A combination of genistein and magnesium enhances the vasodilatory effect via an eNOS pathway and BKCa current amplification

2015 ◽  
Vol 93 (4) ◽  
pp. 215-221 ◽  
Author(s):  
Lina Sun ◽  
Yunlong Hou ◽  
Tingting Zhao ◽  
Shanshan Zhou ◽  
Xiaoran Wang ◽  
...  
Keyword(s):  
Vascular Tone ◽  
Isometric Force ◽  
Mesenteric Arteries ◽  
Combined Effects ◽  
Vasodilatory Effect ◽  
Nos Inhibitor ◽  
Current Amplification ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation ◽  
Patch Clamp Method

The phytoestrogen genistein (GST) and magnesium have been independently shown to regulate vascular tone; however, their individual vasodilatory effects are limited. The aim of this study was to examine the combined effects of GST plus magnesium on vascular tone in mesenteric arteries. The effects of pretreatment with GST (0–200 μmol/L), MgCl2 (0–4.8 mmol/L) and GST plus MgCl2 on 10 μmol/L phenylephrine (PE) precontracted mesenteric arteries in rats were assessed by measuring isometric force. BKCa currents were detected by the patch clamp method. GST caused concentration- and partial endothelium-dependent relaxation. Magnesium resulted in dual adjustment of vascular tone. Magnesium-free solution eliminated the vasodilatation of GST in both endothelium-intact and denuded rings. GST (50 μmol/L) plus magnesium (4.8 mmol/L) caused stronger relaxation in both endothelium-intact and denuded rings. Pretreatment with the nitric oxide synthase (NOS) inhibitor l-N-nitroarginine methyl ester (l-NAME, 100 μmol/L) significantly inhibited the effects of GST, high magnesium, and the combination of GST and magnesium. BKCa currents were amplified to a greater extent when GST (50 μmol/L) was combined with 4.8 versus 1.2 mmol/L Mg2+. Our data suggest that GST plus magnesium provides enhanced vasodilatory effects in rat mesenteric arteries compared with that observed when either is used separately, which was related to an eNOS pathway and BKCa current amplification.

Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

2002 ◽  
Vol 283 (3) ◽  
pp. H893-H898 ◽  
Author(s):  
Stephen J. Armstrong ◽  
Yunlong Zhang ◽  
Ken G. Stewart ◽  
Sandra T. Davidge
Keyword(s):  
Nitric Oxide ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Estrogen Replacement ◽  
Aged Rat ◽  
Arterial Relaxation ◽  
Prostaglandin H ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Endothelium Dependent Relaxation

The reduction in estrogen in postmenopausal women contributes to an increase in vascular dysfunction. Models of aging have shown that this is due, in part, to increased prostaglandin H synthase (PGHS)-dependent vasoconstriction. We showed previously that inducible PGHS-2-dependent vasoconstriction is increased with aging. In the present study, we hypothesized that estrogen suppresses PGHS-2-dependent constriction in the aged rat. Isolated mesenteric arteries from placebo- or estrogen-treated, ovariectomized aged (24 mo) Fisher rats were assessed for endothelium-dependent relaxation in the absence or presence of PGHS inhibitors. PGHS inhibition (meclofenamate, 1 μmol/l) enhanced methacholine-induced relaxation only in the placebo group. Specific PGHS-2 inhibition (NS-398, 10 μmol/l) increased arterial relaxation to a greater extent than PGHS-1 inhibition (valeryl salicylate, 3 mmol/l). Estrogen prevented the PGHS-dependent constrictor effect but did not enhance nitric oxide-dependent relaxation in this model. PGHS-1 and endothelial nitric oxide synthase were not altered by estrogen, whereas PGHS-2 expression was decreased in the estrogen-replaced rats ( P < 0.05). In summary, estrogen replacement improved vasodilation in aged rats by decreasing PGHS-dependent constriction.

scholarly journals Changing standard chow diet promotes vascular NOS dysfunction in Dahl S rats

2012 ◽  
Vol 302 (1) ◽  
pp. R150-R158 ◽  
Author(s):  
Frank T. Spradley ◽  
Dao H. Ho ◽  
Kyu-Tae Kang ◽  
David M. Pollock ◽  
Jennifer S. Pollock
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Methyl Ester ◽  
Mesenteric Arteries ◽  
Chow Diet ◽  
Small Arteries ◽  
Standard Chow Diet ◽  
Small Resistance ◽  
Nos Inhibitor ◽  
Oxide Synthase

We hypothesized that vascular nitric oxide synthase (NOS) function and expression is differentially regulated in adult Dahl salt-sensitive rats maintained on Teklad or American Institutes of Nutrition (AIN)-76A standard chow diets from 3 to 16 wk old. At 16 wk old, acetylcholine (ACh)-mediated vasorelaxation and phenylephrine (PE)-mediated vasoconstriction in the presence and absence of NOS inhibitor, Nω-nitro-l-arginine methyl ester (l-NAME), was assessed in small-resistance mesenteric arteries and aortas. Rats maintained on either diet throughout the study had similar responses to ACh and PE in the presence or absence of l-NAME in both vascular preparations. We reasoned that changing from one diet to another as adults may induce vascular NOS dysfunction. In the absence of l-NAME, small arteries from Teklad-fed rats switched to AIN-76 diet and vice versa had similar responses to ACh and PE. Small-arterial NOS function was maintained in rats switched to AIN-76A from Teklad diet, whereas NOS function in response to ACh and PE was lost in the small arteries from rats changed to Teklad from AIN-76A diet. This loss of NOS function was echoed by reduced expression of NOS3, as well as phosphorylated NOS3. The change in NOS phenotype in the small arteries was observed without changes in blood pressure. Aortic responses to ACh or PE in the presence or absence of l-NAME were similar in all diet groups. These data indicate that changing standard chow diets leads to small arterial NOS dysfunction and reduced NOS signaling, predisposing Dahl salt-sensitive rats to vascular disease.

Abstract 380: Notch4 Uncouples Endothelial Nitric Oxide Synthase Leading to Arteriovenous Malformations

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Lawrence Huang ◽  
Matthew A Nystoriak ◽  
Ji Youn Youn ◽  
Manuel F Navedo ◽  
Hua Cai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Notch Signaling ◽  
Endothelial Nitric Oxide Synthase ◽  
Vascular Tone ◽  
Superoxide Production ◽  
Nos Inhibitor ◽  
Av Shunt ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Notch is distinctively expressed in arterial but not venous endothelial cells. Notch signaling regulates arteriovenous (AV) specification, and mutations in Notch signaling lead to AV malformation (AVM) in mice. AVMs are characterized by abnormal AV shunts that displace capillaries. Mechanisms underlying AVM pathogenesis remain poorly understood, hindering therapeutic development. We reported that endothelial expression of constitutively active Notch4 (Notch4*) in mice initiates AVMs de novo through enlargement of microvessels without an increase in endothelial cell number or proliferation. Here, we hypothesized that Notch4* disrupts endothelial nitric oxide synthase (eNOS) signaling and vascular tone, thereby permitting vessel enlargement and AV shunting. We show that arteries isolated from Notch4* mutant mice exhibited decreased arterial tone compared to controls, suggesting that Notch4* impaired vascular tone. Administering the NOS inhibitor N G -nitro-L-arginine abolished Notch4*-mediated vascular tone impairment. Deletion of the eNOS gene and administration of the NOS inhibitor N G -nitro-L-arginine in the Notch4* mutant mice attenuated Notch4*-induced AVM initiation, measured by decreased AV shunt diameter, delayed AV shunting, reduced hemorrhage, pathological lesions, and improved survival, suggesting that eNOS is essential for Notch4* action. In addition, uncoupled eNOS-derived superoxide production was elevated in the Notch4* mice. Our results show that inhibition of eNOS signaling attenuates Notch4*-mediated AVM formation. Furthermore, Notch4* impairs eNOS activity, leading to superoxide production, which results in arterial dysfunction and AV shunt formation.

Do cholinergic nerves innervating rat mesenteric arteries regulate vascular tone?

2012 ◽  
Vol 303 (11) ◽  
pp. R1147-R1156 ◽  
Author(s):  
Panot Tangsucharit ◽  
Shingo Takatori ◽  
Pengyuan Sun ◽  
Yoshito Zamami ◽  
Mitsuhiro Goda ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Vascular Tone ◽  
Mesenteric Arteries ◽  
Cholinergic Innervation ◽  
Adrenergic Nerve ◽  
Frequency Dependent ◽  
Nitric Oxide Synthase Inhibitor ◽  
6 Hydroxydopamine ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Vascular blood vessels have various types of cholinergic acetylcholine receptors (AChR), but the source of ACh has not been confirmed. Perivascular adrenergic nerves and nonadrenergic calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves innervate rat mesenteric arteries and regulate vascular tone. However, function of cholinergic innervation remains unknown. The present study investigated cholinergic innervation by examining effects of cholinesterase inhibitor (neostigmine), a muscarinic AChR antagonist (atropine), and a nicotinic AChR antagonist (hexamethonium) on adrenergic nerve-mediated vasoconstriction and CGRPergic nerve-mediated vasodilation in rat mesenteric vascular beds without endothelium. In preparations treated with capsaicin (CGRP depletor) or in the presence of Nω-nitro-l-arginine methyl ester (nonselective nitric oxide synthase inhibitor), perivascular nerve stimulation (PNS; 2–12 Hz) evoked a frequency-dependent vasoconstriction. In the same preparations, exogenous norepinephrine induced a concentration-dependent vasoconstriction. Atropine, hexamethonium, and neostigmine had no effect on vasoconstrictor responses to PNS and norepinephrine injections. In denuded preparations, these cholinergic agents did not affect the PNS (12 Hz)-evoked release of norepinephrine in perfusate. In preconstricted preparations without endothelium in the presence of guanethidine (adrenergic neuron blocker), PNS (1–4 Hz) induced a frequency-dependent vasodilation, which was not affected by atropine, hexamethonium, and neostigmine. In denuded preparations treated with capsaicin and guanethidine, PNS did not induce vascular responses, and atropine, neostigmine, and physostigmine had no effect on PNS. Immunohistochemistry study showed choline acetyltransferase-immunopositive fibers, which were resistant to capsaicin and 6-hydroxydopamine (adrenergic toxin). These results suggest that rat mesenteric arteries have cholinergic innervation, which is different from adrenergic and capsaicin-sensitive nerves and not associated with vascular tone regulation.

scholarly journals Helicobacter pyloriEradication Lowers Serum Asymmetric Dimethylarginine Levels

2010 ◽  
Vol 2010 ◽  
pp. 1-4 ◽  
Author(s):  
Selim Aydemir ◽  
Hacı Eren ◽  
Ishak Ozel Tekin ◽  
Ferda Akbay Harmandar ◽  
Nejat Demircan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Tone ◽  
Asymmetric Dimethylarginine ◽  
Microbial Pathogens ◽  
Before And After ◽  
Nos Inhibitor ◽  
The Mean ◽  
H Pylori ◽  
Oxide Synthase ◽  
Regulation Of Vascular Tone

Introduction. Microbial pathogens, one of them isHelicobacter pylori(H. pylori), have frequently been implicated in the atherogenesis. Endothelium-derived nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS) and plays a pivotal role in the regulation of vascular tone. Asymmetric dimethylarginine (ADMA) is the most potent endogenous NOS inhibitor. Elevated levels of ADMA have been reported in many circumstances associated with a high cardiovascular risk. The aim of the present study was to investigate whether the eradication ofH. pyloriinfection affects serum ADMA levels.Materials and Methods. Forty-twoH. pylori-positive patients were enrolled in the study. Triple therapy for 14 days were given to all patients. Serum ADMA levels were measured at baseline and 2 months after therapy.Results. Eradication was achieved in 34 (81%) patients. The mean serum ADMA levels before and after therapy were and  ng/mL in the group withH. pylorieradicated and and  ng/mL in the noneradicated, respectively. We detected statistically significant decreased serum ADMA levels after therapy inH. pylorieradicated group.Conclusion. These findings have indicated that eradication ofH. pyloriinfection may decrease the risk of atherosclerosis and cardiovascular events.

Sitagliptin Attenuates Endothelial Dysfunction of Zucker Diabetic Fatty Rats: Implication of the Antiperoxynitrite and Autophagy

2017 ◽  
Vol 23 (1) ◽  
pp. 66-78 ◽  
Author(s):  
Huanyuan Wang ◽  
Yi Zhou ◽  
Zhiying Guo ◽  
Yu Dong ◽  
Jiahui Xu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
Mesenteric Arteries ◽  
Zucker Rats ◽  
Protective Effects ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

Although the contributions of sitagliptin to endothelial function in diabetes mellitus were previously reported, the potential mechanisms still remain undefined. Our research was intended to explore the underlying mechanisms of protective effects of sitagliptin treatment on endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male lean nondiabetic Zucker rats were used as control and male obese ZDF rats were randomly divided into ZDF and ZDF + sitagliptin groups. The significant decrease in endothelium-dependent relaxation induced by acetylcholine was observed in mesenteric arteries and thoracic aorta rings of ZDF rats. The administration of sitagliptin restored the vascular function effectively. The morphology study showed severe endothelial injuries in thoracic aortas of ZDF rats, and sitagliptin treatment attenuated these changes. The increased malondialdehyde levels and decreased superoxide dismutase activities in serum of ZDF rats were reversed by sitagliptin treatment. Sitagliptin also increased the expression of endothelial nitric oxide synthase and microtubule-associated protein 1 light chain 3 (LC3) and decreased the expression of inducible nitric oxide synthase, 3-nitrotyrosine, and p62 in ZDF rats. After giving Fe (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride porphyrin pentachloride (FeTMPyP, a peroxynitrite [ONOO−] scavenger) or sitagliptin to high-glucose (30 mmol/L, 48 hours) cultured human umbilical vein endothelial cells (HUVECs), the increased levels of Beclin-1 and lysosome-associated membrane protein type 2 were detected. Both FeTMPyP and sitagliptin also significantly increased the number of mRFP-GFP-LC3 dots per cell, suggesting that autophagic flux was increased in HUVECs. Our study indicated that sitagliptin treatment can improve the endothelium-dependent relaxation and attenuate the endothelial impairment of ZDF rats. The protective effects of sitagliptin are possibly related to antiperoxynitrite and promoting autophagy.

scholarly journals Inhibitory effect of valves on endothelium-dependent relaxations to calcium ionophore in canine saphenous vein

2001 ◽  
Vol 280 (2) ◽  
pp. H892-H898 ◽  
Author(s):  
Daihiko Eguchi ◽  
Zvonimir S. Katusic
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Isometric Force ◽  
Calcium Ionophore ◽  
Inhibitory Effect ◽  
Nitric Oxide Synthase Inhibitor ◽  
A 23187 ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

The present study was designed to evaluate endothelium-dependent relaxation to the calcium ionophore A-23187 in isolated canine saphenous veins. Isometric force recordings and cGMP measurements using isolated veins with and without valves were performed. During contractions to U-46619 (3 × 10−7 M), endothelium-dependent relaxations to A-23187 (10−9–10−6 M) were significantly reduced in rings with valves compared with rings without valves. Endothelial removal abolished A-23187-induced relaxation. Relaxations to forskolin (FK; 10−8–10−5 M) and diethylaminodiazen-1-ium-1,2-dionate; DEA-NONOate, 10−9–10−5 M) were identical in rings with and without valves. In rings without valves, a nitric oxide synthase inhibitor, N G-nitro-l-arginine methyl ester (l-NAME; 3 × 10−4 M), and a cyclooxygenase inhibitor, indomethacin (10−5 M), partially reduced A-23187-induced relaxation. However, in rings with valves,l-NAME had no effect, whereas indomethacin abolished the relaxation to A-23187. A selective soluble guanylate cyclase inhibitor, 1 H-[1,2,4]-oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 3×10−6 M), had no effect on the relaxation to A-23187 in either group. In contrast, ODQ abolished the A-23187-induced increase in cGMP levels, suggesting that relaxation to nitric oxide released by A-23187 is independent of increases in cGMP. These results demonstrate that endothelium-dependent relaxation to A-23187 is reduced in regions of veins with valves compared with relaxation in the nonvalvular venous wall. Lower production of nitric oxide in endothelial cells of valvular segments appears to be a mechanism responsible for reduced reactivity to A-23187.

Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling

2007 ◽  
Vol 292 (4) ◽  
pp. H1995-H2003 ◽  
Author(s):  
Zuo-Hui Shao ◽  
Wei-Tien Chang ◽  
Kim Chai Chan ◽  
Kim R. Wojcik ◽  
Chin-Wang Hsu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Therapeutic Hypothermia ◽  
Optimal Timing ◽  
No Production ◽  
Early Reperfusion ◽  
No Signaling ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Pkc Activation

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 ± 3.4% cell death. Hypothermia induction to 25°C was most protective (14.3 ± 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 ± 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 ± 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor Nω-nitro-l-arginine methyl ester (200 μM) reversed these changes and abrogated hypothermia protection. In addition, the PKCε inhibitor myr-PKCε v1-2 (5 μM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase Cε; nitric oxide synthase.

Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats

2002 ◽  
Vol 283 (2) ◽  
pp. R349-R355 ◽  
Author(s):  
Jacqueline Novak ◽  
Rolando J. J. Ramirez ◽  
Robin E. Gandley ◽  
O. David Sherwood ◽  
Kirk P. Conrad
Keyword(s):  
Nitric Oxide ◽  
Virgin Female ◽  
Renal Arteries ◽  
Mesenteric Arteries ◽  
Blood Levels ◽  
Renal Circulation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Myogenic Responses ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Administration of the ovarian hormone relaxin to nonpregnant rats vasodilates the renal circulation comparable to pregnancy. This vasodilation is mediated by endothelin (ET), the ETB receptor, and nitric oxide. Furthermore, endogenous relaxin mediates the renal vasodilation and hyperfiltration that occur during gestation. The goal of this study was to investigate whether myogenic reactivity of small renal and mesenteric arteries is reduced in relaxin-treated rats comparable to the pregnant condition. Relaxin or vehicle was administered to virgin female Long-Evans rats for 5 days at 4 μg/h, thereby producing midgestational blood levels of the hormone. The myogenic responses of small renal arteries (200–300 μm in diameter) isolated from these animals were evaluated in an isobaric arteriograph system. Myogenic reactivity was significantly reduced in the small renal arteries from relaxin-treated compared with vehicle-treated rats. The reduced myogenic responses were mediated by the ETB receptor and nitric oxide since the selective ETB receptor antagonist RES-701–1 and the nitric oxide synthase inhibitor N G-nitro-l-arginine methyl ester restored myogenic reactivity to virgin levels. The influence of relaxin was not limited to the renal circulation because myogenic reactivity was also reduced in small mesenteric arteries isolated from relaxin-treated rats. Thus relaxin administration to nonpregnant rats mimics pregnancy, insofar as myogenic reactivity of small renal and mesenteric arteries is reduced in both conditions.

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