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PubMed2003

Chronic treatment of male rats with daidzein and 17 beta-oestradiol induces the contribution of EDHF to endothelium-dependent relaxation.

1. We investigated the effect of chronic (7 days) treatment of male rats with the isoflavone daidzein (0.2 mg kg(-1) sc per day) or 17beta-oestradiol (0.1 mg kg(-1) sc per day) on the contribution of nitric oxide (NO), prostaglandins and endothelium-derived hyperpolarising factor (EDHF) to endothelium-dependent relaxation of isolated aortic rings. 2. The sensitivity and maximum relaxation to acetylcholine (ACh) were significantly greater in aortic rings from rats treated with daidzein or 17beta-oestradiol, in comparison to vehicle-treated rats. Inhibition of nitric oxide synthase with N-nitro-l-arginine (l-NOARG) abolished ACh-induced relaxation in the aortae from vehicle-treated rats, but only attenuated relaxation in aortae from daidzein or 17beta-oestradiol-treated rats. The presence of haemoglobin in addition to l-NOARG did not cause any further inhibition of relaxation. 3. The cyclooxygenase inhibitor indomethacin had no effect on endothelium-dependent relaxation in aortae from any treatment group. Charybdotoxin (ChTX), which blocks large-conductance calcium-activated potassium channels (BK(Ca)) and intermediate-conductance calcium-activated potassium channels (IK(Ca)), plus apamin, which blocks small-conductance calcium-activated potassium channels (SK(Ca)), but not iberiotoxin, which only blocks BK(Ca), attenuated endothelium-dependent relaxation of aortae from daidzein or 17beta-oestradiol-treated rats. Blockade of K(Ca) channels had no effect on the responses to ACh in aortae from vehicle-treated rats. In aortae from daidzein- or 17beta-oestradiol-treated rats, endothelium-dependent relaxation was also attenuated by inhibition of cytochrome P450 (CYP450) epoxygenase with 6-(2-propargylloxyphenyl)hexanoic acid (PPOH) or inhibition of K(IR) channels and Na(+)/K(+)-ATPase with barium and oubain, respectively. 4. This study demonstrates that endothelium-dependent relaxation of male rat aorta is normally entirely mediated by NO, whereas treatment with daidzein or 17beta-oestradiol stimulates a contribution from a non-NO, nonprostaglandin factor acting through the opening of SK(Ca) and IK(Ca) channels, and involving activation of Na/K-ATPase, K(IR) and CYP450 epoxygenase. This pattern of sensitivity to the tested inhibitors is consistent with the contribution of EDHF to relaxation. Thus, EDHF contributes to the enhanced endothelium-dependent relaxation that is observed after chronic treatment with the phytoestrogen daidzein or with 17beta-oestradiol.

Animals↗
PubMed1996

Effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent relaxation in two-kidney, one-clip Goldblatt hypertensive and sham-operated rats.

1. This study was designed to examine the effect of angiotensin-converting enzyme inhibitors on resistance artery structure and endothelium-dependent relaxation in Goldblatt two-kidney, one-clip hypertensive rats. Four weeks after clipping, hypertensive and sham rats were treated with either perindopril (1 mg day-1 kg-1) or quinapril (3 or 30 mg day-1 kg-1). After 6 weeks mesenteric resistance arteries were mounted in a myograph for measurements of vascular structure. The endothelium-dependent relaxation response to acetylcholine and bradykinin and the response to the nitric oxide donor sodium nitroprusside were recorded. 2. All treatment regimes lowered the blood pressure and reversed both cardiac and resistance artery hypertrophy. Two-kidney, one-clip rats treated with quinapril showed a dose-dependent reduction in media cross-sectional area and media to lumen ratio. 3. Hypertension of 10 weeks' duration was associated with an impaired endothelium-dependent relaxation response to acetylcholine and bradykinin. Treatment with perindopril and either dose of quinapril prevented the development of impaired endothelium-dependent relaxation but had no effect on the response to sodium nitroprusside. Treatment had no effect on endothelium-dependent relaxation in sham rats. 4. Angiotensin-converting enzyme inhibitor treatment is effective in normalizing blood pressure and cardiovascular structural changes. Angiotensin-converting enzyme inhibitor treatment prevented the development of impaired endothelium-dependent relaxation to both acetylcholine and bradykinin. The ability of angiotensin-converting enzyme inhibitors to reverse cardiovascular structural changes and prevent the development of abnormal endothelium-dependent relaxation may contribute to the overall effect of this type of antihypertensive drug.

Acetylcholine↗
PubMed1997

Effect of red wine on endothelium-dependent relaxation in rabbits.

1. Published data on the effects of red wine, ethanol and flavonoids on endothelium-dependent relaxation are equivocal. The present study was undertaken to determine the effects of red wine, ethanol and selected flavonoids present in red wine on endothelium-dependent relaxation. 2. Aortic rings from New Zealand White rabbits were set up in organ baths (20 ml) and contracted with noradrenaline (10(-6) mol/l). An attempt was made to elicit dose-dependent relaxant responses to red wine (15, 30, 40, 80 or 120 microliters), ethanol (5.4, 10.8 and 16.2 microliters) and the flavonoids catechin, epicatechin, quercetin and polymeric phenols (10(-7) to 10(-4) mol/l). In some experiments, endothelium-dependent relaxation to cumulative doses of acetylcholine (10(-9) to 10(-6) mol/l) was determined before and after incubating the rings for 15 min with red wine (120 microliters), ethanol (16.2 microliters), quercetin (10(-5) mol/l), catechin (10(-5) mol/l), epicatechin (10(-5) mol/l) and PPs (10(-5) mol/l) respectively. cGMP was also measured in some rings in the control state and after addition of 120 microliters of red wine, sodium nitroprusside (10(-4) mol/l) and polymeric phenols (10(-5) mol/l). 3. Red wine evoked a dose-dependent relaxation in aortic rings. The highest volumes of wine (120 microliters) relaxed the vessels by 71.35 +/- 7.89% of the maximal contraction (8.95 +/- 0.97 g). Polymeric phenols also relaxed the precontracted rings. These responses were abolished by NG-L-arginine methyl ester (L-NAME) and by removal of endothelium. Addition of red wine, polymeric phenols and sodium nitroprusside increased the cGMP content of the rings. In tissues previously incubated with red wine and polymeric phenols, endothelium-dependent relaxation in response to acetylcholine was attenuated. Ethanol had no such effect. 4. Acute exposure of aortic rings to red wine and polymeric phenols evokes an endothelium-dependent relaxation which is mediated by nitric oxide. However, prior exposure to both red wine and polymeric phenols has a second effect in that it attenuates the endothelium-dependent relaxation evoked by acetylcholine. Since this effect is restored by arginine, it is likely to be due to depletion of substrate for nitric oxide synthase.

Animals↗
PubMedDate not supplied

Long-term oestrogen therapy is associated with improved endothelium-dependent vasodilation in the forearm resistance circulation of biological males.

1. The aim of the present study was to determine the effects of long-term oestrogen on resistance vessel reactivity in biological males. 2. Recent studies have demonstrated that long-term oestrogen therapy favourably alters the lipid profile and improves vasodilator function in the conduit arteries of biological males. Whether a similar benefit is exerted on the resistance circulation is not known. Therefore, we examined the effects of long-term oestrogen therapy on skeletal muscle resistance vessel function in biological males and the potential mechanisms by which it may exert its effects. 3. Forearm blood flow (FBF) and resistance were compared in 15 male-to-female transsexuals being prescribed oestrogen, with 14 age-matched healthy males, at rest and in response to the endothelium-dependent nitric oxide (NO) vasodilator acetylcholine (ACh), the endothelium-independent but NO-mediated vasodilator sodium nitroprusside (SNP), the endothelium-independent and non-NO-mediated vasodilator verapamil (VER) and the endothelium-independent vasoconstrictor phenylephrine (PE). 4. Basal blood flows were similar in the two groups. However, the male-to-female transsexuals had a significant upward and leftward shift in FBF responses to ACh compared with males, with a 52% increase in FBF responses at the highest dose of ACh used. Forearm blood flow in transsexuals rose from a mean (+/- SEM) baseline level of 3.02 +/- 0.25 to a maximum of 19.5 +/- 2.59 mL/min per 100 mL forearm tissue (compared with 3.24 +/- 0.41 and 9.43 +/- 1.97 mL/min per 100 mL forearm tissue, respectively, in males) with the highest dose of ACh (+2.73 micrograms/min per 100 mL; P < 0.0005). Forearm vascular resistance was also significantly reduced in transsexuals compared with males (P < 0.05). Vasodilator responses to SNP, VER and PE were similar in both groups. 5. There were no differences observed in total cholesterol and low-density lipoprotein-cholesterol levels. However, male-to-female transsexuals had 20% higher high-density lipoprotein-cholesterol levels compared with males (1.57 +/- 0.11 vs 1.26 +/- 0.08 mmol/L, respectively; P < 0.05) and 47% higher triglyceride levels (P < 0.005). Serum testosterone levels (an index of oestrogen therapy) was a predictor of responses to endothelium-dependent vasodilation (rs = -0.50; P < 0.01). 6. Long-term oestrogen therapy enhances endothelium-dependent vasodilation in the skeletal muscle microcirculation of biological males. The effects appear to be selective because endothelium-independent vasodilation and vasoconstriction are not altered.

Acetylcholine↗
PubMed1999

Age-related endothelium-dependent vascular relaxation in rat thoracic aorta in response to colforsin.

BACKGROUND: Colforsin, a novel water-soluble forskolin derivative, increases intracellular cyclic AMP by direct stimulation of adenylate cyclase and has strong positive inotropic and vasodilative effects. However, it is not known whether colforsin causes nitric oxide (NO) release and enhances endothelium-dependent vascular relaxation. METHODS: We studied NO production and relaxation on exposure to colforsin in thoracic aorta from rats aged 4, 12 and 60 weeks. RESULTS: When a low concentration of colforsin was added to a solution bathing ring segments of aorta from 12-week-old rats, relaxation was greater in the ring segments with intact endothelium than in those from which the endothelium had been removed. A high concentration of colforsin induced the same degree of relaxation of ring segments with or without endothelium, probably by a direct effect on vascular smooth muscle cells. Production of NO in response to colforsin by cultured endothelial cells from 12-week-old rat aorta was demonstrated by the electron paramagnetic resonance spin trapping method. A low concentration of colforsin relaxed aortic segments with intact endothelium from 4-week-old rats more than those from 12-week-old or 60-week-old rats. Reversal of relaxation by NG-nitro L-arginine, an NO synthesis inhibitor, was most significant in arteries from 4-week-old rats. Production of NO after exposure to colforsin was greater in aortic segments from 4-week-old rats than older rats, as detected by an NO-selective electrode. CONCLUSIONS: Colforsin induces vasodilation in part by releasing NO from the endothelium in rat thoracic aorta. In addition to a direct vasodilative effect on the vascular smooth muscle cells, an endothelium-dependent vasodilative effect is also important in younger arteries.

Aging↗
PubMed2001

Role of endothelium in adenosine receptor-mediated vasorelaxation in hypertensive rats.

The present study was designed to investigate the role of endothelium derived relaxing factor nitric oxide (NO) in adenosine A2 receptor mediated vasorelaxation in normotensive (WKY) and hypertensive (SHR) rat aortic ring preparations. Adenosine analogues, 2-chloroadenosine (CAD) and 5-ethylcarboxamidoadenosine (NECA) produced concentration-dependent (10(-9)-10(-4) M) relaxation in phenylephrine (1 x 10(-6) M) precontracted vascular rings, which was significantly shifted to the right in SHR compared to WKY rats. Endothelium removal attenuated CAD and NECA relaxation responses in both SHR and WKY and abolished the difference in relaxation between SHR and WKY vascular tissues. The relaxation response to CAD was antagonised by adenosine A2 receptor antagonist, 8-sulfophenyltheophylline (8-SPT, 50 x 10(-6) M). The antagonism by 8-SPT was lower in SHR as compared to WKY tissues. L-monomethylarginine (L-LMMA) (30 x 10(-6) M) significantly shifted the CAD relaxation to the right, which was reversed by the addition of L-arginine (100 x 10(-6) M) in both SHR and WKY rats. However, the rightward shift by L-NMMA was smaller in SHR compared to WKY vascular tissues. Vasorelaxation response to acetylcholine (1 x 10(-6) M) was significantly inhibited (50%) in SHR rings compared to WKY. The relaxation produced by sodium nitroprusside (10(-9)-10(-5) M) in endothelium-intact and -denuded aortic rings showed no difference between SHR and WKY. Isoproterenol produced concentration-dependent (10-9-10-5 M) relaxation, which was shifted to the right in SHR compared to WKY rings with an intact endothelium, while the removal of endothelium abolished the difference in the response between SHR and WKY. The results suggest: (i) adenosine A2 receptors mediate vasorelaxation in part through endothelium possibly by releasing nitric oxide (NO); (ii) the impairment of endothelium may be one of the factors for the attenuation of adenosine receptor and receptor-mediated responses in SHR.

Adenosine↗
PubMed2002

Endothelium in hepatic cavernous hemangiomas does not express the hyaluronan receptor for endocytosis.

The liver contains two distinct endothelial cell types: vascular and sinusoidal. Although cavernous hemangioma is the most common benign tumor of the liver, vascular or sinusoidal endothelial cell differentiation has not been described. An endocytic receptor responsible for the uptake and degradation of hyaluronan is present in the sinusoidal endothelium of the liver. The hyaluronan receptor for endocytosis (HARE) may therefore be a useful marker for sinusoidal endothelial cell differentiation. Using monoclonal antibodies specific for HARE, CD31, and factor VIII, we completed an immunohistochemical study of the endothelial cells of both hepatic cavernous hemangiomas and of nonneoplastic human liver. The anti-HARE monoclonal antibodies showed diffuse strong staining of nonneoplastic liver sinusoidal endothelium. No staining of nonsinusoidal endothelium or the endothelial lining of the hemangiomas was seen with anti-HARE. In contrast, diffuse strong staining for factor VIII and CD31 was present in nonsinusoidal endothelium and cavernous hemangioma endothelium. Neither factor VIII nor CD31 staining was present in the sinusoidal endothelium. In conclusion, the endothelium of hepatic cavernous hemangiomas demonstrates vascular but not sinusoidal differentiation based on the absence of HARE and presence of CD31 and factor VIII.

Adult↗
PubMed1988

Difference between endothelium-dependent relaxation in arterial and in venous coronary bypass grafts.

Both the internal mammary artery and the saphenous vein are used to construct coronary-artery bypass grafts. We hypothesized that the release or production of endothelium-derived relaxing factor, which regulates blood flow and inhibits platelet function, may differ in venous and arterial grafts. We therefore studied endothelium-dependent relaxation in internal mammary arteries, internal mammary veins, and saphenous veins obtained from 58 patients undergoing coronary bypass surgery. Vascular rings with and without endothelium were suspended in organ chambers, and isometric tension was recorded. Acetylcholine (10(-8) to 10(-4) M), thrombin (1 U per milliliter), and adenosine diphosphate (10(-7) to 10(-4) M) evoked potent endothelium-dependent relaxation in the mammary artery but weak response in the saphenous vein (P less than 0.005; n = 6 to 27). In the mammary artery, relaxation was greatest in response to acetylcholine (86 +/- 4 percent reduction in norepinephrine-induced tension), followed by thrombin (44 +/- 7 percent) and adenosine diphosphate (39 +/- 8 percent). In the saphenous and mammary veins, relaxation was less than 25 percent. Relaxation was unaffected by indomethacin but was inhibited by methylene blue and hemoglobin (P less than 0.005 and 0.01, respectively), which suggests that endothelium-derived relaxing factor was the mediator. Endothelium-independent relaxation in response to sodium nitroprusside was similar in arteries and veins. We conclude that endothelium-dependent relaxation is greater in the mammary artery than in the saphenous vein. The possibility that this contributes to the higher patency rate among arterial grafts than among venous grafts will require further study.

Acetylcholine↗
PubMed2000

Exogenous hyaluronidase induces release of nitric oxide from the coronary endothelium.

OBJECTIVE: Hyaluronidase, an endogenous enzyme that hydrolyzes mucopolysaccharides, has been shown to enhance myocardial protection when added to preservation solutions. In addition, hyaluronidase infusion reduces injury to ischemic myocardium. Endothelium-derived nitric oxide is an endogenous vasodilator that prevents leukocyte adhesion to the intima and inhibits platelet adhesion and aggregation in the coronary artery. Experiments were undertaken to determine whether the protective action of hyaluronidase could be mediated by the endogenous release of nitric oxide. METHODS: Segments of coronary artery, with and without endothelium, were placed in organ chambers (25 mL) to measure isometric force. Blood vessel segments were contracted with prostaglandin F(2)(alpha) (2 x 10(-6) mol/L) and exposed to hyaluronidase (3-15 units). RESULTS: Hyaluronidase induced vasodilation of arteries with intact endothelium but not of arteries without endothelium (n = 6, P<.05). Endothelium-dependent vasodilation to hyaluronidase was blocked by N(G)-monomethyl-L -arginine (10(-5) mol/L), an inhibitor of nitric oxide synthesis from L -arginine (n = 6, P<.05). Inhibition of vasodilation by N(G)-monomethyl-L -arginine was reversed by L -arginine (10(-4) mol/L) but not D -arginine (10(-4) mol/L; n = 6, each group). Vasodilation to hyaluronidase also was inhibited by hemoglobin (2 x 10(-6) mol/L), a scavenger of the nitric oxide radical (n = 6, P<.05). CONCLUSIONS: Hyaluronidase induces the release of nitric oxide from the coronary endothelium. Because nitric oxide, an endogenous vasodilator, inhibits leukocyte adhesion to the intima in addition to inhibiting platelet adhesion and aggregation, stimulated production of endothelium-derived nitric oxide by exogenous hyaluronidase could be the mechanism of the protective action of hyaluronidase infusion.

Analysis of Variance↗
PubMed2003

Leukocyte-inspired biodegradable particles that selectively and avidly adhere to inflamed endothelium in vitro and in vivo.

We exploited leukocyte-endothelial cell adhesion chemistry to generate biodegradable particles that exhibit highly selective accumulation on inflamed endothelium in vitro and in vivo. Leukocyte-endothelial cell adhesive particles exhibit up to 15-fold higher adhesion to inflamed endothelium, relative to noninflamed endothelium, under in vitro flow conditions similar to that present in blood vessels, a 6-fold higher adhesion to cytokine inflamed endothelium relative to non-cytokine-treated endothelium in vivo, and a 10-fold enhancement in adhesion to trauma-induced inflamed endothelium in vivo due to the addition of a targeting ligand. The leukocyte-inspired particles have adhesion efficiencies similar to that of leukocytes and were shown to target each of the major inducible endothelial cell adhesion molecules (E-selectin, P-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1) that are up-regulated at sites of pathological inflammation. The potential for targeted drug delivery to inflamed endothelium has significant implications for the improved treatment of an array of pathologies, including cardiovascular disease, arthritis, inflammatory bowel disease, and cancer.

Antibodies, Monoclonal↗
PubMedDate not supplied

Ultrastructural damage in vascular endothelium in rats treated with paclitaxel and doxorubicin.

Endothelium is the first physiological barrier between blood and tissues and can be injured by physical or chemical stress, particularly by the drugs used in the cancer therapy. Paclitaxel and doxorubicin are frequently used anticancer drugs and their cardiac side effects are well observed in clinical setting. Their side effects on the endothelium are still not clear enough. There are few investigations assessing the damages elicited by the combination use of chemotherapy agents in animal experimental models. The purpose of this study was to examine and compare the side effects of doxorubicin and paclitaxel on endothelium in vivo. The drugs were administered weekly to rats via intraperitoneal injections singly or in combinations. Lastly, aorta endothelium was examined. The most familiar parts of the aorta endothelium are the nucleus, free ribosomes, Weibel-Palada granules, plasmalemmal vesicles, and clear basement membrane. Examination of the endothelium and the related structures revealed some clear degenerative findings. Notably, administration of a paclitaxel and doxorubicin combinations caused the most dramatic change in ultrastructure, which may disrupt many functions of the endothelium.

Animals↗
PubMed2005

Ultra-low dose beta-irradiation induces constriction of rabbit carotid arteries via the endothelium.

PURPOSE: To investigate the action of ultra-low dose beta-radiation (ULDBR) on isolated segments of blood vessels. MATERIALS AND METHODS: We used the pharmacological model of isolated rabbit carotid arteries with intact or mechanically removed endothelium. Specific vascular responses to beta-irradiation were registered after addition of (90)Sr in the concentration range between 12 and 96 microCi l(-1) to the organ bath containing physiological salt solution (PSS). RESULTS: Intact vascular rings, preconstricted with 20 mM K(+)-PSS, developed an additional constriction upon the addition of (90)Sr depending on the absorbed radiation dose (21.5, 42.9, 85.8, and 171.6 microGy) and the dose rate (51.5, 103.0, 206.0 and 412.0 microGy h(-1)). The vasoconstriction due to (90)Sr was absent in the endothelium-denuded vascular segments indicating the endothelium dependent action of ULDBR. Irradiation did not alter the endothelium dependent relaxation of rabbit carotid arteries induced by acetylcholine. The endothelium dependent responses to ULDBR were abolished after increasing the extra-cellular K(+) to 40 mM. CONCLUSIONS: ULDBR acts on rabbit carotid arteries as a pharmacological signalling agent because ULDBR effects were completely reversible. ULDBR-mediated contractile responses of the vessels are endothelium dependent. The resistance of acetylcholine endothelium-dependent relaxation of rabbit carotid arteries to ULDBR indicates that the polyphosphoinositide-nitric oxide (NO) signalling cascade is not impaired by ULDBR in endothelial cells.

Animals↗
PubMed1996

Mononuclear phagocytes egress from an in vitro model of the vascular wall by migrating across endothelium in the basal to apical direction: role of intercellular adhesion molecule 1 and the CD11/CD18 integrins.

Little is known about how mononuclear phagocytes (MP) are cleared from sites of inflammation as inflammatory lesions resolve. In this study, the possibility that MP could be cleared from tissues by migrating across endothelium in the basal to apical direction was investigated. In an in vitro model of a blood vessel wall consisting of human umbilical vein endothelial cells (HUVEC) grown on amniotic tissue, a majority of MP that initially transmigrated into the amnion later exited by migrating back across the endothelium in the basal to apical direction. MP that egressed from these cultures adhered to the apical surface of the endothelium or were found nonadherent in the medium above the endothelium. Egression of MP continued throughout the 4-d period examined, displaying higher than first order kinetics and a t(1/2) of approximately 24 h. These kinetics were decreased by increasing the volume of medium bathing the cultures, suggesting that a soluble factor(s) regulates the rate of egression. In contrast, the kinetics were accelerated by pretreating the endothelium with IL-1. The initial phase of this increased rate of egression was inhibited by antibodies to inter- cellular adhesion molecule 1 (ICAM-1) or CD18 by 100 and 71%, respectively. Immunostaining revealed that ICAM-1 was present on the apical and basal surfaces of umbilical vein endothelium in vitro and in situ. These data demonstrate that MP can traverse endothelium in the basal to apical direction, and lend insight into the mechanisms by which this process occurs.

Amnion↗
PubMed1990

Imbalance of endothelium-derived relaxing and contracting factors. A new concept in hypertension?

The endothelium has a strategical anatomical position between the circulating blood and vascular smooth muscle cells. It has recently been recognized that endothelial cells play an important regulatory role in the circulation. The cells metabolize or activate vasoactive hormones (ie, norepinephrine, serotonin, bradykinin, angiotensin II), produce substances involved in coagulation and can release endothelium-derived relaxing factors and contracting factors. Nitric oxide and prostacyclin are vasodilators and inhibitors of platelet function. Endothelin is the most potent vasoconstrictor substance known. Thus, the endothelium can profoundly affect platelet adhesion and aggregation, vascular smooth muscle tone and possibly also vascular smooth muscle growth. Under physiological conditions, endothelium-derived relaxing factors appear to dominate. In contrast, in hypertensive and atherosclerotic arteries the release of endothelium-derived relaxing factors and/or the responsiveness of vascular smooth muscle cells to the relaxing factors is reduced, while that of endothelium-derived contracting factors is augmented. This imbalance of endothelium-derived relaxing and contracting factors may be important in the pathogenesis of hypertension and its cardiovascular complications.

Animals↗
PubMed1991

Effects of perindoprilat on endothelium-dependent relaxations and contractions in isolated blood vessels.

Experiments were designed to study the effects of perindoprilat (S 9780) on endothelium-dependent and -independent relaxations and contractions in isolated blood vessels. Rings of either canine femoral, basilar or left anterior descending coronary arteries, pulmonary veins, or thoracic aortas from normotensive and hypertensive rats were suspended in organ chambers for isometric tension measurement. Perindoprilat did not evoke endothelium-dependent or -independent relaxations of femoral arteries, basilar arteries, coronary arteries, or rat aortas. The compound did not affect the endothelium-independent relaxations induced by isoproterenol and nitroglycerin in canine femoral arteries. However, when given to rings of canine basilar and coronary arteries, increasing concentrations of perindoprilat potentiated the endothelium-dependent relaxation to bradykinin. In addition, the drug potentiated the endothelium-dependent relaxations to acetylcholine and thrombin in preparations of canine left anterior descending coronary arteries. In contrast, perindoprilat did not cause changes in tension when given in the presence of either adenosine diphosphate, serotonin, or arginine-vasopressin. The compound did not modify the endothelium-dependent contractions evoked by the calcium ionophore A23187 and acetylcholine in canine basilar arteries. It also did not alter endothelium-dependent contractions to arachidonic acid or to hypoxia in canine pulmonary veins or to acetylcholine in the aorta of the spontaneously hypertensive rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

Impairment of endothelium dependent responses in a rat model of chronic heart failure: effects of an exercise training protocol.

OBJECTIVE: The aim was to document the response of aortic rings from a rat model of heart failure to endothelium dependent and endothelium independent vasodilating agents. The effects of an exercise training schedule upon these responses was studied. METHODS: Heart failure was produced in one group of female Wistar rats by coronary artery occlusion, and sham operations were performed in a matched group. The rats were allowed to recover for six weeks, following which half the rats with heart failure were started on a treadmill exercise schedule for a further six weeks. After this time the rats were killed, and rings of aorta were studied in an organ bath to measure the response to both endothelium dependent and endothelium independent vasoactive agents. RESULTS: The presence of heart failure was confirmed in both the non-trained (NT, n = 5) and trained rats (TR, n = 5), but not in the sham operated animals (SH, n = 6). The constrictor response to prostaglandin F2 alpha was similar in aortic rings from all the animals. The relaxation response to the endothelium dependent vasodilator acetylcholine (10(-7) and 10(-6) M) was impaired in the rats with heart failure compared to the sham operated animals (10% v 33% with 10(-7) M acetylcholine, p < 0.005). The dilator response in the trained rats was not significantly greater than in the non-trained rats (TR 35% v NT 24% with 10(-6) M acetylcholine). There was no difference in the response to sodium nitroprusside (10(-7) and 10(-6) M) between the three groups. CONCLUSIONS: Chronic heart failure impairs the response of aortic rings to the endothelium dependent vasodilator acetylcholine in a rat model of heart failure. The response to sodium nitroprusside, an endothelium independent relaxing agent, is not impaired by heart failure. These findings may help to explain the raised systemic vascular resistance and the failure of vasodilatation in skeletal muscle vasculature which limits exercise capacity in subjects with heart failure.

Acetylcholine↗
PubMed1989

A new endothelium-dependent vasoconstricting factor (EDCF) in pig coronary artery.

In order to investigate the influence of the endothelium on hypoxia-induced vasospasms we examined vascular tone after reduction of the oxygen supply, dependent on endothelial function. Therefore, after ligation of all side branches, vessel segments of porcine or human right coronary arteries or of rabbit abdominal aorta, prepared either with or without endothelium, were cannulated, perfused with Tyrode's solution and arranged in a serial manner (system I: endothelium-denuded vessel followed by a normal segment; system II: normal vessel followed by an endothelium-denuded segment). The pressure gradient over each segment was continuously measured as a function of vessel radius. After 2 h equilibration the oxygen concentration in the perfusion and superfusion solutions was lowered (reduction from 'control' = 95% O2/5% CO2 to 'hypoxia' = 95% N2/5% CO2) leading to a marked long-lasting vasoconstriction in those endothelium-denuded vessel segments which were mounted distal to a normal vessel with an intact endothelium, whereas the other vessels did not change their tone. This hypoxic contraction could be inhibited by pretreatment with either 1 mumol l-1 dexamethasone or quinacrine or indomethacine. From these results it is concluded that endothelium releases a vasoconstricting factor (EDCF) under hypoxic conditions probably dependent on phospholipase A2 and cyclooxygenase. This EDCF may be of pathophysiological importance by inducing or aggravating hypoxic vasospasms.

Animals↗
PubMed1991

Hypercholesterolaemia, atherosclerosis and release of endothelium-derived relaxing factor by aggregating platelets.

In pig coronary arteries atherosclerosis developed progressively after an experimental mechanical injury to the endothelium, despite its regeneration. The atherosclerotic process can be considerably accelerated by a high cholesterol diet. In arteries with regenerated endothelium, there is a reduction of endothelium-dependent relaxations mediated by (a) pertussis toxin-sensitive G protein(s). As this includes the response to platelet-derived serotonin, the ability of the regenerated endothelium to prevent abnormal vasoconstrictions (and presumably to feedback on platelet aggregation) in response to aggregating platelets is seriously curtailed. These changes are exacerbated in atherosclerotic arteries. Bioassay studies demonstrate that reduced endothelium-dependent relaxations are due mainly to a reduced release of endothelium-derived relaxing factor. Thus, endothelial dysfunction, in particular the reduced ability to release endothelium-derived relaxing factor, is a key factor in determining the abnormal responsiveness of the atherosclerotic blood vessel wall.

Animals↗