai1 in Human Microvascular Aging.

The impact of aging on vascular function is heterogeneous depending on the vascular territories. Calcium regulation plays a key role in vascular function and has been implicated in aging-related hypercontractility of corpus cavernosum. We aimed to evaluate stromal interaction molecule (STIM)/Orai system involvement in aging-related vascular alterations in the human macro and microvasculature. Aortae specimens and mesenteric arteries (MA), obtained from 45 organ donors, were functionally evaluated in organ chambers and wire myographs. Subjects were divided into groups either younger or older than 65-years old. The expressions of STIM-1, Orai1, and Orai3 were determined by immunofluorescence in the aorta and MA, and by Western blot in the aorta homogenates. The inhibition of STIM/Orai with YM-58483 (20 μM) reversed adrenergic hypercontractility in MA from older subjects but did not modify aging-related hypercontractility in the aortic strips. Aging was related to an increased expression of Orai1 in human aorta, while Orai1 and STIM-1 were upregulated in MA. STIM-1 and Orai1 protein expressions were inversely correlated to endothelial function in MA. Circulating levels of Orai1 were correlated with the inflammatory factor TNF-α and with the endothelial dysfunction marker asymmetric dimethylarginine. Aging is associated with an increased expression of the STIM/Orai system in human vessels with functional relevance only in the microvascular territory, suggesting its role in aging-related microvascular dysfunction.

Contribution of perivascular adipose tissue to vascular dysfunction in obesity

Background and Aims: Perivascular adipose tissue (PVAT) has emerged as an active component of the blood vessel wall regulating vascular homeostasis. The main goal of this study was to investigate the effects of high-fat diet on PVAT and study its impact on endothelial function of mesenteric arteries of obese animal models.

Trans, trans-2,4-decadienal impairs vascular endothelial function by inducing oxidative/nitrative stress and apoptosis

Aldehydes are implicated in the development of hypertension. Trans, trans-2,4-decadienal (tt-DDE), a dietary α,β-unsaturated aldehyde, is widespread in many food products. However, the role of tt-DDE in the pathophysiology of hypertension remains unknown. This study was designed to investigate whether tt-DDE consumption evokes hypertension and to explore the mechanisms underlying such a role. Sprague-Dawley rats were administered different concentrations of tt-DDE. After 28 days, blood pressure and endothelial function of mesenteric arteries were measured. Results showed that tt-DDE treatment significantly increased blood pressure and impaired endothelial function based on endothelium-dependent vasorelaxation and p-VASP levels. Mechanistically, tt-DDE induced oxidative/nitrative stress in the arteries of rats as evidenced by overproductions of superoxide and peroxynitrite, accompanied with increased expressions of iNOS and gp91phox. To further investigate the effects of tt-DDE on endothelial cells and underlying mechanisms, human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of tt-DDE. tt-DDE induced oxidative/nitrative stress in HUVECs. Moreover, tt-DDE induced endothelial cells apoptosis through JNK-mediated signaling pathway. These results show, for the first time, that oral intake of tt-DDE elevates blood pressure and induces endothelial dysfunction in rats through oxidative/nitrative stress and JNK-mediated apoptosis signaling, indicating that excess ingestion of tt-DDE is a potential risk factor for endothelial dysfunction and hypertension.

FINERENONE REDUCES INTRINSIC ARTERIAL STIFFNESS IN A HYPERTENISVE NON-DIABETIC RAT MODEL OF CHRONIC KIDNEY DISEASE

Objective: Albuminuria development and arterial stiffness is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction in Munich Wistar Frömter (MWF) rats, a non-diabetic model of chronic kidney disease. We tested whether finerenone (FIN), a next-generation, oral, selective, and non-steroidal mineralocorticoid receptor antagonist, reduces arterial stiffness in this model. Design and method: Twelve-week-old MWF with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated for 4-weeks with FIN (10 mg/kg/day, once daily oral gavage) or with vehicle (control, C). Results: Intrinsic arterial stiffness is significantly increased in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN significantly lowered this phenotype in MWF-FIN compared to MWF-C, as observed from the lower βvalues obtained from the stress-strain relationship curve (βMWF-FIN = 7.7 ± 0.4 vs βMWF-C = 9.2 ± 0.5, p < 0.05). FIN also improved endothelial function in MA of MWF-FIN compared to MWF-C through an increase in nitric oxide bioavailability and a reduction in superoxide anion and hydrogen peroxide levels. Of interest, FIN led to an increase in fenestrae's area in the internal elastic lamina (+377%, p < 0.05). This was associated to a decrease in plasma MMP-2 and MMP-9 activity. Conclusions: FIN significantly reduces intrinsic arterial stiffness in MA from MWF rats. This is related to the enlargement of elastin fenestrae area, which may allow a better diffusion from endothelial factors to the underlying smooth muscle layer thereby improving endothelial function.

Adiponectin improves endothelial function in mesenteric arteries of rats fed a high-fat diet: role of perivascular adipose tissue.

Adiponectin, the most abundant peptide secreted by adipocytes, is involved in the regulation of energy metabolism and vascular physiology. Here, we have investigated the effects of exogenous administration of adiponectin on metabolism, vascular reactivity and perivascular adipose tissue (PVAT) of mesenteric arteries in Wistar rats fed a high-fat diet. The effects of adiponectin on NO-dependent and independent vasorelaxation were investigated in isolated mesenteric arteries from 12-month-old male Wistar rats (W12m) fed a high-fat diet (HFD) for 4months and compared with those from age-matched rats given a control diet. Adiponectin ((96μg·day-1 ) was administered by continuous infusion with a minipump, implanted subcutaneously, for 28days. Chronic adiponectin treatment reduced body weight, total cholesterol, free fatty acids, fasting glucose and area under the curve of intraperitoneal glucose tolerance test, compared with HFD rats. It also normalized NO-dependent vasorelaxation increasing endothelial NO synthase (eNOS) phosphorylation in mesenteric arteries of HFD rats. In PVAT from aged (W12m) and HFD rats there was increased expression of chemokines and pro-inflammatory adipokines, the latter being important contributors to endothelial dysfunction. Infusion of adiponectin reduced these changes. Adiponectin normalized endothelial cell function by a mechanism that involved increased eNOS phoshorylation and decreased PVAT inflammation. Detailed characterization of the adiponectin signalling pathway in the vasculature and perivascular fat is likely to provide novel approaches to the management of atherosclerosis and metabolic disease. This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Minimally Modified LDL-Induced Impairment of Endothelium-Dependent Relaxation in Small Mesenteric Arteries of Mice

Minimally modified low-density lipoprotein (mmLDL) is a well-known risk factor for cardiovascular diseases. The present study was designed to investigate the role of mmLDL in the endothelium-dependent relaxation of mouse mesenteric arteries. A sensitive myograph system was employed to examine the endothelial function of mesenteric arteries. mRNA and protein expression levels were determined using real-time PCR and Western blotting, respectively. The ultramicrostructure of mesenteric vascular beds was investigated using a transmission electron microscope. The results showed that mmLDL significantly impaired the acetylcholine-induced (3 × 10−¹⁰ to 1 × 10−⁴<smlcap>M</smlcap>) endothelium-dependent relaxation of mouse mesenteric arteries with markedly reduced pIC₅₀ (p < 0.05) and R_max values (p < 0.001). In addition, mmLDL increased the levels of superoxide production and nitrotyrosine concentration and impaired the endothelial microstructure with decreased K_Ca3.1 and K_Ca2.3 expression. In conclusion, mmLDL increases superoxide and nitrotyrosine levels, damages endothelial microstructure with decreased K_Ca3.1 and K_Ca2.3 expression, and ultimately attenuates relaxation mediated by nitric oxide- and endothelium-derived hyperpolarizing factor.

Sexual dimorphism in mesenteric arterial function of a novel rat model of type 2 diabetes, UC Davis‐Type 2 Diabetes Mellitus (UCD‐T2DM)

This is the first study to characterize the vascular functions in a well characterized and validated polygenic rat model of type 2 diabetes (UC Davis‐Type 2 Diabetes Mellitus, UCD‐T2DM), exhibiting etiology more similar to clinical T2DM in humans than other rodent models. The objectives of this study were to investigate whether 1) the endothelium‐dependent and ‐independent vasodilation in mesenteric arteries (MA) are impaired, 2) sex differences exist in the development of abnormal vascular responses, and 3) the relative contributions of endothelium derived relaxing factors in modulating vascular reactivity of MA is altered in UCD‐T2DM Rats.Endothelium‐dependent vasodilation to acetylcholine (ACh, 10−8 to 10−5 M) in pre‐contracted arteries with phenylephrine (PE, 2 μM) was measured before and after pre‐treatment with indomethacin (cyclooxygenase inhibitor, 10 μM), L‐NAME (nitric oxide synthase inhibitor, 200 μM), or barium chloride (KIR blocker, 100 μM) plus ouabain (Na+‐K+‐ATPase inhibitor, 10 μM). Vascular responses to sodium nitroprusside (SNP) (endothelium‐independent vasodilator, 10−9 to 10−5 M) and contractile agents such as PE (10−7 to 3×10−5 M) or endothelin‐1 (ET‐1, 10−10 to 10−7 M) were also determined.Both ACh‐ and SNP‐induced relaxation were significantly impaired in MA of diabetic rats, regardless of sex. However, the extent of impairment was greater in female diabetic rats compared to male diabetic animals. Diabetes also significantly increased sensitivity to PE or ET‐1 in females compared to males. Finally, the relative importance of endothelium‐derived hyperpolarizing factor (EDHF) to vascular regulation was lost in diabetic rats, regardless of sex.These data, for the first time, show that the endothelial function in MA of UCD‐T2DM Rats is impaired in both sexes, possibly due to the loss of EDHF, initially a major vasodilatory factor. Furthermore, we showed a greater predisposition of MA to injury in diabetic female rats, in part due to a higher sensitivity of female arteries to contractile agents.

Mechanism of vascular dysfunction due to circulating factors in women with pre-eclampsia.

Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in pre-eclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide (NO) and prostaglandin (PG) bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Responses to methacholine (MCh) were obtained using wire myography to assess endothelial function pathways. Vascular superoxide level was measured via dihydroethidium staining and nitric oxide synthase (NOS) expression via Western blots. PE plasma significantly increased superoxide levels and impaired endothelial dysfunction in uterine arteries (Emax 79.9±5.6% compared with 44.9±6.3%, P=0.0004), which was restored in the presence of oxidant scavengers or PG synthesis inhibition. Uterine artery vasodilation was abolished in the presence of pan-NOS inhibitor (P<0.0001) in both NP- and PE-treated vessels, but inducible nitric oxide synthase (iNOS)-dependent vasodilation was present only in NP-treated arteries. Uterine arteries exposed to PE plasma exhibit an increased endothelial NOS expression and a decreased iNOS expression. PE plasma did not alter endothelial function in mesenteric arteries, suggesting that the effect of circulating factors was vascular-bed-specific. We have shown that circulating factors lead to endothelial dysfunction via altered oxidative stress and vasodilator pathways. The present study contributes to our understanding of the pathophysiology and finding a potential target for intervention in PE.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Preserves Endothelial Function in Mesenteric Arteries from Type 1 Diabetic Rats without Decreasing Plasma Glucose

The aim of the study was to investigate the effect of the DPP-4 inhibitor linagliptin on the mechanism(s) of endothelium-dependent relaxation in mesenteric arteries from STZ-induced diabetic rats. Both normal and diabetic animals received linagliptin (2 mg/kg) daily by oral gavage for a period of 4 weeks. To measure superoxide generation in mesenteric arteries, lucigenin-enhanced chemiluminescence was used. ACh-induced relaxation of mesenteric arteries was assessed using organ bath techniques and Western blotting was used to investigate protein expression. Pharmacological tools (1μM TRAM-34, 1μM apamin, 100 nM Ibtx, 100 μM L-NNA, 10 μM ODQ) were used to distinguish between NO and EDH-mediated relaxation. Linagliptin did not affect plasma glucose, but did decrease vascular superoxide levels. Diabetes reduced responses to ACh but did not affect endothelium-independent responses to SNP. Linagliptin improved endothelial function indicated by a significant increase in responses to ACh. Diabetes impaired the contribution of both nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) to endothelium-dependent relaxation and linagliptin treatment significantly enhanced the contribution of both relaxing factors. Western blotting demonstrated that diabetes also increased expression of Nox2 and decreased expression and dimerization of endothelial NO synthase, effects that were reversed by linagliptin. These findings demonstrate treatment of type 1 diabetic rats with linagliptin significantly reduced vascular superoxide levels and preserved both NO and EDH-mediated relaxation indicating that linagliptin can improve endothelial function in diabetes independently of any glucose lowering activity.

Advanced glycation end products impair KCa3.1- and KCa2.3-mediated vasodilatation via oxidative stress in rat mesenteric arteries

The present study was designed to investigate the role of advanced glycation end products (AGEs) in intermediate-conductance and small-conductance Ca(2+)-activated potassium channels (KCa3.1 and KCa2.3)-mediated relaxation in rat resistance arteries and the underlying mechanism. The endothelial function of mesenteric arteries was assessed with the use of wire myography. Expression levels of KCa3.1 and KCa2.3 were measured by using Western blot. Reactive oxygen species (ROS) were measured by using dihydroethidium and 2', 7'-dichlorofluorescein diacetate. KCa3.1 and KCa2.3-mediated vasodilatation responses to acetylcholine and NS309 (opener of KCa3.1 and KCa2.3) were impaired by incubation of the third-order mesenteric arteries from normal rats with AGEs (200 μg ml(-1) for 3 h). In cultured human umbilical vein endothelial cells (HUVECs), AGEs increased ROS level and decreased the protein expression of KCa3.1 and KCa2.3. Antioxidant alpha lipoic acid restored the impairment in both vasodilatation function and expression of KCa3.1 and KCa2.3. H2O2 could mimic the effect of AGEs on the protein expression of KCa3.1 and KCa2.3 in cultured HUVECs. These results demonstrate for the first time that AGEs impaired KCa3.1 and KCa2.3-mediated vasodilatation in rat mesenteric arteries via downregulation of both KCa3.1 and KCa2.3, in which the enhanced oxidative stress was involved.

High blood pressure-lowering and vasoprotective effects of milk products in experimental hypertension

Milk casein-derived angiotensin-converting enzyme (ACE)-inhibitory tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to have antihypertensive effects in human subjects and to attenuate the development of hypertension in experimental models. The aim of the present study was to investigate the effect of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols on already established hypertension, endothelial dysfunction and aortic gene expression. Male spontaneously hypertensive rats (SHR) with baseline systolic blood pressure (SBP) of 195 mmHg were given either active milk (tripeptides and plant sterols), milk or water ad libitum for 6 weeks. SBP was measured weekly by the tail-cuff method. The endothelial function of mesenteric arteries was investigated at the end of the study. Aortas were collected for DNA microarray study (Affymetrix Rat Gene 1.0 ST Array). The main finding was that active milk decreased SBP by 16 mmHg compared with water (178 (SEM 3) v. 195 (SEM 3) mmHg; P < 0.001). Milk also had an antihypertensive effect. Active milk improved mesenteric artery endothelial dysfunction by NO-dependent and endothelium-derived hyperpolarising factor-dependent mechanisms. Treatment with active milk caused mild changes in aortic gene expression; twenty-seven genes were up-regulated and eighty-two down-regulated. Using the criteria for fold change (fc) < 0.833 or > 1.2 and P < 0.05, the most affected (down-regulated) signalling pathways were hedgehog, chemokine and leucocyte transendothelial migration pathways. ACE expression was also slightly decreased (fc 0.86; P = 0.047). In conclusion, long-term treatment with fermented milk enriched with tripeptides and plant sterols decreases SBP, improves endothelial dysfunction and affects signalling pathways related to inflammatory responses in SHR.

Heme oxygenase-1 induction restores high-blood-flow-dependent remodeling and endothelial function in mesenteric arteries of old rats

Aging is associated with reduced structural and functional adaptation to chronic changes in blood flow (shear stress) in small arteries. As heme oxygenase-1 (HO-1) is induced by hemodynamic forces in vascular smooth muscle and endothelial cells, we hypothesized that it might improve flow-dependent remodeling in aging. First-order mesenteric arteries from 3 and 16-month-old rats were exposed to high, low, or normal flow by alternate ligation in vivo. Rats were treated with the HO-1 inducer, cobalt protoporphyrin (CoPP, 5 mg/kg) or vehicle. 14 days later, local blood flow was measured in vivo, and arteries were studied in vitro. Despite an equivalent change in blood flow, diameter enlargement in the high-flow arteries was blunted in old compared to young rats and was associated with decreased endothelium-dependent relaxation to acetylcholine. In old rats, HO-1 induction with CoPP restored outward remodeling, via a paradoxical reactive oxygen species-dependent mechanism, and was associated with a Mn-superoxide dismutase (SOD) overexpression, as well as a significant reduction of mitochondrial aconitase activity, used as a biomarker for oxidative stress. The heme oxygenase activity inhibitor, Sn-protoporphyrin, and the SOD-mimetic, TEMPOL, prevented the effect of CoPP on remodeling and oxidative status in old rats. Furthermore, HO-1 induction improved endothelial function, in association with increased endothelial nitric oxide synthase protein expression and phosphorylation (Ser-1177). In low-flow arteries, inward remodeling was unaffected by aging or by CoPP. Thus, in old rats, CoPP-induced up-regulation of HO-1 restored high-flow-dependent remodeling (diameter enlargement) and improved endothelial function in mesenteric arteries. This opens new perspectives in the treatment of ischemic diseases in aging.

Impairment of both nitric oxide‐mediated and EDHF‐type relaxation in small mesenteric arteries from rats with streptozotocin‐induced diabetes

To investigate whether diabetes affects either or both nitric oxide (NO)-mediated and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation in endothelium-dependent relaxation of mesenteric arteries from streptozotocin-induced diabetic rats. Wire myography was employed to examine endothelial function of mesenteric arteries. Superoxide levels were measured by L-012 and lucigenin-enhanced chemiluminescence. Western blotting was used to quantify protein expression levels. Superoxide levels were significantly increased in diabetic mesenteric arteries compared with normal arteries. Diabetes significantly reduced the sensitivity to the endothelium-dependent relaxant, acetylcholine (ACh) in mesenteric arteries. When the contribution of NO to relaxation was abolished by N-nitro-L-arginine (L-NNA) + a soluble guanylate cyclase inhibitor (ODQ), the sensitivity to ACh was significantly decreased in the diabetic arteries compared with normal arteries, indicating an impaired EDHF-type relaxation despite increased expression of intermediate- and small-conductance calcium-activated potassium channels. Conversely, when the contribution of EDHF was inhibited with TRAM-34 + apamin + iberiotoxin, maximum relaxations to ACh were significantly decreased in diabetic compared with normal arteries, suggesting that the contribution of NO was also impaired by diabetes. Basal levels of NO release, indicated by contraction to L-NNA, were also significantly decreased in diabetic arteries. Western blot analysis demonstrated that diabetic arteries had an increased expression of Nox2, decreased pSer⁴⁷³ Akt and a reduced proportion of endothelial NO synthase (eNOS) expressed as a dimer, indicating uncoupling. The contribution of both NO and EDHF-type relaxations was impaired in diabetes and was caused by increased oxidative stress, decreased pSer⁴⁷³ Akt and/or eNOS uncoupling.

Atorvastatin Prevents Endothelial Dysfunction in Mesenteric Arteries From Spontaneously Hypertensive Rats

We investigated the effect of atorvastatin on cyclooxygenase (COX) contribution to endothelial dysfunction in spontaneously hypertensive rat (SHR) mesenteric resistance arteries. Atorvastatin (10 mg/kg per day, oral gavage) or its vehicle was administered for 2 weeks to male SHR or Wistar-Kyoto rats. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In Wistar-Kyoto rats, relaxation to acetylcholine was inhibited byNG-nitro-l-arginine methyl ester and unaffected by SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), or ascorbic acid. In SHRs, the response to acetylcholine was attenuated, less sensitive toNG-nitro-l-arginine methyl ester, unaffected by SC-560, and enhanced by DuP-697 or SQ-29548 (thromboxane-prostanoid receptor antagonist) to a similar extent. Endothelium-dependent relaxation was normalized by ascorbic acid or apocynin (NADPH oxidase inhibitor), which also restored the inhibition byNG-nitro-l-arginine methyl ester. In atorvastatin-treated SHRs, relaxation to acetylcholine was normalized, fully sensitive toNG-nitro-l-arginine methyl ester, and not affected by SC-560, DuP-697, SQ 29548, or antioxidants. Dihydroethidium assay showed an increased intravascular superoxide generation in SHRs, which was abrogated by atorvastatin. RT-PCR revealed a COX-2 induction in SHR arteries, which was downregulated by atorvastatin. The release of prostacyclin and 8-isoprostane was higher from SHR than Wistar-Kyoto mesenteric vessels. COX-2 inhibition and apocynin decreased 8-isoprostane without affecting prostacyclin levels. Atorvastatin increased phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS1177, and inducible NO synthase levels in SHR mesenteric vessels and decreased 8-isoprostane release. In conclusion, COX-2-derived 8-isoprostane contributes to endothelial dysfunction in SHR mesenteric arteries. Atorvastatin restores NO availability by increasing phosphorylated extracellular signal-regulated kinase 1/2, pAkt, peNOS1177, and inducible NO synthase levels and by abrogating vascular NADPH oxidase-driven superoxide production, which also results in a downregulation of COX-2-dependent 8-isoprostane generation.

Cyclooxygenase-1 Is Involved in Endothelial Dysfunction of Mesenteric Small Arteries From Angiotensin II–Infused Mice

Angiotensin II induces endothelial dysfunction by reducing NO availability and increasing reactive oxygen species. We assessed whether cyclooxygenase (COX)-1 or COX-2 participate in the angiotensin II-induced endothelial dysfunction in murine mesenteric small arteries and examined the role of reduced nicotinamide-adenine dinucleotide phosphate-dependent reactive oxygen species production. Mice received angiotensin II (600 ng/kg per minute, SC), saline (controls), angiotensin II + apocynin (reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, 2.5 mg/day), or apocynin alone for 2 weeks. Endothelial function of mesenteric arteries was assessed by pressurized myograph. In controls, acetylcholine-induced relaxation was inhibited by NG-monomethyl-L-arginine and unaffected by DFU (COX-2 inhibitor), SC-560 (COX-1 inhibitor), or ascorbic acid. In angiotensin II-infused animals, the attenuated response to acetylcholine was less sensitive to NG-monomethyl-L-arginine, unaffected by DFU, and enhanced by SC-560 and, similarly, by SQ-29548, a thromboxane-prostanoid receptor antagonist. Moreover, response to acetylcholine was unchanged by ozagrel, a thromboxane synthase inhibitor, and normalized by ascorbic acid. Apocynin prevented the angiotensin II-induced vascular dysfunctions. In angiotensin II-infused mice, RT-PCR analysis showed a significant COX-2 downregulation, whereas COX-1 expression was upregulated. These changes were unaffected by apocynin. Modulation of COX isoform by angiotensin II was also documented by immunohistochemistry. In small mesenteric vessels, the reduced NO availability and oxidant excess, which characterize endothelial dysfunction secondary to angiotensin II, are associated with a reduced COX-2 and an increased COX-1 function and expression. Angiotensin II causes an oxidative stress-independent COX-1 overexpression, whereas angiotensin II-mediated oxidant excess production stimulates COX-1 activity to produce a contracting prostanoid endowed with agonist activity on thromboxane-prostanoid receptors.

Genetic modification of vascular endothelial function as therapeutic strategy in heart failure

in patients with chronic heart failure, endothelial dysfunction contributes to increased systemic vascular resistance, decreased exercise tolerance, and reduced tissue perfusion. One of the better-characterized mechanisms responsible for endothelial dysfunction is the increased production of

Effects of chronic vitamin E deficiency on vascular function ‐ a study of sympathetic nerves, smooth muscle and endothelium of the mesenteric arterial bed of the rat

1. Male rats were deprived as weanlings of dietary vitamin E for 2, 4, 6, 10 and 12 months. Mesenteric arterial beds from these rats and from age-matched controls were isolated and perfused with Krebs solution at a constant flow rate (5 ml min-1). The function of perivascular sympathetic nerves, smooth muscle and endothelium was assessed. 2. At 12 months vitamin E deficient rats exhibited the characteristic symptoms of vitamin E deficiency, namely poor coat condition, muscle wasting, kyphoscoliosis and impaired gait. In the isolated mesenteric arterial bed electrical field stimulation (EFS) of perivascular nerves (4-32 Hz, 90 V, 1 ms, for 30 s) elicited frequency-dependent vasoconstrictor responses which were unaffected by vitamin E deficiency except at 12 months, at which age responses were significantly greater than those of the controls at 24 and 32 Hz (P < 0.01). 3. Exogenous noradrenaline (NA; 0.15-500 nmol) elicited dose-dependent vasoconstriction which was similar in vitamin E-deficient and control preparations at all ages. Potassium chloride (0.15 mmol) also produced similar vasoconstrictor responses in vitamin E-deficient and control preparations at each age. 4. Tone of the preparations was raised by continuous perfusion with methoxamine (4-70 microM), producing similar increases in perfusion pressure in vitamin E-deficient and control preparations at each age. Endothelium-dependent dose-dependent vasodilatation to adenosine 5'-triphosphate was significantly impaired in mesenteric arterial beds from 12 month-old vitamin E-deficient rats compared with the controls (P < 0.05). Relaxation to acetylcholine was not significantly different at any age. 5. Endothelium-independent vasodilatation to sodium nitroprusside was similar in vitamin E-deficient rats and age-matched controls. 6. These results suggest that long term (12 months) deprivation of dietary vitamin E may impair endothelial function in mesenteric arteries of the rat. Sympathetic perivascular nerve constrictor function was increased at 12 months. There were no functionally expressed changes in the vascular smooth muscle, which appears to be more resilient to the effects of oxidative stress in vitamin E deficiency.

Salt-induced hypertension in the dog

ARTICLESSalt-induced hypertension in the dogJA VogelJA VogelPublished Online:01 Jan 1966https://doi.org/10.1152/ajplegacy.1966.210.1.186MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByNutritional Management for Dogs and Cats with Chronic Kidney DiseaseVeterinary Clinics of North America: Small Animal Practice, Vol. 51, No. 3Weight-gain induced changes in renal perfusion assessed by contrast-enhanced ultrasound precede increases in urinary protein excretion suggestive of glomerular and tubular injury and normalize after weight-loss in dogs21 April 2020 | PLOS ONE, Vol. 15, No. 4The time course of salt-induced hypertension, and why it matters15 December 2008 | International Journal of Obesity, Vol. 32, No. S6High-salt diet and responses of the pressurized mesenteric artery of the dog to noradrenaline and acetylcholineClinical and Experimental Pharmacology and Physiology, Vol. 31, No. 10Change in endothelial function in mesenteric arteries of sprague‐dawley rats fed a high salt diet1 August 2002 | The Journal of Physiology, Vol. 543, No. 1The Mechanism of Sodium-Dependent Low Renin HypertensionMechanism, prevention and therapy of sodium-dependent hypertensionThe American Journal of Medicine, Vol. 69, No. 5Unproved HypothesesNew England Journal of Medicine, Vol. 299, No. 9The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertensionThe American Journal of Medicine, Vol. 64, No. 2The Toxicity of Salt26 September 2008 | CRC Critical Reviews in Toxicology, Vol. 5, No. 4High sodium-low potassium environment and hypertensionThe American Journal of Cardiology, Vol. 38, No. 6Experimental Induction of HypertensionRecent developments in electro-organic synthesisDie Naturwissenschaften, Vol. 56, No. 8Physiologie und Pathologie des Renin/Angiotensin-Systems More from this issue > Volume 210Issue 1January 1966Pages 186-190 Copyright & PermissionsCopyright © 1966 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1966.210.1.186PubMed5903139History Published online 1 January 1966 Published in print 1 January 1966 Metrics