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PubMed1986

Thimerosal induces endothelium-dependent vascular smooth muscle relaxations by interacting with thiol groups. Relaxations are likely to be mediated by endothelium-derived relaxing factor (EDRF).

The sulfhydryl reagent thimerosal, as well as acetylcholine and Ca2+-ionophore A23187, produced concentration-dependent relaxations of intact rabbit aortic strips. The ability of strips to relax in response to these agents was dependent on the presence of vascular endothelium. Purposely removing the endothelium led to a complete loss of the relaxation responses. Thimerosal was at least as efficacious as A23187 in inducing endothelium-dependent relaxations, but its relaxations developed much slower than those induced by A23187 or acetylcholine. A small concentration of thimerosal that had no appreciable effect by itself, potentiated the relaxing response to acetylcholine in endothelium-intact preparations. Endothelium-dependent relaxations induced by larger concentrations of thimerosal, as well as relaxations produced by acetylcholine, were inhibited by the antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid, by haemoglobin, and by the inhibitor of soluble guanylate cyclase methylene blue. Indomethacin had no effect on these relaxations. The thiol compounds glutathione, 2-mercaptoethanol and a low concentration of dithiothreitol prevented (and reversed) relaxations induced by thimerosal, but had little or no effect on ACh relaxations. A high concentration of dithiothreitol also markedly inhibited the ACh relaxation. These results are consistent with the hypothesis that thimerosal stimulates endothelial cells to produce a relaxing substance whose properties are similar or the same as those of the endothelium-derived relaxing factor (EDRF) released in response to acetylcholine or A23187. The biochemical mechanism by which thimerosal induces the formation and/or release of this relaxing substance is likely to be different from ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1997

Endothelium inhibits the palytoxin-induced depolarization and Ca2+ mobilization in porcine coronary artery through endothelium-derived hyperpolarizing factor and nitric oxide released by palytoxin.

Palytoxin induced increases in cytosolic Ca2+ and tension, which were dependent on external Ca2+, and depolarized the membrane in endothelium-denuded porcine coronary arteries. When the endothelium was present, however, these effects were greatly inhibited, suggesting that some factors from endothelium inhibited the palytoxin-actions. Pretreatment with 100 microM N omega-nitro-L-arginine partially reversed the inhibitory effect of endothelium on the Ca2+ movement and the contraction but not that on the depolarization. Pretreatment with 10 microM indomethacin did not affect the inhibition. These results suggest that palytoxin released both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) from the endothelium, both of which counteracted the actions of palytoxin on smooth muscle cells. It is thought that the palytoxin-induced depolarization was attenuated by hyperpolarization due to EDHF.

Acrylamides↗
PubMed2000

Butanolic fraction from Cuphea carthagenensis Jacq McBride relaxes rat thoracic aorta through endothelium-dependent and endothelium-independent mechanisms.

This study evaluated the vasorelaxant properties of the crude hydroalcoholic extract (CE) of Cuphea carthagenensis, as well as its butanolic (BF) and ethyl acetate (EA) fractions, in rings of rat thoracic aorta. In endothelium-intact rings contracted with phenylephrine (30-100 nM), cumulative additions of increasing concentrations of CE, BF, and EA of C. carthagenensis (0.1 microg/ml-3 mg/ml) caused graded relaxations, with BF displaying the lowest median inhibitory concentration (IC5; mean, 6.8 microg/ml; 95% confidence limits, 3.3-14.2). BF-induced relaxations of endothelium-intact rings were virtually abolished by prior incubation with the NO-synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG; 10 or 30 microM), and were markedly reduced after guanylate cyclase inhibition with either methylene blue (10 microM) or ODQ (1 microM; 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). The inhibition of BF-induced relaxation by L-NOARG was prevented to a large extent by simultaneous incubation with L-arginine (1 mM). In endothelium-denuded rings contracted with phenylephrine, CE and BF caused graded relaxations only at doses >100 microg/ml, whereas the NO-donors SNAP (S-nitroso-N-acetyl-penicillamine) and SIN-1 (3-morpholino-sydnonimine) induced full relaxation at 1 microM. BF (100 microg/ml), which caused little relaxation per se of endothelium-denuded rings, potentiated the relaxant effects of SNAP and even more so of SIN-1 (which, unlike SNAP, also releases superoxide anion O2- in addition to NO), in a manner qualitatively similar to that seen with SOD (superoxide dismutase) against SIN-1. These data indicate that the BF of C. carthagenensis induces relaxation of the rat thoracic aorta by two mechanisms: (a) an endothelium-dependent component of action, which clearly depends on the NO/cyclic guanosine monophosphate (cGMP) pathway and can be attributed, at least in part, to free radical-scavenging properties; and (b) an endothelium-independent component of action, which becomes evident at higher doses (> or = 100 microg/ml) and remains to be further characterized. These results suggest that this native South American plant might be beneficial in cardiovascular disease.

Animals↗
PubMed1992

Evidence for endothelium-dependent and endothelium-independent vasodilation in human skin flaps.

Acetylcholine (ACh) and nitroglycerin (NTG) were used as probes to study endothelium-dependent and endothelium-independent vascular relaxation in isolated perfused transverse paraumbilical human skin flaps. It was observed that ACh (10(-6) M) significantly (p < 0.05) decreased the vascular resistance and increased dermal capillary perfusion (assessed by surface fluorometry) in norepinephrine (NE, 10(-6) M) preconstricted skin flaps, despite the presence of a cyclooxygenase inhibitor (indomethacin, 3 x 10(-5) M) and a beta-adrenergic receptor antagonist (propranolol, 10(-6) M). The ability of ACh to induce vascular relaxation in NE-preconstricted skin flaps was lost after damaging the vascular endothelial lining with saponin perfusion (100 mg.L-1, 5 min). In contrast, NTG (10(-6) M) induced vascular relaxation to a similar extent before and after saponin treatment. In a separate study, ACh was seen to induce vascular relaxation in a concentration-dependent manner in skin flaps preconstricted with NE (10(-6) M). This vascular relaxation effect of ACh over the dose range of 10(-9)-10(-5) M was significantly (p < 0.01) inhibited in the presence of N omega-nitro-L-arginine (10(-5) M), a nitric oxide (NO) synthesis inhibitor. These observations were taken to indicate the presence of endothelium-dependent and endothelium-independent vascular relaxation in human skin flaps and that the ACh-induced endothelium-dependent relaxation is probably mediated by NO. The importance of impairment of endothelium-dependent relaxation in the pathogenesis of skin flap ischemia, and the potential use of topical nitrovasodilators or NO donors for prevention and (or) treatment of skin flap ischemia were also discussed.

Acetylcholine↗
PubMed1991

Effect of age on rabbit aortic responses to relaxant endothelium-dependent and endothelium-independent agents.

The aim of this study was to evaluate the effects of aging on endothelium-dependent and endothelium-independent relaxation of rabbit thoracic aorta from New Zealand white rabbits aged 4-6 and 7-12 months. The contractile response to noradrenaline (NA) decreased with increasing age, but NA [EC50] did not vary significantly. Acetylcholine (Ach)-induced relaxation of aortic rings precontracted with NA [EC50] did not change significantly with increasing age. The relaxation induced by ATP of aortic rings, precontracted with NA [EC50], was significantly greater in young than in adult rabbits. This difference between young and adult animals became more evident in aortic rings deprived of endothelium: in adult animals, the ATP-induced relaxation of aortic rings with endothelium was significantly greater than in the rings without endothelium. The endothelium-independent relaxation by sodium nitrite (NaNO2) at lower concentrations was significantly greater in young than in adult rabbit aortic rings precontracted with NA [EC50]. Concluding, the age-induced changes in vascular response in male New Zealand white rabbits are related to an impaired mechanism at smooth muscle level.

Adenosine Triphosphate↗
PubMedDate not supplied

Endothelium-dependent and endothelium-independent flow regulation in coronary vascular regions supplied by arterial and venous bypass grafts.

The endothelium-dependent and endothelium-independent vasodilation of arterial and venous coronary bypass grafts and of epicardial conduit vessels and microcirculatory coronary vessels supplied by these grafts was investigated. Vasodilatory response and flow regulation were tested with cumulative intracoronary doses of acetylcholine (25 and 50 micrograms i.c.), nitroglycerin (0.3 mg i.c.), and papaverine (10 mg i.c.) in 10 patients (age 60 +/- 2.3 years) with arterial grafts and in 16 patients (age 57.7 +/- 1.5 years) with venous grafts. The effect of acetylcholine on arterial and venous bypass grafts and on large conduit arteries was evaluated by quantitative coronary angiography. Coronary blood flow velocity changes as a parameter of microcirculatory function were measured by intraluminal Doppler ultrasound. Indices for coronary flow and coronary resistance were calculated from the mean Doppler flow velocity and the computed cross-sectional vascular area. The coronary resistance decreased endothelium dependent after 25 and 50 micrograms of acetylcholine by 16 +/- 30% (p < 0.05 vs. control) and 22 +/- 25% (p < 0.05 vs. control), respectively, in regions supplied by venous grafts and by 48 +/- 20% (p < 0.05 vs. control and vs. venous graft) and 41 +/- 32% (p < 0.05 vs. control), respectively, in regions supplied by arterial grafts. The coronary resistance decreased endothelium independent after 0.3 mg nitroglycerin and 10 mg papaverine by 18 +/- 56% (p < 0.05 vs. control) and 39 +/- 29% (p < 0.05 vs. control), respectively in regions supplied by venous grafts and by 45 +/- 45% (p < 0.05 vs. control) and 70 +/- 12% (p < 0.05 vs. control and vs. venous graft), respectively in regions supplied by arterial grafts. In conclusion, during the long-term course after coronary artery bypass grafting, vascular regions supplied by arterial grafts have a better preserved endothelium-dependent and endothelium-independent flow reserve as compared with vascular regions supplied by venous grafts.

Acetylcholine↗
PubMed1993

Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension.

BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilation. Because the endothelium exerts its action on the vascular smooth muscle through the release of several substances, it is important to identify which of these factors is involved in the abnormal response of hypertensive arteries. METHODS AND RESULTS: To investigate the role of endothelium-derived nitric oxide in this abnormality, we studied the vascular effect of the arginine analogue NG-monomethyl-L-arginine, an inhibitor of the endothelial synthesis of nitric oxide, under baseline conditions and during infusion of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, a direct smooth muscle dilator. The study included 11 hypertensive patients (seven men; age, 46.5 +/- 9 years) and 10 normal control subjects (seven men; age, 45.7 +/- 7 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow was similar in normal control subjects and hypertensive patients (2.97 +/- 0.7 versus 2.86 +/- 1.1 mL.min-1.100 mL-1, respectively). NG-monomethyl-L-arginine produced a significantly greater decrease in blood flow in control subjects than in patients (1.08 +/- 0.6 versus 0.32 +/- 0.4 mL.min-1.100 mL-1; p < 0.004). The vasodilator response to acetylcholine was reduced in patients compared with control subjects (maximum flow, 8.2 +/- 4 versus 16.4 +/- 8 mL.min-1.100 mL-1; p < 0.001). NG-monomethyl-L-arginine blunted the vasodilator response to acetylcholine in control subjects (maximum flow decreased from 16.4 +/- 8 to 7.01 +/- 3 mL.min-1.100 mL-1; p < 0.004); however, the arginine analogue did not significantly alter the response to acetylcholine in hypertensive patients (maximum flow, 8.2 +/- 4 versus 8.01 +/- 5 mL.min-1.100 mL-1). NG-monomethyl-L-arginine did not modify the vasodilator response to sodium nitroprusside in either control subjects or patients. CONCLUSIONS: These findings indicate that patients with essential hypertension have a defect in the endothelium-derived nitric oxide system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators.

Acetylcholine↗
PubMed1993

Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension.

BACKGROUND: Patients with essential hypertension have a deficit in the endothelium-derived nitric oxide system that results in impaired endothelium-dependent vascular relaxation. The objective of this study was to determine whether this abnormality is caused by a deficiency of substrate for nitric oxide synthesis. METHODS AND RESULTS: The vascular responses to acetylcholine (an endothelium-dependent vasodilator infused at 7.5, 15, and 30 micrograms/min) and sodium nitroprusside (a direct smooth muscle dilator infused at 0.8, 1.6, and 3.2 micrograms/min) were studied during combined administration of dextrose 5% or L-arginine (substrate for nitric oxide synthesis infused at 40 mumol/min) in 12 normal control subjects (seven men and five women; age, 49.3 +/- 7 years) and 14 hypertensive patients (nine men and five women; age, 48.4 +/- 7 years). In addition, the effect of D-arginine (stereoisomer of arginine that is not a precursor of nitric oxide) on the vascular responses to acetylcholine was studied in eight normal control subjects and seven hypertensive patients. Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain gauge plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with normal control subjects (maximum flow, 8.9 +/- 5 versus 15.7 +/- 6 mL.min-1.100 mL-1, respectively; p < 0.007); however, no difference was observed in the response to sodium nitroprusside (11.4 +/- 6 and 11.7 +/- mL.min-1.100 mL-1, respectively). L-Arginine did not significantly change basal blood flow or vascular resistance in either group. In normal control subjects, the infusion of L-arginine significantly augmented the vasodilator response to acetylcholine (maximum flow, 15.7 +/- 6 versus 21.4 +/- 8 mL.min-1.100 mL-1 before and after L-arginine, respectively; p < 0.001). In contrast, in hypertensive patients, the infusion of L-arginine did not alter the response to acetylcholine (maximum flow, 8.9 +/- 5 and 8.4 +/- 4 mL.min-1.100 mL-1 before and after L-arginine, respectively). The administration of L-arginine did not modify the response to sodium nitroprusside in either group. Similarly, the infusion of D-arginine did not alter the response to acetylcholine in either group. CONCLUSIONS: In normal humans, availability of substrate for production of nitric oxide is a rate-limiting step for endothelium-dependent vascular relaxation. In contrast, increased availability of nitric oxide precursor does not modify endothelium-mediated vasodilation in hypertensive patients. These findings provide further evidence of a defect in the endothelium-derived nitric oxide system in hypertension and indicate that this abnormality is not related to decreased availability of substrate for nitric oxide production.

Acetylcholine↗
PubMed1995

A comparison of the relaxation responses of isolated cavernosal smooth muscles by endothelium-independent and endothelium-dependent vasodilators in diabetic men with impotence.

This study was intended to explore the effects of endothelium-independent, direct smooth muscle relaxants(papaverine, verapamil) and endothelium-dependent vasodilators(acetylcholine, bradykinin, adenosine) on the isolated cavernosal smooth muscle strips taken from diabetic men with impotence. When smooth muscle contraction was evoked with norepinephrine for the study of relaxation to these vasodilators, the tension induced was similar in diabetic and non-diabetic men with importance. Papaverine showed the strongest relaxation response followed by verapamil, acetylcholine, bradykinin and adenosine both in non-diabetic and in diabetic men. Relaxation of the cavernosal tissues to endothelium-independent vasodilators was similar in non-diabetic and diabetic men. However, the relaxation response of the tissues to endothelium-dependent vasodilators was significantly reduced in the diabetic group compared with that in the non-diabetic group (p < 0.05). In conclusion, the impairment of endothelium-mediated relaxation of cavernosal smooth muscle seems to play a more important role in the pathogenesis of diabetogenic impotence rather than the problem of smooth muscle itself. This finding forms a rational basis for the use of intracavernosal injections of vasodilators to induce endothelium-independent relaxation of the cavernosal smooth muscle in the patients with diabetogenic impotence.

Adult↗
PubMed1998

Endothelium-dependent relaxation of canine pulmonary artery endothelium after prolonged preservation.

OBJECTIVE: Experiments were designed to investigate the effect of Euro-Collins (EC) solution and University of Wisconsin (UW) solution on function of pulmonary arterial endothelium. METHODS: Third order canine pulmonary artery segments were preserved in cold (4 degrees C) UW (group 1, n = 8) or EC (group 2, n = 9) solutions for 16 hours. The preserved (group 1 and 2) and control (group 3, n = 7) pulmonary arterial segments with and without endothelium were studied in vitro in organ chambers to measure isometric tension. RESULTS: The endothelium-dependent relaxation to acetylcholine and adenosine diphosphate of group 1 and 3 were significantly better than those of group 2. CONCLUSIONS: We concluded that endothelium-dependent relaxation of canine pulmonary arterial endothelium to receptor-dependent acetylcholine and adenosine diphosphate were impaired after preservation with Euro-Collins solution. However, endothelium-dependent relaxation of pulmonary segments were well maintained after preservation with University of Wisconsin solution.

Animals↗
PubMed1989

Probing of the canine mammary artery damages endothelium and impairs vasodilation resulting from prostacyclin and endothelium-derived relaxing factor.

It is routine practice for many cardiac surgeons to probe internal mammary arteries to dilate them before their use. The effects of such probing on endothelium integrity, prostacyclin production, and vasodilation resulting from endothelium-derived relaxing factor and from prostacyclin were investigated in vessels isolated from mongrel dogs. Dose-dependent relaxation responses of isolated segments of probed and unprobed mammary arteries to the endothelium-dependent vasodilators methacholine, calcium ionophore (A23187), and melittin were determined in both the presence and absence of indomethacin. Prostacyclin production by probed versus unprobed vascular segments was determined under basal and A23187-stimulated conditions by radioimmunoassay for 6-keto-prostaglandin F1 alpha, and endothelial integrity was determined by scanning electron microscopy. Scanning electron micrographs of segments revealed marked endothelial cell disruption in probed versus unprobed vessels. The dose-dependent relaxation responses to all drugs studied were significantly impaired (p less than 0.05) in probed versus unprobed vessels in both the presence and absence of indomethacin. In addition, prostacyclin release as measured by production of 6-keto-prostaglandin F1 alpha was significantly (p less than 0.05) impaired in probed versus unprobed vessels under both basal and A23187-stimulated conditions. These results imply that routine probing of the internal mammary artery may damage endothelium, impair prostacyclin production, and impair endothelium-dependent vasodilation resulting from both prostacyclin and endothelium-derived relaxing factor.

Animals↗
PubMed1989

Effects of antihypertensive agents on endothelium-dependent and endothelium-independent relaxations.

1. Antihypertensive agents normalize blood pressure and restore depressed endothelium-dependent relaxations in experimental models of hypertension, but little is known regarding whether antihypertensive agents themselves can directly modulate responses to agonists of endothelium-dependent or independent relaxations, or contractions. 2. Normal rats were treated with either tap water, captopril, hydralazine or enalapril in their drinking water for 2 weeks, following which endothelium-dependent and endothelium-independent relaxations were tested with acetylcholine and sodium nitroprusside, respectively, in aortic rings suspended in organ chambers. 3. All antihypertensive agents caused slight but similar potentiation of sodium nitroprusside-induced relaxations. However, their effects on acetylcholine-induced relaxations were quite different: captopril had a marked potentiating effect, hydrazaline a slight potentiating effect, and enalapril had no significant effect on these relaxations. 4. The relaxations induced by acetylcholine and potentiated by captopril were not altered when indomethacin was included in the tissue bath. However, pyrogallol, an inhibitor of endothelium-derived relaxing factor (EDRF), markedly inhibited these relaxations suggesting that captopril's effect may involve EDRF. 5. SQ 14,534, a stereoisomer of captopril which is 100 fold less potent in inhibiting angiotensin converting enzyme, also significantly enhanced acetylcholine induced relaxations. Thus the effects of both captopril and SQ 14,534 upon EDRF appear independent of the effects of these compounds on the angiotensin converting enzyme. 6. We conclude that certain antihypertensive agents may modulate endothelium-dependent relaxations in response to agonists, and that these properties may be of therapeutic importance in cardiovascular diseases.

Acetylcholine↗
PubMed1992

[Effect of endothelium-derived nitric oxide and prostaglandins on the endothelium-dependent vascular refractoriness to angiotensin II in pregnant rabbits].

Recently we demonstrated that the vascular response to angiotensin II (A-II) was attenuated in an endothelium-dependent manner by using the isolated ring specimen iliac arteries of pregnant rabbits. In this paper we investigated the possibility that three vasoactive substances, thromboxane A2(TXA2), prostacyclin (PGI2), and endothelium-derived nitric oxide (EDNO), might be involved in this refractoriness to A-II during pregnancy, by measuring the changes in the vascular response to A-II (pA2, intrinsic activity) of the isolated arterial rings of rabbits before and after the addition of an inhibitor specific for each of these three substances. Sodium ozagrel, TXA2 synthetase inhibitor, decreased the vascular response to A-II more in the blood vessels of pregnant rabbits, regardless of whether the endothelium was intact or denuded, than in the blood vessels of non pregnant rabbits. Tranylcypromine, a PGI2 synthetase inhibitor, significantly increased contractility in the blood vessels with intact endothelium of pregnant rabbits (i.a. = 1.39 +/- 0.099, n = 11, mean +/- SEM), compared to that in the blood vessels with intact endothelium of non pregnant rabbits (i.a. = 1.08 +/- 0.090, n = 7). Methylene blue, a guanylate cyclase inhibitor which blocks the effect of EDNO, amplified the vascular response in blood vessels with intact endothelium of both groups, and more intensely in the blood vessels of pregnant rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1985

Blockade of endothelium-dependent relaxation by the amiloride analog dichlorobenzamil: possible role of Na+/Ca++ exchange in the release of endothelium-derived relaxant factor.

The importance of extracellular calcium for the expression of endothelium-dependent relaxation was examined in isolated rat aortic rings contracted by methoxamine. The endothelium-dependent relaxation generated by acetylcholine or the calcium ionophore A23187 was eliminated when rings were placed in physiological buffer to which calcium had not been added. The endothelium-independent relaxation to sodium nitroprusside was still elicited in the presence of this "low calcium" buffer. Pretreatment of aortic rings with high concentrations of nifedipine (5 X 10(-7) M) or verapamil (10(-5) M) caused a comparable displacement to the right (2-3 times) in the relaxant dose-response curve for acetylcholine, A23187 and sodium nitroprusside with little or no changes in the maximal relaxation obtained with these vasodilators. Increasing concentrations of dichlorobenzamil, an analog of amiloride and a recently described inhibitor of calcium influx via sodium-calcium exchange, functionally antagonized and abolished the relaxations elicited by acetylcholine and A23187, but had no appreciable effect on the relaxations to sodium nitroprusside or atrial natriuretic factor (an endothelium-independent vasodilator). Similar results were obtained using isolated rabbit aortic rings. Thus, although the presence of extracellular calcium is critically required for the expression of endothelium-dependent relaxation, the associated calcium translocation is not blocked by the organic calcium entry blockers. The results with dichlorobenzamil suggest that sodium-calcium exchange may be an important mechanistic step in the release of endothelium-derived relaxant factor.

Acetylcholine↗
PubMed1998

Calcium dobesilate increases endothelium-dependent relaxation in endothelium-injured rabbit aorta.

Calcium dobesilate (DOBE) is an orally administered angioprotective agent which is used in some vascular diseases such as diabetic retinopathy, although its mechanism of action is not yet fully understood. The aim of this work was to correlate previous rising single quote, left (low)in vitro' findings carried out in our laboratory with an rising single quote, left (low)ex vivo' model of endothelium-injury by overdose of vitamin D2. Male New Zealand White rabbits were used. The study was divided into two protocols. Protocol 1: 10 days of treatment; and Protocol 2: 30 days of treatment. Rabbits in each group were treated with vitamin D2 (200"000 IU day-1) for the first 2 days and two groups were subsequently treated with DOBE at different doses (50 mg kg-1 per day or 500 mg kg-1 per day). The concentration-response curve induced by NA (10(-8)-10(-4) M) in aorta arteries was shifted downwards in the groups treated with DOBE (in both Protocol 1 and 2), whereas only in Protocol 2 (30 days of treatment) was this curve affected in the hypervitaminic group. The endothelium-dependent relaxation induced by ACh (10(-8)-10(-5) M) decreased in the hypervitaminic groups (in both Protocol 1 and 2) but only in Protocol 2 (30 days of treatment) was the endothelium-dependent relaxation restored to normal (control, untreated group) in both DOBE-treated groups. The endothelium-independent relaxation induced by sodium nitroprusside (SNP) (10(-8)-10(-4) M) decreased in the hypervitaminic groups only in Protocol 1. We did not find differences in the DOBE-treated groups in any protocol compared with the control (untreated) group. These findings show evidence that DOBE restored endothelial functionality in endothelium-injured rabbit aorta only after 30 days of treatment. (c) 1998 The Italian Pharmacological Society.

Acetylcholine↗
PubMed1989

Vascular endothelium in ischemic heart disease: possible role for endothelium-derived relaxing factor.

The nature, mechanism of action, and roles of endothelium-derived relaxant factor (EDRF) are reviewed, particularly in relation to the coordination of vascular behavior in response to changes in flow, coronary spasm, and platelet aggregation. Vascular endothelium performs a multiplicity of roles. It is an active sieve for macromolecules and leukocytes, a negatively charged "lubricant" for passage of negatively charged red cells and platelets, and a factory for Von Willebrand factor, glycoaminoglycans, and plasminogen activator and its inhibitor. It is also a processing plant that metabolizes adenosine nucleotides to adenosine and activates angiotensin. Endothelium also produces prostacyclin and endothelium-derived relaxant factor, which act synergistically and through different pathways to the common ends of relaxing vascular smooth muscle and inhibiting platelet aggregation. Most recently it has been shown to also produce a constrictor agent called endothelin, a peptide whose structure has now been elucidated. This review will concentrate on EDRF, the recently discovered vasodilator agent that is continuously released by all vascular endothelium. It would be premature to define the role of EDRF in ischemic heart disease. It may, however, be timely to consider the ways in which EDRF might be relevant, based on a review of what is at present known.

Animals↗
PubMed1997

Impairment of endothelium-dependent but not of endothelium-independent dilatation in guinea-pig aorta rings incubated in the presence of elevated glucose.

1. Purine compounds such as ATP and adenosine, respectively endothelium-dependent and- independent vasodilators, are largely involved in the control of vascular tone and vascular reactivity to contracting stimuli. We investigated the relaxing activity of ATP and adenosine in guinea-pig aorta rings exposed for 6 h to elevated glucose concentration (50 mM), in order to mimic hyperglycaemic conditions. Guinea-pigs were reserpine-treated (2 mg kg-1, i.p., 48 and 24 h before death). 2. Rings of aortae incubated in 50 mM glucose, contracted submaximally by 1 microM noradrenaline, lost endothelium-dependent relaxation in response to acetylcholine (10 nM to 10 microM). Aortae incubated with 50 mM mannose, as a hyperosmotic control, relaxed to acetylcholine normally. Rings of aortae incubated in 50 mM glucose, contracted submaximally by 3 mM 4-aminopyridine, lost endothelium-dependent relaxation in response to ATP (30 microM) whereas endothelium-independent relaxation in response to adenosine (0.3 mM) was well preserved. 4. The relaxation induced by A23187 or sodium nitroprusside (10 nM to 0.1 microM) did not differ between rings exposed to control (5.5 mM) or elevated glucose (50 mM) and contracted submaximally by 3 mM 4-aminopyridine. 5. When incubated with aortic tissue in the presence of elevated glucose, the cyclo-oxygenase inhibitors, indomethacin (10 microM) and mefenamic acid (30 microM), or the scavenger of superoxide anions, superoxide dismutase (150 u ml-1), prevented the impairment of ATP-mediated relaxation. 6. The present results indicate that endothelium-dependent, receptor-induced relaxation in response to acetylcholine and ATP is impaired in guinea-pig aorta rings exposed to elevated glucose. The endothelial dysfunction caused by glucose might be located at a step between receptor activation and intracellular calcium increase, and might be related to an increased metabolism of arachidonic acid coupled to an increased production, or to a reduced inactivation of superoxide anions.

Acetylcholine↗
PubMed1991

Effect of destruction of the vascular endothelium upon pressure/flow relations and endothelium-dependent vasodilatation in resistance beds of spontaneously hypertensive rats.

1. Pressure/flow relationships were determined in the in situ blood-perfused superior mesenteric and hindquarters vascular beds of spontaneously hypertensive rats and Wistar-Kyoto normotensive rats before and after destruction of the endothelium with detergent. The effects of indomethacin on the regression of pressure on flow were also investigated in the spontaneously hypertensive rats, as were the endothelium-dependent relaxations in response to carbachol in the mesenteric bed. 2. In the spontaneously hypertensive rats the regression line of pressure on flow in the two vascular beds was both steeper and more elevated than in the Wistar-Kyoto rats, showing that there was greater resistance to flow in the hypertensive animals. Destruction of the endothelium significantly increased the slope of the regression in both Wistar-Kyoto and spontaneously hypertensive rats: the increases in the Wistar-Kyoto rats were 2.4 +/- 0.3 fold (mesenteric) and 2.0 +/- 0.5 fold (hindquarters) which were comparable with the respective increases of 1.6 +/- 0.3 fold and 1.8 +/- 0.3 fold in the spontaneously hypertensive rats. 3. Indomethacin (5 mg/kg, intravenously) had no effect on the pressure/flow relations in either of the vascular beds of the spontaneously hypertensive rats. 4. The dose-response curves for the endothelium-dependent vasodilatation in response to carbachol were not significantly different in spontaneously hypertensive and Wistar-Kyoto rats. 5. The results suggest that tonic release of endothelium-derived relaxing factor has similar effects in modulating resistance vessel tone in vivo in both hypertensive and normotensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗