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PubMed2005

Endothelium-dependent and direct relaxation induced by ethyl acetate extract from Flos Chrysanthemi in rat thoracic aorta.

The aims of the present study were to investigate the vasoactive effects of ethyl acetate extract from Flos Chrysanthemi (FCE) and its mechanisms on the rat thoracic aorta. FCE (9.4-150 mg/L) caused a concentration-dependent relaxation on endothelium-intact rings precontracted with phenylephrine (PE, 10(-6)M) or a high level of K+ (6x10(-2)M). By removal of endothelium, the effect was not abolished but reduced significantly. N(G)-nitro-l-arginine methyl ester (l-NAME) (10(-4) M), methylene blue (10(-5) M) significantly inhibited the effect of FCE. Meanwhile, NO synthase of aorta in FCE group was markedly elevated versus the control. However, indomethacin did not influence FCE effect. SKF-525A combined with l-NAME had the same effect as l-NAME. Tetraethylammonium, BaCl2, 4-aminopyridine, 5-HD and propranolol also did not influence the vascular effect of FCE, but glibenclamide significantly attenuated its vasodilation. FCE did not reduce PE-induced transient contraction in Ca(2+)-free medium, but inhibited PE-induced contraction in K(+)-free solution or Ca2+ caused contraction after PE induced a stable contraction in Ca(2+)-free solution. It is concluded that FCE induced both endothelium-dependent and -independent relaxation. NO and cGMP-mediated pathway are likely involved in the endothelium-dependent relaxation, whereas inhibition of voltage-dependent Ca2+ channel, receptor-operate Ca2+ channel and activation of K(ATP) contribute in part to the endothelium-independent relaxation.

Animals↗
PubMed2004

Vascular endothelium is the organ chiefly responsible for the catabolism of plasma asymmetric dimethylarginine--an explanation for the elevation of plasma ADMA in disorders characterized by endothelial dysfunction.

Plasma levels of asymmetric dimethylarginine (ADMA), an endogenously produced competitive inhibitor of nitric oxide synthase (NOS), have been found to be elevated in a large number of disorders characterized by endothelial dysfunction; this remarkable phenomenon has yet to receive a plausible explanation. ADMA arises by proteolysis of methylated proteins throughout the body; the majority of this ADMA is catabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), found in many tissues, including those that express NOS. Since the production of ADMA can be considered constitutive, and little intact ADMA emerges in the urine, impaired catabolism is most likely responsible for elevations of plasma ADMA. The association of elevated ADMA with endotheliopathy is readily explained if we assume that vascular endothelium is the organ chiefly responsible for the catabolism of plasma ADMA--a view that is credible owing to the privileged access of endothelium to plasma, the capacity of endothelium for active transport of arginine (and methylated arginines), and the ample DDAH activity of healthy endothelial cells--and further assume that endothelial dysfunction is often attended by a loss of DDAH activity and/or an impairment of arginine transport, reducing the efficiency of ADMA catabolism. Indeed, there is recent evidence that DDAH is inhibited by endothelial oxidative stress, a typical feature of endotheliopathy; there is also some reason to suspect that arginine transport may be less efficient in dysfunctional endothelium. From this perspective, increased plasma ADMA is not the primary cause of the endothelial dysfunction in various disorders, but rather its effect--though the rise in ADMA can then exacerbate this dysfunction by inhibiting endothelial NOS. Supplemental arginine should be of some clinical benefit in disorders characterized by elevated ADMA, since it can offset that adverse impact of ADMA on NOS activity, and possibly exert other beneficial effects on endothelium--but it cannot be expected to reverse the primary cause of the endothelial dysfunction. Whether or not ADMA plays an important pathogenic role, it seems likely to emerge as a potent risk factor for adverse vascular events, since it may be viewed as a barometer of endothelial health.

Amidohydrolases↗
PubMed2004

Marinobufagenin may mediate the impact of salty diets on left ventricular hypertrophy by disrupting the protective function of coronary microvascular endothelium.

Individuals who eat salty diets and who are "salt-sensitive" tend to have increased left ventricular mass, independent of blood pressure; this phenomenon awaits an explanation. It is clear that local up-regulation of angiotensin II (AngII) production and activity play a key role in the induction of left ventricular hypertrophy (LVH). Recent evidence suggests that a healthy coronary microvascular endothelium opposes this effect by serving as a paracrine source of nitric oxide (NO), a natural antagonist of AngII activity, and that up-regulation of this mechanism can account for the protective role of bradykinin with respect to LVH. The coronary microvasculature also possesses NAD(P)H oxidase activity that can generate superoxide, inimical to the bioactivity of endothelial NO. There is now good reason to believe that the triterpenoid marinobufagenin (MBG), a selective inhibitor of the alpha-1 isoform of the sodium pump, mediates the impact of salty diets on blood pressure;production of MBG by the adrenal cortex is boosted when salt-sensitive animals are fed salty diets. It is hypothesized that coronary microvascular endothelium expresses the alpha-1 isoform of the sodium pump, and that MBG thus can target this endothelium. If that is the case, MBG would be expected to decrease membrane potential in these cells;as a consequence, superoxide production would be up-regulated, NO synthase activity would be down-regulated, and myocardial NO bioactivity would thus be suppressed. This would offer a satisfying explanation for the impact of salt and salt-sensitivity on risk for LVH. If expression of the alpha-1 isoform of the sodium pump is a more general property of vascular endothelium, MBG may suppress NO bioactivity in other regions of the vascular tree, thereby contributing to other adverse effects elicited by salty diets: reduced arterial compliance, medial hypertrophy, impaired endothelium-dependent vasodilation, hypertensive/diabetic glomerulopathy, increased risk for stroke, and hypertension.

Angiotensin II↗
PubMed2005

Marinobufagenin may mediate the impact of salty diets on left ventricular hypertrophy by disrupting the protective function of coronary microvascular endothelium.

Individuals who eat salty diets and who are "salt-sensitive" tend to have increased left ventricular mass, independent of blood pressure; this phenomenon awaits an explanation. It is clear that local up-regulation of angiotensin II (AngII) production and activity play a key role in the induction of left ventricular hypertrophy (LVH). Recent evidence suggests that a healthy coronary microvascular endothelium opposes this effect by serving as a paracrine source of nitric oxide (NO), a natural antagonist of AngII activity, and that up-regulation of this mechanism can account for the protective role of bradykinin with respect to LVH. The coronary microvasculature also possesses NAD(P)H oxidase activity that can generate superoxide, inimical to the bioactivity of endothelial NO. There is now good reason to believe that the triterpenoid marinobufagenin (MBG), a selective inhibitor of the alpha-1 isoform of the sodium pump, mediates the impact of salty diets on blood pressure; production of MBG by the adrenal cortex is boosted when salt-sensitive animals are fed salty diets. It is hypothesized that coronary microvascular endothelium expresses the alpha-1 isoform of the sodium pump, and that MBG thus can target this endothelium. If that is the case, MBG would be expected to decrease membrane potential in these cells; as a consequence, superoxide production would be up-regulated, NO synthase activity would be down-regulated, and myocardial NO bioactivity would thus be suppressed. This would offer a satisfying explanation for the impact of salt and salt-sensitivity on risk for LVH. If expression of the alpha-1 isoform of the sodium pump is a more general property of vascular endothelium, MBG may suppress NO bioactivity in other regions of the vascular tree, thereby contributing to other adverse effects elicited by salty diets: reduced arterial compliance, medial hypertrophy, impaired endothelium-dependent vasodilation, hypertensive/diabetic glomerulopathy, increased risk for stroke, and hypertension.

Angiotensin II↗
PubMed2005

Mechanism of the endothelium-dependent vasodilator effect of an alcohol-free extract obtained from a vinifera grape skin.

An alcohol-free grape-skin extract (GSE) obtained from skins of Vitis labrusca has significant anti-hypertensive, antioxidant and vasodilator effects. According to our previous results, the vasodilator effect of GSE in the isolated mesenteric vascular bed (MVB) of the rat is dependent on endothelium and partially dependent on nitric oxide (NO). In the MVB of the rat pre-contracted with norepinephrine (NE), bolus injections of GSE induced a long-lasting dose-dependent vasodilation that is significantly reduced after the treatment with 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ). Additionally, in vessels pre-contracted with norepinephrine and depolarized with KCl (25 mM) or treated with Ca(2+)-dependent K(+)-channel blockers charybdotoxin (ChTx) plus apamin, the vasodilator effect of GSE was significantly reduced and almost abolished by ChTx plus apamin plus L-NAME. However, the vasodilator effect of GSE was unaffected by D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (HOE-140), atropine, yohimbine, pyrilamine and 4-aminopyridine (4-AP). The vasoconstriction response elicited by bolus injection of KCl was not affected by GSE, whereas the vasoconstrictor response induced by NE was dose-dependently and completed inhibited by GSE in the presence but not in the absence of endothelium. However, NE-induced vasoconstriction in calcium-free condition or without endothelium was not reduced by GSE. The present results demonstrate that GSE induces a vasodilator effect in the rat MVB, which is dependent on NO in combination with endothelium-derived hyperpolarizing factor (EDHF). Additionally, our results indicated that extracellular Ca(2+) has an important role on the endothelium-dependent vasodilator effect induced by GSE.

Alcohols↗
PubMed2006

Endothelium-dependent vasodilation induced by Hancornia speciosa in rat superior mesenteric artery.

The vasodilator effect of the ethanolic extract of leaves from Hancornia speciosa Gomes (HSE) was evaluated in superior mesenteric artery rings. HSE produced a concentration-dependent vasodilation (IC50 = 10.8 +/- 4.0 microg/mL) in arterial rings pre-contracted with phenylephrine, which was completely abolished in endothelium-denuded vessels. Endothelium-dependent vasodilation induced by HSE was strongly reduced by L-NAME (100 microM), a nitric oxide (NO) synthase inhibitor, but neither by atropine, a muscarinic receptor antagonist (1 microM), nor by indomethacin (10 microM), a cyclooxygenase inhibitor. In rings pre-contracted with 80 mM KCl, the vasodilator effect of HSE was shifted to the right and was completely abolished in the presence of L-NAME (100 microM). Similar effects were obtained in mesenteric rings pre-contracted with phenylephrine in the presence of KCl 25 mM alone or in addition to 100 microM L-NAME. In addition, BaCl2 (1 mM) dramatically reduced the vasodilation induced by HSE. Together, these findings led us to conclude that HSE induces an endothelium-dependent vasodilation in rat mesenteric artery, by a mechanism dependent on NO, on the activation of potassium channels and endothelium-derived hyperpolarizing factor release. Rutin, identified as a major peak in the HPLC fingerprint obtained for HSE, might contribute for the observed vasodilator effect, since it was able to induce an endothelium-dependent vasodilation in rat superior mesenteric arteries.

Animals↗
PubMed2005

Endothelium-dependent pulmonary artery vasorelaxation is dysfunctional in males but not females after acute lung injury.

BACKGROUND: Mortality after acute respiratory distress syndrome is higher in males than in females. Gender differences in pulmonary vascular reactivity and local inflammatory response may explain this disparity. We hypothesized that endothelium-dependent pulmonary vasorelaxation is impaired in males and that this effect is related to differences in local inflammatory cytokine expression from the pulmonary vasculature. METHODS: Pulmonary artery (PA) rings (n = 12-16 per group) were isolated from adult male and female Sprague-Dawley rats treated with endotoxin (Salmonella typhimurium lipopolysaccharide, 20 mg/kg IP) or vehicle (0.9% normal saline), and connected to force transducers for measurement of isometric force displacement. Dose-response curves (0.01-10 micromol/L) to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside were generated. PA rings were also evaluated for inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin 1beta messenger RNA (mRNA) by reverse transcriptase-polymerase chain reaction. RESULTS: Endotoxin had no effect on the maximum PA contraction in males (564.4 +/- 37.37 mg vs 633.3 +/- 54.67 mg vehicle) or females (446.3 +/- 20.00 mg vs 444.2 +/- 33.02 mg vehicle), but endothelium-dependent vasodilation was significantly decreased in males (47.49 +/- 5.63% vs 77.61 +/- 9.41% vehicle). Endothelium-independent vasodilation remained intact during endotoxemia. Endotoxin increased the PA expression of inducible nitric oxide synthase mRNA, but there was no gender difference. There was no change in expression of PA tumor necrosis factor, whereas endotoxemic males, but not females, had increased interleukin 1beta mRNA, compared with vehicle. CONCLUSIONS: These results suggest that sepsis-induced vascular dysfunction differs between males and females, and, therefore, treatment of acute lung injury may require gender-specific therapies.

Animals↗
PubMed2004

Age- and endothelium-dependent changes in coronary artery reactivity to serotonin and calcium.

The influence of ageing and endothelium removal on the sensitivity and contractile response of rat coronary arteries to intracellular Ca2+ ([Ca2+]i) during activation with serotonin (5-HT) and membrane depolarisation with 125 mM K+ was investigated. The sensitivity and contractile response of coronary arteries to 5-HT were significantly higher in 2-year-old than in 3-month-old rats. The receptor responsible for the 5-HT-induced contractions in coronary arteries belongs to a population of 5-HT2 receptors in both young and old rats based on the Schild plot. The resting levels of [Ca2+]i and active tension were both increased by age and endothelium removal. During depolarisation with 125 mM K+, the sensitivity to [Ca2+]i and maximal tension induced by [Ca2+]i were not affected by age or endothelium. During activation with 10 microM 5-HT, the maximal tension induced by [Ca2+]i was increased by age but not affected by endothelium, whereas the sensitivity to [Ca2+]i was increased by endothelium removal. In conclusion, ageing is associated with an increased sensitivity to 5-HT in rat coronary small arteries. The increased sensitivity to 5-HT seems to involve an augmented contractile response to [Ca 2+]i in 5-HT-activated coronary arteries and a diminished endothelial basal vasodilator function.

Aging↗
PubMed1993

Effect of the vascular endothelium on norepinephrine-induced contractions in uterine radial arteries from the nonpregnant and pregnant human uterus.

OBJECTIVE: Our purpose was to investigate the role of the endothelium in the human uterine arterial response to norepinephrine in the nonpregnant and pregnant states. STUDY DESIGN: Tissue was obtained from six pregnant and six nonpregnant women undergoing cesarean section or hysterectomy. Uterine radial arteries were isolated and subjected to norepinephrine dose-response curves with and without intact endothelium. RESULTS: Responses were obtained over a dose range of 10(-8) to 10(-4) norepinephrine. Initially there was no difference between vessels from pregnant and nonpregnant patients, but removal of the endothelium significantly increased the response in vessels from pregnant women. Addition of nitro-L-arginine methyl ester when the endothelium was intact did not alter the dose-response curves. CONCLUSIONS: In pregnancy human uterine radial arteries are more sensitive to norepinephrine than during the nonpregnant state. This increase is countered by an endothelium-derived relaxing factor. The factor is unlikely to be nitric oxide.

Arginine↗
PubMed1994

Gestational changes in endothelium-dependent vasorelaxation in human umbilical artery.

OBJECTIVE: We intended to clarify whether (1) the amount of endothelium-derived vasorelaxing factor or nitric oxide released by histamine is sufficient to cause relaxation in human umbilical artery at different stages of gestation and (2) the functional role of endothelium-derived relaxing factor changes with the progress of gestation. STUDY DESIGN: By means of a bioassay cascade technique with very thin muscle strips, which allows rapid diffusional access of applied drugs (of the order of a few seconds), contractile properties were examined. RESULTS: At 18 to 22 weeks of gestation histamine produced only a minor contraction, but as gestation progressed the contractile responses increased. L-NG-nitro-arginine greatly enhanced the histamine-induced contractions. Histamine produced a concentration-dependent relaxation during the maintained contraction induced by 39 mmol/L K+ in tissues from 18 to 22 weeks or 30 to 32 weeks but not 38 to 41 weeks of gestation. Thus the concentration-relaxation relationship for histamine showed decreased sensitivity during gestation. The histamine-induced relaxation was enhanced by superoxide dismutase and completely blocked by L-NG-nitro-arginine or mepyramine (H1 antagonist). The concentration-relaxation relationship for the action of glycerol trinitrate relaxation decreased as gestation progressed. In a bioassay cascade an endothelium-intact umbilical artery from 18 to 22 or 38 to 41 weeks of gestation was used as a "donor" and L-NG-nitro-arginine-treated umbilical artery from 18 to 22 and 38 to 41 weeks as a "detector." In the presence of histamine the perfusate that had passed through a donor from 18 to 22 weeks (but not 38 to 41 weeks) attenuated the high K(+)-induced contraction in the detector only from 18 to 22 weeks. CONCLUSION: These results suggest that the amount of endothelium-derived relaxing factor and the sensitivity of smooth muscle to endothelium-derived relaxing factor decreased with the progress of gestation.

Arginine↗
PubMed1996

The effect of thrombus on the vascular endothelium of arterialized vein grafts.

BACKGROUND: It is known that vein grafts can be salvaged by clot removal, but patency rates are diminished. This study was designed to determine the effects of thrombus on vascular endothelium and the ability of the endothelium to recover normal function. METHODS: Thirty external jugular vein grafts were placed as bilateral femoral artery interposition grafts in 15 mongrel dogs and allowed to arterialize for a period of at least 12 weeks. Six control grafts were not exposed to thrombus (C-NT). Six other control grafts were exposed to thrombus for 7 days and removed, ie, allowed no in vivo recovery (C-T). The remaining 18 grafts in 9 canines were exposed to autologous thrombus for 5 days and then flow was restored. The right femoral graft was removed 7 days after thrombectomy and the left removed 30 days after thrombectomy. At the time of removal, the grafts were perfused with a balanced salt solution alone and then with arachidonic acid added to the same volume of the salt solution. Perfusates were collected at 5, 15, and 30 minutes. These perfusates were assayed for the presence of 6-keto-prosglandin F1 alpha (6-keto-PGF1(1 alpha)), a metabolite of prostacyclin (PGI2). Over the 30-day recovery period, the amounts of 6-keto-PGF1(1 alpha) produced with and without arachidonic acid added were compared to assess endothelial response. Electron micrographs of the endothelium of all vein grafts were compared to the assay findings. RESULTS: When arachidonic acid was added to the perfusion system, there was a several fold increase in the production of 6-keto-PGF1(1 alpha) over baseline in all grafts allowed recovery. Grafts (C-T) that were allowed no in vivo recovery had no response to arachidonic acid. Ratios of 6-keto-PGF1(1 alpha) production with arachidonic acid stimulation to 6-keto-PGF1(1 alpha) production without stimulation were calculated to compare endothelial function. The electron micrographs showed the vascular endothelium to be severely injured after contact with thrombus, but recovered by 7 days. CONCLUSIONS: This study suggests that the endothelium of canine vein grafts is injured by contact with thrombus for 5 days but can recover structure and function. This recovery is detectable at 7 days post-thrombectomy.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

The endothelium in clinical cardiac transplantation.

Cardiac transplantation is the most successful therapy for refractory heart failure, but clinical transplantation is still confronted with the problems of acute rejection and acute pump failure. The limiting factor in achieving prolonged survival remains cardiac allograft vasculopathy. In recent years it has become apparent that from brain death onward, the cardiac endothelium plays a key role in these acute and chronic events. Brain death is associated with an inflammatory response that primes the endothelium for cumulative injury during the subsequent stages of ischemic cold storage, reperfusion and allorecognition. As a structural and functional interface, the endothelium is the site at which inflammatory cells move from the bloodstream through the vessel wall into the parenchyma. The endothelium interacts with the complement system, the coagulation and inflammatory cascades, circulating leukocytes, the immune system, the smooth muscle in the vessel wall, and the surrounding matrix and cardiomyocytes. A better understanding of its many roles may lead to expansion of our therapeutic possibilities and better outcomes overall. This article reviews the possible roles of the endothelium in relation to cardiac transplantation, and discusses the diagnostic and therapeutic modalities that are available to date.

Animals↗
PubMed1989

Surgical preparation impairs release of endothelium-derived relaxing factor from human saphenous vein.

Release of endothelium-derived relaxing factor was measured from freshly isolated human saphenous vein and from vein subject to routine surgical preparation for coronary artery bypass grafting. Surgical preparation led to a significant decline in endothelium-derived relaxing factor release as compared with freshly isolated vein, and these changes were associated with loss of endothelial coverage. Storage of freshly isolated vein in blood but not in Hartmann's solution also resulted in a decline in maximally stimulated endothelium-derived relaxing factor release that was not associated with loss of endothelium. Reduced production of endothelium-derived relaxing factor, a potent vasodilator and inhibitor of platelet adhesion and aggregation, may be implicated in the etiology of early vein graft thrombosis.

Animals↗
PubMed1998

High-flow gas insufflation to facilitate MIDCABG: effects on coronary endothelium.

BACKGROUND: During less invasive coronary bypass operations on the beating heart, as well as conventional operations using continuous warm cardioplegia, a precise anastomosis is facilitated by a bloodless field. To maintain a clear field, many surgeons use high-flow gas insufflation. However, the potentially damaging effects of gas insufflation on coronary endothelium have not been elucidated. METHODS: Seven pigs underwent median sternotomy. Between two coronary occluders, an arteriotomy in the mid left anterior descending coronary artery (LAD) was performed. In the experimental group (n = 5), the operative field was kept clear by exposing the arteriotomy to a catheter-directed stream of carbon dioxide at 15 L/min. In the control group (n = 2), the arteriotomy was left open to room air. After 20 minutes, the segments of LAD exposed to carbon dioxide or room air, and the unexposed proximal LAD and right coronary artery, were processed, sectioned, and stained together. A murine anti-human tie-2 monoclonal antibody was used to identify endothelium. RESULTS: All unexposed LAD and right coronary artery segments and all LAD segments exposed only to room air demonstrated normal, contiguous staining of endothelium with the murine anti-human tie-2 monoclonal antibody. In contrast, all LAD segments exposed to high-flow carbon dioxide gas insufflation demonstrated near-complete loss of endothelium. CONCLUSIONS: These data demonstrate that high-flow carbon dioxide gas insufflation denudes the coronary artery of its endothelium. This exposes blood elements to the subendothelium and promotes clotting, and endothelial loss may promote smooth muscle cell migration and proliferation. These events set the stage for early and late graft failure.

Animals↗
PubMed1986

Endothelium dependent vascular relaxation by arginine containing polypeptides.

The vascular endothelium appears obligatory for the expression of the vasodilating property of most polypeptides. A number of polypeptides were studied on the rat aortic ring preparation which was pre-contracted with phenylephrine and only basic polypeptides containing one or more arginine residues elicited relaxation which was endothelium dependent. These peptides included melittin and poly-L-Arg. The basic polypeptide poly-L-Lys also elicited endothelium dependent relaxation, but to a lesser extent than arginine containing polypeptides. Two basic polypeptides, apamin and mastoparan do not promote endothelium dependent relaxation. The former contains arginine between disulfide bonds and in the latter arginine is absent. Basic amino acids and dipeptides which contain arginine, and also polyamines did not elicit relaxation even at high concentrations (10(-3) M). The relaxation elicited by melittin, poly-L-Arg and poly-L-Lys was inhibited by ETYA, NDGA, p-bromophenacyl bromide and not by indomethacin. Methylene blue, an inhibitor of soluble guanylate cyclase, also abolished the relaxation. We suggest that arginine containing peptides may relax vascular smooth muscle by acting directly on the vascular smooth muscle (eg: atriopeptins) and/or or by eliciting release of a relaxing factor(s) from the endothelium.

Animals↗
PubMed2002

Role of endothelium in hyperemia during cortical spreading depression (CSD) in the rat.

The purpose of this study was to examine whether endothelium-mediated dilation is responsible for the cortical hyperemia that occurs during cortical spreading depression (CSD) in rats using three different approaches. The first approach taken was the acute pharmacological inhibition of the predominant endothelium-centered dilator systems, using indomethacin, a cyclooxygenase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, and miconazole, a cytochrome P-450 epoxygenase inhibitor. The second approach used was the acute general pharmacological impairment of endothelial function by the intravascular administration of phorbol 12, 13-dibutyrate (PDBu). The third approach taken was the chronic impairment of endothelium-dependent dilator responses by diet in insulin resistant (IR) rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry. CSD was elicited by the topical application of potassium chloride. Pharmacological inhibition of endothelium-dependent dilator factors did not affect CSD. For example, with 20 mg/kg L-NAME, CBF peak of the first series of CSDs was 377 +/- 67% of baseline CBF. After drug administration, CBF peaks of the second and the third series of CSDs were 451 +/- 67% and 390 +/- 69% (n=5, P=n.s.), respectively. Control and IR animals and those treated with indomethacin, miconazole and PDBu showed similar results. We also calculated the area under the CBF curve to fully represent the extent of hyperemia during CSD. However, there were no significant differences in the CBF area with any treatment compared to control animals. Thus, our results provide strong evidence that endothelium-mediated mechanisms have minimal effects on the CSD-associated hyperemia.

Acetylcholine↗
PubMed2000

Endothelium-dependent relaxation of rat aorta and main pulmonary artery by the phytoestrogens genistein and daidzein.

OBJECTIVE: The dietary phytoestrogens genistein and daidzein have been shown to relax agonist-preconstricted arteries in vitro; the mechanisms of relaxation remain incompletely understood. This study aimed to determine whether the relaxation of phenylephrine (PE)-constricted rat aorta and main pulmonary artery by genistein and daidzein was endothelium-dependent. METHODS: Effects of endothelial-denudation, and pretreatment with with 100 microM L-N(G)-nitroarginine methyl ester (L-NAME) and/or 10 microM indomethacin on relaxation of PE (1 microM)-preconstricted contractures by genistein (1-100 microM) and daidzein (3-100 microM) were assessed by measuring isometric force development by rat arterial rings. The effect of L-NAME on relaxation to 17beta-estradiol (10 microM) was also measured in aorta. RESULTS AND CONCLUSIONS: Genistein and daidzein caused concentration-dependent relaxation of aorta rings preconstricted with PE (1 microM). The IC50 values were 5.7 microM (n=8, 95% confidence limits 4.3-7.7 microM) and 36.7 microM (n=12, 95% confidence limits 25.7-44.1 microM), respectively. Removal of the endothelium and pretreatment with L-NAME (100 microM) significantly inhibited relaxation at 3, 10 and 30 microM genistein and 10 and 30 microM daidzein. The contracture evoked in rat aorta by depolarization with 75 mM K+ solution was similarly relaxed by genistein in a partially endothelium-dependent manner. 17Beta-estradiol (10 microM) caused a 48.7+/-5.0% (n=11) relaxation of the PE contracture, which was significantly reduced to 25.1+/-5.3% (n=7) by L-NAME. Relaxations brought about by 17beta-estradiol, genistein, and daidzein were not significantly affected by the genomic estrogen receptor antagonist ICI 182,780 (10 microM). Similar endothelium-dependent effects of genistein were observed in the main pulmonary artery. The results show that the relaxation of these rat arteries by concentrations of genistein and daidzein which overlap those present in human plasma after ingestion of soybean-containing meals is largely endothelium dependent.

Animals↗
PubMed2001

Effect of age on electrical field stimulation (EFS)-induced endothelium-dependent vasodilation in male and female rats.

OBJECTIVE: The purpose of this study was to determine whether the effect of age on electrical field stimulation (EFS)-induced endothelium-dependent vasodilation was different in males and females. METHODS: Young (3 month) and old (25 month) Fisher 344 rats were studied: young females (YF, n=34), young males (YM, n=28), old females (OF, n=19), and old males (OM, n=24). Isolated mesenteric resistance arteries (endothelium-intact and denuded) were pressurized, and outer diameter was monitored. EFS-response curves (0.1-8 Hz) were performed in preconstricted arteries in the presence of guanethidine. EFS responses were expressed as percent relaxation from preconstricted diameter. Area under the curve (AUC) was calculated and comparisons were made using ANOVA and t-tests. RESULTS: Males became less responsive to EFS-induced vasodilation with age, while responses among females were unaffected (AUC: YM=344+/-23, OM=253+/-25, P=0.008; YF=397+/-21, OF=365+/-25, P=0.33). Endothelial denudation produced a significant decrease in EFS-induced dilation among all rat groups. The effect of denudation was greater in young animals compared to old. Incubation with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (LNA) significantly decreased EFS responsiveness among all of the rat groups. CONCLUSIONS: EFS-induced vasodilation declines with age among males. In YF and YM endothelium-dependent EFS-induced vasodilation is mediated by the release of endothelium-derived NO. With age, endothelial function declines, which is likely due to a decrease in the production of endothelium-derived NO. A decline in endothelial-derived NO is likely responsible for the decrease in EFS-induced vasodilation with age among males.

Aging↗