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At least 19 recordsLinked to original sources

PubMed1999

Inhibition of endothelium-dependent vascular relaxation by lysophosphatidylcholine: impact of lysophosphatidylcholine on mechanisms involving endothelium-derived nitric oxide and endothelium derived hyperpolarizing factor.

Hyperlipidemia has been associated with an increase in the incidence of atherosclerosis. The oxidation of low density lipoprotein (LDL) plays an important role in the initiation and progression of atherosclerosis, one of its effects being the inhibition of endothelium dependent relaxation (EDR). The elevated level of lysophosphatidylcholine (LPC) in oxidatively modified LDL has been shown to be a biochemical factor responsible for the impairment of EDR in vascular ring preparations. Several endothelium-derived modulators are thought to control vascular responsiveness. The present work examined whether acetylcholine (ACh)-induced EDR in rat aorta (pre-contracted with phenylephrine, PE) involved both endothelium-derived nitric oxide (EDNO) and endothelium-dependent hyperpolarizing factor (EDHF) and whether LPC inhibited either of these selectively. Indomethacin (10(-5) M), had no significant effect on EDR, indicating that products of cyclooxygenase, including prostacyclin, are not involved. Treatment with either N(W)-nitro-L-arginine methyl ester (L-NAME, 6.8 microM) to inhibit the production of EDNO or with elevated K+ (15 mM), to block the hyperpolarizing effect of EDHF impaired EDR considerably (each of these shifting the inhibitory dose-response relationship to ACh by almost one log unit); in muscles treated with both of these agents EDR was completely inhibited. In each of L-NAME- and K-treated muscles, the addition of LPC (20 microM) further impaired EDR. LPC did not independently raise the tone of resting- or PE-contracted aorta. We conclude that the inhibition of EDR of rat aorta by LPC involves the actions of both EDNO and EDHF.

Acetylcholine↗

PubMed1999

P2u receptor-mediated release of endothelium-derived relaxing factor/nitric oxide and endothelium-derived hyperpolarizing factor from cerebrovascular endothelium in rats.

BACKGROUND AND PURPOSE: Stimulation of P2u purinoceptors by UTP on endothelium dilates the rat middle cerebral artery (MCA) through the release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) and an unknown relaxing factor. The purpose of this study was to determine whether this unknown relaxing factor is endothelium-derived hyperpolarizing factor (EDHF). METHODS: Rat MCAs were isolated, cannulated, pressurized, and luminally perfused. UTP was added to the luminal perfusate to elicit dilations. RESULTS: Resting outside diameter of the MCAs in one study was 209+/-7 micrometer (n=10). The MCAs showed concentration-dependent dilations with UTP administration. Inhibition of NO synthase with NG-nitro-L-arginine methyl ester (L-NAME) (1 micromol/L to 1 mmol/L) did not diminish the maximum response to UTP but did shift the concentration-response curve to the right. Scavenging NO with hemoglobin (1 or 10 micromol/L) or inhibition of guanylate cyclase with ODQ (1 or 10 micromol/L) had effects on the UTP-mediated dilations similar to those of L-NAME. In the presence of L-NAME, dilations induced by 10 micromol/L UTP were accompanied by 13+/-2 mV (P<0.009) hyperpolarization of the vascular smooth muscle membrane potential (-28+/-2 to -41+/-1 mV). Iberiotoxin (100 nmol/L), blocker of the large-conductance calcium-activated K channels, sometimes blocked the dilation, but its effects were variable. Charybdotoxin (100 nmol/L), also a blocker of the large-conductance calcium-activated K channels, abolished the L-NAME-insensitive component of the dilation to UTP. CONCLUSIONS: Stimulation of P2u purinoceptors on the endothelium of the rat MCA released EDHF, in addition to EDRF/NO, and dilated the rat MCA by opening an atypical calcium-activated K channel.

4-Aminopyridine↗

PubMed1991

Low level hyperlipidemia impairs endothelium-dependent relaxation of porcine coronary arteries by two mechanisms. Functional change in endothelium and impairment of endothelium-dependent relaxation by two mediators.

We evaluated the effect of a low level of hyperlipidemia and the effects of in vitro exposure to atherogenic lipoproteins (LDL, VLDL) on the vascular responsiveness of isolated porcine coronary arteries. Firstly we studied the change in vascular responsiveness induced by feeding a cholesterol-rich diet to pigs for 4 and 9 weeks (C4 and C9 pigs). The serum cholesterol level in pigs fed a cholesterol-rich diet reached 218.5 +/- 32.9 mg/dl compared with 85.5 +/- 8.4 mg/dl in the controls. Segments of the left descending coronary artery were examined. The contraction induced by KCl or prostaglandin F2 alpha was not altered significantly by hypercholesterolemia nor was the relaxation induced by the Ca2+ ionophore, A23187, or by nitroglycerin. Endothelium-dependent relaxation (EDR) evoked by high, but not low, concentrations of bradykinin was reduced in the C4 pigs as compared with those in normal animals. EDRs evoked by bradykinin, substance P, and serotonin were significantly reduced in C9 pigs. Histologically, as observed by light and electron microscopy, fatty changes or intimal thickenings were not seen in the coronary arteries of the C4 pigs. Minimal changes (intimal thickening and fragmentation of internal elastic lamina) were observed only in parts of arteries of the C9 pigs. Secondly, the direct effects of LDL and VLDL on vascular responsiveness were studied. Although preincubation with LDL inhibited the EDR caused by exposure to bradykinin and A23187 in the coronary arteries of normal and cholesterol-fed pigs, preincubation with LDL inhibited the arterial relaxation induced by exposure to substance P or serotonin in both the C4 and the C9 pigs, but not in the control animals. The degree of inhibition was especially marked in the C9 pigs. The inhibitory effect of VLDL on EDR was weaker than that of LDL. Indomethacin (5 microM) did not alter this inhibitory effect of lipoproteins. Neither LDL nor VLDL had any effect on the vascular relaxation induced by nitroglycerin. These results are consistent with the idea that endothelium-dependent arterial relaxation is attenuated even at the very early stage of cholesterol-induced atherosclerosis. Atherogenic lipoproteins may further impair the decreased EDR in the arteries of hyperlipidemic pigs by two factors: one released on stimulation with bradykinin and the calcium ionophore A23187, the other released on stimulation with substance P and serotonin.

Animals↗

PubMed1989

Natural course of the impairment of endothelium-dependent relaxations after balloon endothelium removal in porcine coronary arteries. Possible dysfunction of a pertussis toxin-sensitive G protein.

The purposes of the present study were to examine the natural course of the impairment of endothelium-dependent relaxations during a regeneration and tissue repair process after balloon endothelium removal and to elucidate the cellular mechanism(s) underlying it. Twenty-three male Yorkshire pigs underwent balloon endothelium removal along the proximal portion of either the left anterior descending or circumflex coronary artery and were then maintained on a regular chow for 4, 8, 16, or 24 weeks. Endothelium-dependent responses were examined in vitro in rings taken from the control and previously denuded arteries studied in parallel. Morphometric analysis revealed that intimal thickening developed only at the previously denuded area. In the previously denuded arteries with regenerated endothelium, the endothelium-dependent relaxations to UK 14304 (a selective alpha 2-adrenergic agonist), serotonin, and aggregating platelets were impaired 4 weeks after endothelium removal and remained so throughout the study. The endothelium-dependent relaxations to thrombin and adenosine diphosphate became depressed 8 weeks after endothelium removal and those to bradykinin became depressed 16 weeks after endothelium removal, while those to the calcium ionophore A23187 were maintained throughout the study. Endothelium-dependent relaxations to all vasoactive agents were unaltered in the control arteries. In the control arteries, pertussis toxin, an inhibitor of certain G proteins, markedly inhibited the endothelium-dependent relaxations to UK 14304 and serotonin and partially inhibited those to thrombin and aggregating platelets. The responses inhibited by the toxin in control arteries were significantly reduced in the reduced in the previously denuded arteries with regenerated endothelium. The inhibitory effect of pertussis toxin was markedly reduced in those arteries with regenerated endothelium. In quiescent rings, the presence of normal endothelium inhibited the contractions caused by serotonin and aggregating platelets; this endothelium-dependent depression was markedly impaired in the previously denuded arteries throughout the study. Direct relaxation of the coronary smooth muscle to nitric oxide or sodium nitroprusside or direct contraction to KCl or serotonin were comparable between the control and previously denuded arteries. These experiments indicate that endothelium-dependent relaxations progressively worsen after regeneration of the endothelium and that the dysfunction of a pertussis toxin-sensitive G protein partly account for the endothelial dysfunction in the chronic regenerated state.

Adenosine Diphosphate↗

PubMed1991

Effects of metabolic inhibitors on endothelium-dependent and endothelium-independent vasodilatation of rat and rabbit aorta.

1. Basal release of endothelium-derived relaxing factor (EDRF) rendered endothelium-containing rings of rat aorta 4.7 fold less sensitive to the contractile actions of phenylephrine and depressed the maximum response when compared with endothelium-denuded rings. The responsiveness and maximum response to phenylephrine was, however, similar in rings of rabbit aorta with or without endothelium. 2. Rotenone (1 nM-0.1 microM), an inhibitor of oxidative phosphorylation, induced a profound, irreversible blockade of phenylephrine-induced tone in endothelium-containing and endothelium-denuded rings of rat aorta, but induced only slight inhibition of tone in rings of rabbit aorta. 3. 2-Deoxy glucose (10 mM), an inhibitor of glycolysis, had no effect on phenylephrine-induced contraction in endothelium-denuded rings of rat aorta, but inhibited reversibly the endothelium-dependent depression of contraction in endothelium containing rings. 2-Deoxy glucose had no effect on phenylephrine-induced contraction in rings of rabbit aorta with or without endothelium. 4. Rotenone (0.1 microM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings or rat and rabbit aorta. In endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate of isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCl-contracted, endothelium-denuded rings of rat aorta was also unaffected. 5. 2-Deoxy glucose (10 mM) inhibited acetylcholine-induced, endothelium-dependent relaxation of phenylephrine-contracted rings of rat and rabbit aorta. In endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate and by isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCIcontracted, endothelium-denuded rings of rat aorta was also unaffected. 6. These data suggest that in rabbit and in rat aorta, rotenone inhibits acetylcholine-induced relaxation by inhibiting EDRF production, and by depressing smooth muscle sensitivity to EDRF, respectively. They further suggest that 2-deoxy glucose inhibits acetylcholine-induced relaxation in both tissues by depressing the sensitivity to EDRF, probably as a result of reduced synthesis of cyclic GMP. The additional possibility that 2-deoxy glucose inhibits EDRF production warrants further investigation. 7. The blockade by 2-deoxy glucose of the endothelium-dependent depression of phenylephrine-induced tone in rat aorta probably reflects blockade of the actions of spontaneously released EDRF.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1987

Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin.

To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded area or from the proximal left circumflex coronary artery. The experiments were performed 8 days or 4 weeks after the denudation. Endothelial regrowth was confirmed by histologic examination 8 days after the denudation and by demonstrating the presence of endothelium-dependent relaxations to bradykinin; at that time aggregating platelets evoked normal endothelium-dependent responses. However, 4 weeks after the denudation, the relaxations to aggregating platelets were markedly depressed although continuous endothelial lining was present, and the endothelium-dependent responses to bradykinin, adenosine diphosphate, the Ca2+-ionophore A23187, platelet activating factor, and thrombin were unaltered. Four weeks after denudation, endothelium-dependent relaxations to serotonin were depressed. Higher concentration of serotonin induced endothelium-dependent contractions in quiescent rings with regenerated endothelium, suggesting that regenerated endothelial cells may produce endothelium-derived constricting factor(s) and release less endothelium-derived relaxing factor(s) when exposed to the monoamine. The endothelium-dependent relaxation to serotonin was not reduced by the S2-serotonergic antagonist ketanserin but prevented by the combined S1- and S2-serotonergic blocker methiothepin. The platelet-induced relaxation was due to released serotonin and adenine nucleotides in control left circumflex coronary arteries, but in left anterior descending coronary artery with regenerated endothelium, it was due solely to the latter. The platelet-induced contractions were due to activation of receptors on the smooth muscle cells. Four weeks after denudation, regenerated endothelial cells were morphologically different from native cells; they were elongated and cuboidal, and the number of the cells had increased twofold. At this state, eccentric myointimal thickening was present in the previously denuded portion. These experiments indicate that the protective role of endothelial cells against the vasoconstriction induced by aggregating platelets is depressed in the chronic regenerated state. A lack of responsiveness to serotonin appears to be the cause for the endothelial dysfunction.

Adenosine Diphosphate↗

PubMed1986

Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor.

The selective cyclic GMP phosphodiesterase inhibitor M&B 22948 and the less selective phosphodiesterase inhibitors papaverine and isobutylmethylxanthine (IBMX) each induced a component of relaxation of rat aortic rings that was endothelium-dependent. The most selective agent at inducing endothelium-dependent relaxation was M&B 22948, which caused little relaxation of endothelium-denuded rings at concentrations that produced almost complete relaxation of endothelium-containing rings. Although endothelium-dependent components of relaxation induced by papaverine and IBMX were clearly present, they were less well separated from the endothelium-independent components of relaxation. In the aorta of the rabbit, M&B 22948 and papaverine were less affective at inducing an endothelium-dependent component of relaxation than in the aorta of the rat, and IBMX produced no discernible endothelium-dependent component. The endothelium-dependent components of relaxation induced by M&B 22948, papaverine and IBMX on rat and rabbit aorta were probably dependent on endothelium-derived relaxing factor (EDRF), because they were associated with concomitant endothelium-dependent rises in cyclic GMP, and these components of relaxation as well as the rises in cyclic GMP were completely blocked by the EDRF-blocking agent hemoglobin. The action of hemoglobin was entirely specific, as none of the endothelium-independent components of relaxation induced by any of the phosphodiesterase inhibitors was affected by this hemoprotein. It is likely that the phosphodiesterase inhibitors induce their endothelium-dependent components of relaxation by inhibiting the hydrolysis of cyclic GMP formed in response to EDRF released spontaneously from endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1991

Participation of endothelium-derived relaxing factor and role of cyclic GMP in inhibitory effects of endothelium on contractile responses elicited by alpha-adrenoceptor agonists in rat aorta.

The participation of NO production and the role of cyclic GMP in inhibitory function of endothelium were investigated in rat aortic rings exposed to alpha-adrenoceptor agonists. Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) depressed more markedly not only maximal contractions but also equipotent contractions elicited by two partial agonists (indanidine and B-HT 920) than responses to the full agonist phenylephrine. The influence of endothelium on maximal responses to the three agonists was abolished by both the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methylester (L-NAME, 30 microM) and by the guanylate cyclase inhibitor methylene blue (methylene blue, 0.3 and 1 microM). Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) increased the EC50 value of phenylephrine. This effect was more pronounced in the case of endothelium (10-fold), however, than in the case of 8-Br cyclic GMP (fourfold at 30 microM), and the rightward shift produced by endothelium remained significant (twofold) in the presence of L-NAME or methylene blue. In addition, the effect of 8-Br cyclic GMP on phenylephrine-induced contractions was considerably enhanced in the presence of endothelium or after partial alkylation of receptors by phenoxybenzamine in endothelium-denuded rings. These results indicate that the L-arginine-NO-cyclic GMP pathway accounts for most of the inhibitory influence of endothelium on alpha-adrenergic responses in aortic rings. They indicate differential effects of cyclic GMP depending on the agonist and show that 8-Br cyclic GMP does not impair the basal inhibitory effect of endothelium on aortic contraction to alpha-adrenergic agonists.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Alteration of endothelium-dependent hyperpolarizations in porcine coronary arteries with regenerated endothelium.

The present study was designed to test the ability of regenerated endothelium to evoke endothelium-dependent hyperpolarizations. Hyperpolarizations induced by serotonin and bradykinin were compared in isolated porcine coronary arteries with native or regenerated endothelium, 4 weeks after balloon endothelial denudation. The experiments were performed in the presence of inhibitors of nitric oxide synthase (Nomega-nitro-L-arginine) and cyclooxygenase (indomethacin). The transmembrane potential was measured using conventional glass microelectrodes. Smooth muscle cells from coronary arteries with regenerated endothelium were depolarized in comparison with control coronary arteries from the same hearts. Spontaneous membrane potential oscillations of small amplitude or spikes were observed in some of these arteries but never in arteries with native endothelium. In coronary arteries from control pigs, both serotonin and bradykinin induced concentration-dependent hyperpolarizations. In the presence of ketanserin, 10 micromol/L serotonin induced a transient hyperpolarization in control coronary arteries. Four weeks after balloon denudation, the response to serotonin was normal in arteries with native endothelium, but the hyperpolarization was significantly lower in coronary arteries with regenerated endothelium. In control arteries, the endothelium-dependent hyperpolarization obtained with bradykinin (30 nmol/L) was reproducible. Four weeks after balloon denudation, comparable hyperpolarizations were obtained in coronary arteries with native endothelium. By contrast, in arteries with regenerated endothelium, the hyperpolarization to bradykinin became voltage-dependent. In the most depolarized cells, the hyperpolarization to bradykinin was augmented. The changes in resting membrane potential and the alteration in endothelium-dependent hyperpolarizations observed in the coronary arteries with regenerated endothelium may contribute to the reduced response to serotonin and the unchanged relaxation to bradykinin described previously.

Animals↗

PubMed1991

Superoxide anion mediates the endothelium-dependent contractions to serotonin by regenerated endothelium.

The endothelium modulates vascular tone by releasing a variety of vasoactive compounds that relax or contract the underlying vascular smooth muscle. We have previously demonstrated that regenerated endothelium exhibits endothelium-dependent hypercontraction to the platelet-derived compound serotonin (or 5-HT). To determine if this hypercontraction is mediated by superoxide anion produced by the endothelium, we performed balloon catheter denudation on the thoracic and abdominal aorta of male Lewis rats. Eight weeks after arterial injury, endothelium-dependent responses to serotonin were examined in tissue bath experiments. Vascular rings (5 mm in length), with and without endothelium, were contracted with norepinephrine and then exposed to serotonin (10(-9) to 3 x 10(-5) mol/L). Vascular rings with regenerated endothelium exhibited hypercontraction to serotonin (251% +/- 25% of initial norepinephrine contraction; p less than 0.05 compared with control rings, 175% +/- 13%). Removal of the endothelium (133% +/- 6%) or treatment with superoxide dismutase (184% +/- 7%), with or without catalase, prevented the endothelium-dependent constrictor effect of the serotonin. Ketanserin suppressed the vasoconstrictor effect of serotonin on control (93% +/- 15%) and regenerated (105% +/- 9%) rings with endothelium, indicating that the serotonin effect is mediated through the 5-HT2-serotonergic receptor. Deferoxamine or heat-inactivated superoxide dismutase did not modify the response. These observations support the hypothesis that superoxide anion is an endothelium-derived contracting factor produced by regenerated endothelium after intimal injury.

Animals↗

PubMed1998

Endothelium-dependent and endothelium-independent flow reserve in vascular regions supplied by the internal mammary artery before and after bypass grafting.

OBJECTIVE: It was the goal of this study to compare endothelium-dependent and endothelium-independent flow reserve in vascular regions supplied by the left internal mammary artery before and after bypass graft surgery. METHODS: The native internal mammary artery in situ was investigated in 13 patients (age 61.8 +/- 8.0 years) with angiographically proven coronary artery disease. The internal mammary artery after bypass grafting was investigated in ten patients (age 60.8 +/- 7.3 years) 3.5 +/- 2.8 years after the operation. Flow reserve was evaluated endothelium-dependent with acetylcholine (ACh 25 and 50 microg i.c.) and endothelium-independent with nitroglycerin (NTG 0.3 mg i.c.) followed by papaverin (10 mg i.c.). Flow indices were calculated from intraluminal Doppler blood flow velocity measurements and the vascular cross-sectional area as determined by quantitative angiography. An index for vascular resistance was defined as the ratio of pressure gradient and resting or peak flow. RESULTS: After endothelium-dependent stimulation with acetylcholine 25 microg (50 microg), flow in the internal mammary increased by 352.3 +/- 152% (412 +/- 145%) before surgery, whereas it increased only by 213 +/- 134% (193 +/- 120%) after surgery (P < 0.05). Endothelium independent stimulation with papaverin resulted in a flow increase of 391 +/- 234% before surgery vs. 315 +/- 135% after surgery (n.s.). The resistance index decreased after endothelium-dependent stimulation with acetylcholine 25 microg(50 microg) to 35 +/- 16.8% (28 +/- 8.9%) before surgery, whereas it decreased only to 59 +/- 26% (72 +/- 43%) after surgery (P < 0.05). Endothelium independent stimulation with papaverin resulted in a decrease of the vascular resistance index to 31 +/- 14% before surgery vs. 32 +/- 14% after surgery (n.s.). CONCLUSION: Vascular regions supplied by the internal mammary artery as a graft demonstrate a significantly reduced endothelium-dependent flow reserve but a preserved endothelium-independent flow reserve as compared to vascular regions supplied by the native internal mammary artery. The selective decrease in endothelium-dependent flow reserve may be due to microvascular changes in the myocardial region supplied by the internal mammary artery after bypass grafting.

Aged↗

PubMed1991

Endothelium-dependent and endothelium-independent vasodilatation of the hepatic artery of the rabbit.

1. The isolated hepatic artery of the rabbit contracted to exogenously applied noradrenaline (NA). There was no significant difference in the maximal contraction or the EC50 value in vessels where the endothelium was present and in endothelium-denuded preparations. 2. Acetylcholine (ACh) induced a vasodilatation of vessels preconstricted with NA which was entirely dependent on the endothelium. 3. Adenosine 5'-triphosphate (ATP), 2-methylthio ATP, adenosine and sodium nitroprusside induced concentration-dependent, sustained relaxations of vessels in which tone had been induced with NA. The relaxation responses were not reduced after removal of the endothelium. 8-Phenyltheophylline antagonized the relaxation response produced by adenosine, but not that due to ATP at lower concentrations. The maximum response to ATP was reduced in the presence of 8-phenyltheophylline. 4. alpha,beta-Methylene ATP produced further contraction of vessels preconstricted with NA in both endothelium-denuded preparations and in vessels where the endothelium remained intact. 5. Immunohistochemical analysis was used to show the presence of nerve fibres containing substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) in the hepatic artery. Application of SP induced a concentration-dependent relaxation which was entirely dependent on the presence of an intact endothelium. CGRP and VIP, however, elicited concentration-dependent relaxations which were independent of the endothelium. 7. It is concluded that in the rabbit hepatic artery, responses to ACh are dependent on the presence of intact endothelium. P1-, P2x- and P2y-purinoceptors, mediating relaxation to adenosine, vasoconstriction to ATP and vasodilatation to ATP respectively, are located on vascular smooth muscle. Furthermore, CGRP and VIP mediate a direct vasodilatation of smooth muscle both in the absence and the presence of the endothelium, whereas SP produces a relaxation via receptors located on the endothelium.

Animals↗

PubMed1989

Endothelium-dependent inhibition of ergonovine-induced contraction is impaired in porcine coronary arteries with regenerated endothelium.

The inhibitory effects of the endothelium against ergonovine-induced contraction were examined in isolated porcine coronary arteries under normal conditions and after endothelial regeneration. Endothelium-dependent responses were examined in vitro in normal Yorkshire pigs (n = 16) and in pigs that had undergone balloon endothelium removal of the left anterior descending coronary artery (LAD) 4 weeks before the study (n = 10). The presence of a complete endothelial lining was confirmed histologically. In rings from normal arteries contracted with prostaglandin F2 alpha in the presence of indomethacin and ketanserin (a 5-HT2-serotonergic blocker), ergonovine caused endothelium-dependent relaxations. They were attenuated by rauwolscine (an alpha 2-adrenergic blocker), inhibited by methiothepin (a combined 5-HT1- and 5-HT2-serotonergic blocker) or by pertussis toxin (an inhibitor of several G proteins) and abolished by oxyhemoglobin (a selective inactivator of endothelium-derived relaxing factor). In quiescent rings from normal arteries, ergonovine caused contractions that were inhibited by the presence of the endothelium; this endothelium-dependent inhibition was abolished by oxyhemoglobin. The direct contractions were not affected by prazosin (an alpha 1-adrenergic blocker), rauwolscine, 6-hydroxydopamine (an agent causing chemical sympathetectomy), or diphenhydramine (an H1-histaminergic blocker) but were inhibited by ketanserin. In rings with regenerated endothelium contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations to ergonovine were reduced significantly and were not inhibited by pertussis toxin. In quiescent rings with regenerated endothelium, the endothelium-dependent inhibition of ergonovine-induced contraction was less.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Endothelin-1 releases endothelium-derived endoperoxides and thromboxane A2 in porcine coronary arteries with regenerated endothelium.

AIM: To determine the role of endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated endothelium. METHODS: Rings of porcine coronary arteries, with and without endothelium of previously deendothelialized left anterior descending coronary arteries and native left circumflex coronary arteries, were suspended in conventional organ chambers for the measurement of isometric force. RESULTS: In quiescent rings of the previously deendothelialized left anterior descending coronary artery treated with the NO-synthase inhibitor nitro-L-arginine, endothelin-1 caused contractions which were larger in rings with than that in those without endothelium. Under the same experimental conditions, in the left circumflex coronary artery, the contractions to endothelin-1 were augmented markedly by the removal of the endothelium. In rings with endothelium of the previously deendothelialized left anterior descending coronary artery, indometacin (inhibitor of cyclooxygenase) and ridogrel (thromboxane A2 receptor antagonist and inhibitor of thromboxane synthase) inhibited contractions to endothelin-1. Dazoxiben (inhibitor of thromboxane synthase) inhibited, to the same extent as indometacin and ridogel, the response to higher concentrations of endothelin-1. The endothelium-dependent component of the response to lower concentrations of endothelin-1 was inhibited by indometacin and ridogrel, but not by dazoxiben. In rings without endothelium of both previously deendothelialized left anterior descending and native left circumflex coronary arteries, indometacin and ridogrel did not affect the contractions to endothelin-1. CONCLUSION: These findings suggest that in regenerated endothelium, high concentrations of endothelin-1 stimulate the release of thromboxane A2. Endoperoxides generated by activation of endothelial cyclooxygenase may be the endothelium-derived contracting factor(s) released in regenerated endothelium by lower concentrations of the peptide.

Animals↗

PubMed1986

Structural features of isolated, fractionated bone marrow endothelium compared to sinus endothelium in situ.

Structural features of isolated, fractionated rat bone marrow endothelium were compared to those of marrow sinus endothelium in situ. Marrow endothelium was purified, first by density gradient sedimentation on Percoll and then subjected to centrifugal elutriation. Using antifactor VIII antibody staining (indirect immunofluorescent method), preparations of greater than 50% purified endothelium were obtained. By SEM, these cells were about 10 microns in size and showed smooth surface and numerous invaginations. These features were also observed in the in situ endothelium obtained by perfusion-fixation and freeze-cracking. In addition, in situ endothelium displayed numerous hemopoietic cells in migration through the endothelium. By TEM, isolated endothelium showed numerous vesiculations, giving the cell sponge-like appearance. This corresponded to numerous intracellular vesicles in sinus endothelium in situ, reflecting high magnitude of fluid and molecular transport across the endothelium. Weibel-Palade bodies were not seen in either form of the endothelium, despite the positive reaction for factor VIII-related antigen. This finding suggested that the cell, while possessing factor VIII-related antigen, does not store this protein.

Animals↗

PubMed1995

The combined 5-HT2 receptor and calcium channel inhibitor LU49938 restores endothelium dependent responses in the regenerated endothelium of the porcine coronary artery.

OBJECTIVE: The aim was to evaluate the effect of the combined 5-hydroxytryptamine-2 (5-HT2) receptor antagonist and calcium channel inhibitor LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)] amino-2-isopropyl-2(3.4.5-trimethoxyphenyl)-valeronitrilhydrochloride ) on the endothelium dependent responsiveness of porcine coronary arteries with native and regenerated endothelium. METHODS: Male Yorkshire pigs were assigned randomly to one of four groups: (1) controls; (2) pigs receiving LU49938 daily (5 mg.kg-1) for four weeks; (3) pigs undergoing balloon de-endothelialisation of the left anterior descending coronary artery; and (4) pigs undergoing balloon de-endothelialisation and receiving LU49938 daily. At four weeks, quantitative coronary angiography, organ chamber experiments, and morphometric studies of the tissues were performed. RESULTS: Treatment with LU49938 did not affect the endothelium dependent responses in native porcine coronary arteries. Intracoronary injection of serotonin caused significantly greater coronary vasoconstriction in group 3 compared with group 4. The cross sectional area of the intima and media of previously de-endothelialised left anterior descending coronary artery increased significantly in group 3, but not in group 4. In arteries with regenerated endothelium, augmented endothelium dependent contractions were noted not only in response to serotonin, but also in response to platelets, noradrenaline, and endothelin-1. The endothelium dependent relaxations to platelets, serotonin, and UK14304 were impaired in the regenerated endothelium, but not those to adenosine diphosphate and SIN-1. However, following four weeks of treatment with LU49938, the pertussis toxin sensitive endothelium dependent responses were restored. The augmented endothelium dependent contraction to endothelin-1 was not altered by the treatment. CONCLUSIONS: Chronic treatment with LU49938 restores endothelium dependent, pertussis toxin sensitive, G protein mediated responses in the regenerated endothelium of the porcine coronary artery, and inhibits the intimal thickening following arterial injury.

Adrenergic alpha-Antagonists↗

PubMed2003

Raloxifene does not influence flow-mediated endothelium-dependent and endothelium-independent vasodilatation of osteopenic postmenopausal women.

OBJECTIVE: The study was undertaken to evaluate whether raloxifene influences endothelium-dependent and endothelium-independent vasodilatation in women. STUDY DESIGN: In a double-blind, placebo-controlled randomized study, 30 osteopenic but otherwise healthy postmenopausal women received either placebo (n = 15 with one dropout) or raloxifene (60 mg/d, n = 15). Brachial artery flow-mediated endothelium-dependent and endothelium-independent vasodilatation was evaluated by ultrasound before and after 6 months of treatment, along with lipid and glucose metabolism. Endothelium-dependent dilatation was evaluated after a 4-minute block of artery blood flow through a cuff insufflated at suprasystolic blood pressure. Endothelium-independent vasodilatation was evaluated after sublingual nitroglycerin administration (400 microg). RESULTS: Placebo did not modify any vascular or metabolic parameter. Raloxifene significantly decreased low-density lipoprotein levels (4.60 +/- 0.18 mmol/L vs 3.94 +/- 0.30 mmol/L, P <.015) but did not modify endothelium-dependent (21.6% +/- 4.6% vs 20.6% +/- 3.8%) or endothelium-independent vasodilatation (26.3% +/- 5.1% vs 32.0% +/- 5.5%). CONCLUSION: Prolonged administration of raloxifene does not influence endothelium-dependent and endothelium-independent vasodilatation of osteopenic but otherwise healthy postmenopausal women.

Blood Circulation↗

PubMed1999

Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.

Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that induces vasodilation and increases endothelial release of nitric oxide (NO). NO is also reported to modulate leukocyte-endothelium interaction. Therefore, we hypothesized that VEGF might inhibit leukocyte-endothelium interaction via increased release of NO from the vascular endothelium. We used intravital microscopy of the rat mesenteric microcirculation to measure leukocyte-endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to the rat (120 microg/kg, i.v., bolus). Superfusion of the rat mesentery with either 0.5 U/ml thrombin or 50 microM L-NAME consistently increased the number of rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling, adherence, and transmigration in rat mesenteric venules. In addition, adherence of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro was significantly reduced in mesenteric arteries isolated from VEGF-treated rats (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold increase in basal NO release from aortic tissue of rats injected with VEGF, at 4 and 24 h posttreatment (P<0. 01 vs. aortic tissue from control rats). Finally, systemic administration of VEGF to ecNOS-deficient mice failed to inhibit leukocyte-endothelium interactions observed in peri-intestinal venules. We concluded that VEGF is a potent inhibitor of leukocyte-endothelium interaction, and this effect is specifically correlated to augmentation of NO release from the vascular endothelium.--Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.

Animals↗