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At least 199 records · Page 11Linked to original sources
PubMed1991

Characterization of the 5-HT receptor mediating endothelium-dependent relaxation in porcine vena cava.

1. 5-Hydroxytryptamine (5-HT) relaxes rings of neonatal porcine isolated vena cava by both an endothelium-dependent and an endothelium-independent mechanism. The receptor mediating the latter response has been shown to be a 5-HT1-like receptor (positively coupled to adenylyl cyclase) located on the vascular smooth muscle. The features of the endothelium-dependent response to 5-HT in this preparation are now described. 2. In ring preparations contracted with the stable thromboxane-A2-mimetic, U-46619 (10 nM), and in the presence of the 5-HT2 receptor antagonist ketanserin (1 microM), low concentrations of 5-HT (1-100 nM) evoked an endothelium-dependent, rapid, 'spike-like' relaxation. Higher concentrations of 5-HT (0.1-10 microM) elicited a more sustained, but endothelium-independent relaxation. 3. Relaxation induced by low concentrations (1-100 nM) of 5-HT was abolished by endothelium removal, and was markedly (but not totally) inhibited by the guanylate cyclase inhibitor, methylene blue (10 microM) or by the inhibitor of endothelium-derived nitric oxide (NO) synthesis, L-NG-monomethylarginine (L-NMMA; 100-500 microM). 4. The endothelium-dependent response to 5-HT was mimicked by alpha-methyl-5-HT, 5-methoxytryptamine, tryptamine and 2-methyl-5-HT, but not by sumatriptan or 8-hydroxy-di-n-propylaminotetralin (8-OH-DPAT) at concentrations up to 10 microM. In contrast, relaxation evoked by 5-carboxamidotryptamine (5-CT) was endothelium-independent. 5. The endothelium-dependent relaxation induced by 5-HT or alpha-methyl-5-HT was antagonized by methysergide, methiothepin, cyproheptadine and metergoline, but not by ketanserin, spiperone, ondansetron, verapamil, cyanopindolol, mesulergine, ICS 205-930, or indomethacin. 6. These results suggest that the endothelium-dependent relaxation of porcine vena cava induced by 5-HT is largely mediated by the release of NO (although other endothelium-derived relaxing factors may also be involved) and that 5-HT is acting at a receptor which is not '5-HT1-like', 5-HT2, 5-HT3 or 5-HT4 and is not comparable to recognised 5-HT receptor ligand binding sites. The characteristics of this receptor are discussed in relation to the endothelial 5-HT receptor types in other blood vessels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Analysis of the depressant effect of the endothelium on contractions of rabbit isolated basilar artery to 5-hydroxytryptamine.

1. The effects of endothelium removal and of a number of pharmacological agents known to modify endothelial cell function on the contractile response of rabbit isolated basilar arteries to 5-hydroxytryptamine (5-HT) and other vasoconstrictors were studied. 2. Endothelium removal slightly reduced the contractile response to potassium chloride (40 mM) but markedly augmented and potentiated contractions to 5-HT (1 nM-10 microM). 3. L-NG-nitro-arginine (L-NOARG, 1-30 microM), an inhibitor of nitric oxide formation in vascular endothelial cells, evoked endothelium-dependent contraction, and augmented and potentiated contractions to 5-HT in endothelium-intact but not endothelium-denuded tissues. Prior incubation with L-arginine (1 mM), but not D-arginine (1 mM), abolished these effects of L-NOARG (1 microM). L-NOARG (30 microM) also augmented contractions of endothelium-intact tissues to noradrenaline, prostaglandin F2 alpha, and to a lesser degree endothelin-1. 4. Neither glibenclamide (3 microM) nor N-ethylmaleimide (1 microM), putative inhibitors of the effects of endothelium-derived hyperpolarizing factor (EDHF) and of agonist-stimulated endothelium-derived relaxing factor (EDRF) release respectively, had any effect on either resting tension or the contractile response to 5-HT. In some tissues indomethacin (3 microM), a cyclo-oxygenase inhibitor, produced a small contraction and augmented the contractile response to 5-HT, but in most cases indomethacin was without effect. 5. In endothelium-intact tissues precontracted with uridine 5'-triphosphate (UTP; 100 microM), 5-HT did not evoke relaxation but rather caused further contraction. Under the same conditions acetylcholine (0.01-10 microM) evoked endothelium-dependent relaxation.6. These data demonstrate that the endothelium profoundly depresses contractions of rabbit isolated basilar artery to 5-HT, and that this phenomenon can be fully accounted for by the release of an L-NOARG-sensitive relaxing factor. Neither glibenclamide-sensitive EDHF nor cyclo-oxygenase products plays a major role. As we could find no evidence that 5-HT stimulates the production of EDRF per se, and L-NOARG caused endothelium-dependent contraction and augmented contractions to other vasoconstrictor agents, it seems likely that a basal release of EDRF underlies this phenomenon.

Animals↗
PubMed1993

Involvement of nitric oxide in the endothelium-dependent relaxation induced by hydrogen peroxide in the rabbit aorta.

1. The effects of hydrogen peroxide (H2O2, 0.1-1 mM) on the tone of the rings of rabbit aorta precontracted with phenylephrine (0.2-0.3 microM) were studied. 2. H2O2 induced a concentration-dependent relaxation of both the intact and endothelium-denuded rings. However, in the presence of intact endothelium, H2O2-induced responses were 2-3 fold larger than in its absence, demonstrating the existence of endothelium-independent and endothelium-dependent components of the vasorelaxant action of H2O2. 3. The endothelium-dependent component of H2O2-induced relaxation was prevented by NG-nitro-L-arginine methyl ester (L-NAME, 30 microM) or NG-monomethyl-L-arginine (300 microM), inhibitors of nitric oxide synthase (NOS), in a manner that was reversible by L-, but not by D-arginine (2mM). The inhibitors of NOS did not affect the responses of denuded rings. 4. Methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, blocked H2O2-induced relaxation of both the intact and denuded rings. 5. H2O2 (1 mM) enhanced the efflux of cyclic GMP from both the endothelium-intact and denuded rings. The effect of H2O2 was 4 fold greater in the presence of intact endothelium and this endothelium-dependent component was abolished after the inhibition of NOS by L-NAME (30 microM). 6. In contrast to the effects of H2O2, the vasorelaxant action of stable organic peroxides, tert-butyl hydroperoxide or cumene hydroperoxide, did not have an endothelium-dependent component. Moreover, they did not potentiate the efflux of cyclic GMP from the rings of rabbit aorta. 7. Exogenous donors of NO, specifically, 3-morpholinosydnonimine (SIN-1), glyceryl trinitrate or sodium nitroprusside were used to decrease the tone of denuded rings to the level induced by endogenous NO released from intact endothelium. This procedure did not influence the vasorelaxant activity of H202, showing that H202 does not potentiate the vasorelaxant action of NO within the smooth muscle.8. Thus, H202-induced relaxation in the rabbit aorta has both endothelium-dependent and independent components. The endothelium-dependent component of the relaxant action of H202 is due to enhanced endothelial synthesis of NO.

Amino Acid Oxidoreductases↗
PubMed1997

Modulation by the endothelium of the inhibitory effects of pinacidil and nimodipine on endothelin-induced contraction in cerebral arteries.

The effects of pinacidil and nimodipine on endothelin-1-induced contractions in isolated cerebral arteries with and without endothelium were compared. The sensitivity to endothelin-1 was increased (0.5 log units) in the rabbit basilar artery after removal of the endothelium. The nitric oxide synthase inhibitor N omega-nitro-L-arginine (0.1 mM) also increased the sensitivity to endothelin-1 (0.6 log units) in basilar arteries with endothelium, whereas N omega-nitro-D-arginine (0.1 mM) and indomethacin (3 microM) had no effect, indicating that withdrawal of endothelium-derived nitric oxide may account for the enhancement of the endothelin-1-induced contraction after endothelial denudation. Pinacidil (1 microM) shifted the concentration-response curve for endothelin-1 to the right without affecting the maximal response in arteries without endothelium, but had no effect on the endothelin-1-induced contraction in vessels with endothelium. Nimodipine (1 microM) reduced the maximal endothelin-1-induced contraction by approximately 50% in both the presence and absence of endothelium, whereas the sensitivity to endothelin-1 was reduced only in vessels without endothelium. Incubation in "calcium-free" medium reduced the maximal endothelin-1-induced contraction by 69% and 80% in vessels with and without endothelium, respectively. In human pial arteries with endothelium, pinacidil did not affect the endothelin-1-induced contraction, whereas nimodipine and exposure to "calcium-free" solution reduced the maximal response by 31% and 74% respectively. The results show that, in the rabbit, pinacidil and to a lesser extent nimodipine preferentially act on cerebral arteries with disrupted endothelium, indicating that vasoactive factors liberated from the endothelium may modify the effect of a vasodilator.

Animals↗
PubMed1992

Flows of liquid and electrical current through monolayers of cultured bovine arterial endothelium.

1. Monolayers of arterial endothelium on porous membranes were exposed to a constant pressure between 15 and 35 cmH2O. The rates of liquid flow per unit area (Jv/A) through the monolayers were monitored, together with the electrical resistance (Rm) of the endothelium. 2. At constant pressure, Jv/A decreased with an approximately exponential time course, towards a stable baseline value. This behaviour resembles the sealing previously described for cultured vascular endothelium. At 30-35 cmH2O and 37 degrees C, the mean (+/- S.E.M.) half-time (t1/2) of the decrease in Jv/A (the sealing t1/2) was 548 +/- 141 S (n = 5). The difference between the initial and baseline values of Jv/A was expressed as a fraction of the initial value. The mean (+/- S.E.M.) of this sealing fraction was 0.64 +/- 0.03 (n = 5). Mean (+/- S.E.M.) hydraulic permeability (Lp) was 23.9 +/- 6.4 x 10(-7) cm S-1 cmH2O-1 (n = 9), when measured after sealing. Endothelium appeared damaged after sealing at 30-35 cmH2O and 37 degrees C. 3. Sealing was also observed using glutaraldehyde-fixed endothelium at 30-33 cmH2O and 26-28 degrees C. There was no significant difference between the mean sealing t1/2 of these fixed monolayers, and that of unfixed endothelium at 30-35 cmH2O and 37 degrees C. However, mean sealing fraction was significantly larger for the fixed monolayers than for unfixed endothelium at 30-35 cmH2O and 37 degrees C. There were no significant difference between the post-sealing Lps of these fixed and unfixed monolayers, although the fixed monolayers appeared undamaged after sealing. 4. For unfixed endothelium, Rm was lower after sealing at 30-35 cmH2O and 37 degrees C than before pressure application. There was no significant difference between endothelial Rm before and after sealing, for glutaraldehyde-fixed monolayers. 5. Sealing was also observed at 0 degree C, using unfixed endothelium at 30 cmH2O. Mean sealing t1/2 was not significantly different from that of unfixed endothelium at 30 cmH2O and 37 degrees C. However, mean sealing fraction was significantly smaller at 0 degree C than at 37 degrees C. Unfixed endothelium appeared undamaged after sealing at 30 cmH2O and 0 degree C. Despite this, the post-sealing Lp was not significantly different from that of unfixed endothelium sealed at 30 cmH2O and 37 degrees C, after allowance was made for the effect of temperature on Lp. Rm was not measured in these experiments. 6. It is proposed that sealing is due to pressure-induced deformation of monolayers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Endothelium inhibits responses of rabbit carotid artery to adrenergic nerve stimulation.

Transmural electrical stimulation of isolated ring segments of the rabbit carotid artery caused frequency-dependent contractions; these were blocked by tetrodotoxin or prazosin. Mechanical or chemical removal of the endothelium markedly augmented responses to electrical stimulation. Inhibition of norepinephrine uptake and metabolism with cocaine, hydrocortisone, and pargyline increased contractions in rings with endothelium more than those without endothelium, but responses remained greater in rings denuded of endothelium. Methylene blue, an inhibitor of guanylate cyclase, enhanced responses to electrical stimulation of rings with intact endothelium only. Combined inhibition of guanylate cyclase and norepinephrine disposition increased the contractions and abolished the difference between the responses of rings with and without endothelium. In a perfusion-cascade system, the perfusate of donor segments with endothelium relaxed a bioassay ring without endothelium. Electrical stimulation of the segment caused no further relaxation of the bioassay ring. However, contractions caused by electrically stimulating the bioassay ring were depressed during superfusion with the perfusate of segments with, but not without, endothelium, indicating that vasodilators spontaneously released from the endothelium inhibit responses to nerve stimulation. These observations suggest that inhibition by the endothelium of the response to adrenergic nerve stimulation results from 1) spontaneous release of endothelium-derived vasodilators and 2) disposition of norepinephrine by the endothelial cells.

Animals↗
PubMed1986

Endothelium-dependent responses to platelets and serotonin in spontaneously hypertensive rats.

We studied endothelium-dependent responses to substances released from aggregating platelets in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rings of thoracic aorta with and without endothelium were taken from adult rats and suspended for isometric tension recording in organ chambers containing modified Krebs-Ringer bicarbonate solution. Aggregating platelets caused statistically similar contractions in rings without endothelium in both strains. In rings with endothelium from SHR the contractions were significantly more pronounced than in rings with endothelium from WKY. In contracted rings with endothelium, serotonin caused a slight relaxation at lower concentrations but contraction at higher concentrations; only contractions were seen in rings without endothelium. The higher concentrations of the monoamine caused contractions, which in the SHR but not in the WKY were larger in the presence than in the absence of endothelium. In both strains adenosine diphosphate induced concentration-dependent relaxation in rings with endothelium but not in those without it; at high concentrations of adenosine diphosphate, the relaxation responses were significantly smaller in the SHR than in the WKY. Endothelium-dependent relaxation in response to thrombin did not differ in the two strains. The increased contraction in response to aggregating platelets and serotonin and the decreased relaxation in response to adenosine diphosphate in the SHR suggest that functional changes occur in the endothelium in this model of hypertension, possibly because of the release of one or more endothelium-derived contracting factors.

Acetylcholine↗
PubMed1999

Possible involvement of Ca2+ entry and its pharmacological characteristics responsible for endothelium-dependent, NO-mediated relaxation induced by thapsigargin in guinea-pig aorta.

Thapsigargin, a specific inhibitor of Ca(2+)-pump Ca(2+)-ATPase in the sarcoplasmic/endoplasmic reticulum (SR/ER), produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features of thapsigargin-induced endothelium-dependent relaxation were functionally characterized in the isolated guinea-pig aorta especially focusing on the Ca2+ mobilization mechanisms in endothelial cells. Thapsigargin-induced endothelium-dependent vascular relaxation was markedly suppressed by N(G)-nitro-L-arginine (L-NNA) and calmidazolium, suggesting that the vascular relaxation to thapsigargin is largely attributable to endothelium-derived nitric oxide (NO) produced as a result of the activation of Ca2+, calmodulin-dependent NO synthase (NOS). Removal of Ca2+ from the external solution abolished the endothelium-dependent relaxation of guinea-pig aorta in response to thapsigargin. Thapsigargin-induced endothelium-dependent relaxation was inhibited more strongly compared with the endothelium-independent relaxation to an NO donor, SIN-1 (3-(4-morpholinyl)-sydnonimine), when the artery preparation was preconstricted with a high concentration (80 mM) of KCl instead of agonistic stimulation. Endothelium-dependent relaxation induced by thapsigargin was not affected by diltiazem, a blocker of L-type voltage-gated Ca2+ channels. SK&F96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1 H-imidazole) and Ni2+, both of which block capacitative Ca(2+) entry, did not show any appreciable inhibitory effects on the endothelium-dependent relaxation to thapsigargin. These findings suggest that in guinea-pig aorta, endothelium-dependent NO-mediated relaxation induced by thapsigargin is preceded by the increase in the cytosolic free Ca2+ concentrations ([Ca2+]cyt) following the depletion of stored Ca2+ in thapsigargin-sensitive store sites in endothelial cells. Although the increase in [Ca2+]cyt responsible for the activation of endothelium NOS leading to thapsigargin-induced vascular relaxation may be ascribed to the capacitative Ca2+ entry from extracellular space, the Ca2+ entry mechanism stimulated with thapsigargin is deficient in sensitivity to SK&F96365 and Ni2+ in the endothelium of guinea-pig aorta.

Animals↗
PubMed2000

Magnesium removal impairs the regulatory role of rat endothelium.

Vascular endothelium has been shown to play an important role in the regulation of vascular tone and, hence, impairment of the endothelium may induce hypertension. Although magnesium (Mg) deficiency could induce hypertension, the role of Mg on the endothelium is unclear. We examined the effects of Mg removal on endothelium-dependent and -independent responses using ring preparations of femoral arteries obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Norepinephrine (10(-9)-10(-4) M) evoked concentration-dependent contractions in arteries with endothelium. The maximal response was greater in SHR than in WKY. Removal of external Mg augmented the contraction in WKY but not in SHR. As a result, the contraction obtained in arteries with endothelium was identical in the two groups. Removal of the endothelium enhanced the contraction in both strains, with a greater response occurring in WKY than in SHR in Krebs, but not in Mg-free, solution. As a result, in arteries without endothelium, the contractions were identical in WKY and SHR both in Krebs and Mg-free solutions. Acetylcholine (10(-9)-10(-4) M) evoked concentration-dependent relaxation in arteries with, but not in those without, endothelium obtained from WKY and SHR. The relaxation did not differ between the two strains, nor was it altered by Mg removal. Thus, Mg removal impairs inhibitory function of the endothelium against contraction induced by norepinephrine, without affecting endothelium-dependent relaxation in response to acetylcholine, in the rat femoral artery. The effect of Mg removal is not apparent in SHR. The fact that after removal of external Mg the contraction in response to norepinephrine in arteries with endothelium is identical in WKY and SHR suggests that a normotensive artery with Mg deficiency may mimic a hypertensive artery through endothelial impairment.

Acetylcholine↗
PubMed1991

Endothelium-dependent regulation of vascular tone of the porcine ophthalmic artery.

The endothelium produces relaxing and contracting substances, among them nitric oxide and endothelin. The role of the endothelium was investigated in the regulation of vascular tone in isolated porcine ophthalmic arteries suspended in a myograph system for isometric tension recording. In quiescent arteries with endothelium, the inhibitor of nitric oxide formation from L-arginine, L-NG-monomethyl arginine (L-NMMA), evoked endothelium-dependent contractions which were reversed by L-, but not D-arginine. In arteries contracted with serotonin, bradykinin evoked potent endothelium-dependent relaxations; L-NMMA markedly reduced the sensitivity but not the maximal response. Acetylcholine caused relaxations in preparations with endothelium but contractions in those without endothelium; L-NMMA prevented the relaxations and unmasked the contractions. The relaxations to the nitrovasodilator SIN-1 were more pronounced in preparations without than with endothelium. In quiescent arteries, quick stretching evoked endothelium-dependent contractions which were prevented by indomethacin. Endothelin-1, serotonin, and norepinephrine evoked concentration-dependent contractions with pD2 values of 8.1 +/- 0.1, 6.9 +/- 0.1, and 5.9 +/- 0.1, respectively. Removal of the endothelium markedly augmented the contractions induced by serotonin but not endothelin and norepinephrine. Thus, the endothelium profoundly affects vascular tone of the porcine ophthalmic artery. Endothelium-derived nitric oxide is released both under basal conditions and after stimulation with acetylcholine and bradykinin. It may play an important protective role in the circulation against vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Endothelium-derived relaxing factors. A perspective from in vivo data.

We review below published studies of endothelium-dependent vasodilation in vivo. Endothelium-dependent vasodilation has been demonstrated in conduit arteries in vivo and in the cerebral, coronary, mesenteric, and femoral vascular beds as well as in the microcirculation of the brain and the microcirculation of cremaster muscle. The available evidence, although not complete, strongly suggests that the endothelium-derived relaxing factor generated by acetylcholine in the cerebral microcirculation is a nitrosothiol. The endothelium-derived relaxing factor generated by bradykinin in this vascular bed is an oxygen radical generated in association with enhanced arachidonate metabolism via cyclooxygenase. In the microcirculation of skeletal muscle, on the other hand, the vasodilation from bradykinin is mediated partly by prostacyclin and partly by an endothelium-derived relaxing factor similar to that generated by acetylcholine. Basal secretion of endothelium-derived relaxing factor is controversial in vivo but is usually present in vitro. On the other hand, it appears that endothelium-derived relaxing factor mediates flow-dependent vasodilation in both large vessels and in the microcirculation in vivo. The generation and release of endothelium-derived relaxing factor from endothelium may be abnormal in a variety of conditions including acute and chronic hypertension, atherosclerosis, and ischemia followed by reperfusion. Several mechanisms for these abnormalities have been identified. These include inability to generate endothelium-derived relaxing factor or destruction of endothelium-derived relaxing factor by oxidants after its release in the extracellular space. These abnormalities in endothelium-dependent relaxation may contribute to the vascular abnormalities in these conditions.

Animals↗
PubMed1991

Endothelium-derived relaxing and contracting factors.

Key discoveries in the past decade revealed that the endothelium can modulate the tone of underlying vascular smooth muscle by the synthesis/release of potent vasorelaxant (endothelium-derived relaxing factors; EDRF) and vasoconstrictor substances (endothelium-derived contracting factors; EDCF). It has become evident that the synthesis and release of these substances contribute to the multitude of physiological functions the vascular endothelium performs. Accumulating evidence suggests that at least one of the EDRFs is identical with nitric oxide (NO) or a labile nitroso compound, which is produced from L-arginine by an NADPH- and Ca(2+)-dependent enzyme, arginine oxidase. The existence of more than one chemically distinct EDRF has been proposed, including an endothelium-derived hyperpolarizing factor (EDHF). The target of EDRF (NO) is soluble guanylate cyclase (increase in cyclic GMP) while EDHF appears to activate a K(+)-channel in vascular smooth muscle. Recent data suggest that muscarinic receptor subtypes selectively mediate the release of EDRF(NO) (M2) and EDHF (M1). EDRF(NO) affects not only the underlying vascular smooth muscle, but also platelets, inhibiting their aggregation and adhesion to the endothelium. The antiaggregatory effect of EDRF is synergistic with prostacyclin, so their combined release may represent a physiological mechanism aimed at preventing thrombus formation. An additional proposed biological function of EDRF(NO) is cytoprotection by virtue of scavenging superoxide radicals. The endothelium can also mediate vasoconstriction by the release of a variety of endothelium-derived contracting factors (EDCF). Other than the unique peptide endothelin, the nature of EDCFs has not yet been firmly established. Autoregulation of cerebral and renal blood flow and hypoxic pulmonary vasoconstriction may represent the physiological role of endothelium-dependent vasoconstriction. Growing evidence indicates that the endothelium can serve as a unique mechanoreceptor, sensing and transducing physical stimuli (e.g., shear forces, pressure) into changes in vascular tone by the release of EDRFs or EDCFs. In physiological states, a delicate balance exists between endothelium-derived vasodilators and vasoconstrictors. Alterations in this balance can result in local (vasospasm) and generalized (hypertension) increase in vascular tone and also in facilitated thrombus formation. Endothelial dysfunction may also contribute to the pathophysiology of angiopathies associated with hypercholesterolemia and atherosclerosis.

Animals↗
PubMed1988

Loss of endothelium-dependent relaxation in mouse cerebral microvessels may be rapidly reversible.

This study demonstrates that a loss of endothelium-dependent relaxation in brain microvessels can be rapidly reversible. This loss was produced by injuring the endothelium in situ with a HeNe laser in the presence of intravascular Evans blue. The noxious stimulus has previously been shown not to damage vascular smooth muscle. The loss of endothelium-dependent relaxation was manifest by loss of dilating responses to both acetylcholine (ACh) and bradykinin (BK). Both agents have been shown by others to produce an endothelium-dependent relaxation in large vessels, caused by endothelial release of one or more endothelium-dependent relaxing factor(s) or EDRF(s). Previous studies have not tested for rapid return of endothelium-dependent relaxation after initial loss. In large vessels this might not be expected if reports concerning the necessary removal of large amounts of endothelium are correct. In cerebral microvessels, however, we have already shown apparent loss of EDRF following only minimal ultrastructural alteration of intact endothelial cells. The question remained whether these morphologic alterations reflected the onset of irreversible changes. The present study suggests that these cells were not irreversibly damaged, at least with respect to apparent modulation of endothelium-dependent responses. Recovery of responses to both ACh and BK occurred within 1 hr of initial injury and initial loss of endothelium-dependent relaxation. Recovery within 1 hr did not occur at the center of laser injury, but at a site of impaired response 55 micron away. Previous studies had suggested less dramatic injury of endothelium here compared with endothelium at the center of laser impact.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Indomethacin attenuates the constriction of canine epicardial coronary arteries to acetylcholine in the absence of endothelium: contribution of platelets to vasoconstriction in vivo.

This study was designed to evaluate the in vivo effect of acetylcholine on endothelial-damaged canine epicardial coronary arteries and the potential contribution of platelets to those acetylcholine-induced responses. Changes in left anterior descending artery cross-sectional area were determined by quantitative angiography in the closed chest anesthetized dog. Baseline cross-sectional area of the left anterior descending artery was not changed by removal of the endothelium by balloon-tipped catheter. Increased constrictor tone produced by prostaglandin F2 alpha was comparable in endothelium-intact and endothelium-removed vessels, supporting an endothelium-independent mechanism for prostaglandin F2 alpha in vivo. Acetylcholine produced anterior descending artery vasodilation with the endothelium intact; a comparable maximal dilator response was also obtained in the presence of increased constrictor tone (prostaglandin F2 alpha). In contrast, acetylcholine produced vasoconstriction of the anterior descending artery when the endothelium was removed. To evaluate the mechanism of acetylcholine-induced vasoconstriction in endothelium-removed vessels, the same protocol was completed in the presence of the platelet inhibitor indomethacin. Indomethacin did not alter baseline cross-sectional area or the dilator response to acetylcholine in endothelium-intact vessels. In contrast, the constrictor response in endothelium-removed vessels was antagonized, and a dilator response comparable with that in endothelium-intact vessels was produced by acetylcholine. The results of this study provide an experimental basis for the observations in human studies in which apparently atherosclerotic vessels constrict in response to acetylcholine. Removal of the endothelium in vivo abolishes the dilator response to acetylcholine and converts the acetylcholine response to vasoconstriction or vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1989

Hypercholesterolemia causes generalized impairment of endothelium-dependent relaxation to aggregating platelets in porcine arteries.

The role of the endothelium in response to aggregating platelets was examined in porcine coronary and peripheral (carotid, femoral and renal) arteries from normal and hypercholesterolemic pigs. Male Yorkshire pigs were fed either a normal diet or a 2% high cholesterol diet for 10 weeks. Endothelium-dependent responses were examined in vitro. In all arteries from control animals, aggregating platelets caused endothelium-dependent relaxations, which were augmented by ketanserin (a 5-HT2-serotonergic blocker), attenuated by apyrase (an adenosine diphosphatase and triphosphatase) or methiothepin (a combined 5-HT1 and 5-HT2-serotonergic blocker) and were almost abolished by a combination of apyrase and methiothepin. The platelet-induced relaxations were most pronounced in the coronary arteries. Adenosine diphosphate caused endothelium-dependent relaxations, which were significantly attenuated by apyrase. Serotonin also caused endothelium-dependent relaxations, which were significantly attenuated by methiothepin but augmented by ketanserin. The endothelium-dependent relaxations to adenosine diphosphate were most pronounced in coronary arteries and those to serotonin in coronary and renal arteries. In cholesterol-fed animals, the endothelium-dependent relaxations to aggregating platelets, adenosine diphosphate and serotonin were impaired in all four arteries. These experiments indicate that 1) the endothelium exerts inhibitory effects against aggregating platelets in porcine coronary and peripheral arteries; 2) platelet-induced endothelium-dependent relaxations are achieved by purinergic and 5-HT1-serotonergic receptors on the endothelium; and 3) hypercholesterolemia reduces the endothelium-dependent relaxations to aggregating platelets in a generalized manner because it impairs the relaxations to adenosine diphosphate and serotonin released from the platelets.

Animals↗
PubMed1994

Endothelium-dependent vasodilation of peripheral conduit arteries in patients with heart failure.

Endothelium-dependent vasodilation of peripheral resistance vessels is abnormal in patients with heart failure, but there are little in vivo data on endothelium-dependent vasodilation of peripheral conduit vessels. This study assessed endothelium-dependent vasodilation of forearm conduit and resistance vessels in normal subjects and patients with heart failure. The effects of intraarterial endothelium-dependent and endothelium-independent vasodilators on both forearm conduit (brachial artery) and resistance vessels were assessed in 9 patients with New York Heart Association class II-III heart failure and 11 normal subjects of similar age. Brachial artery diameter was measured by two-dimensional, moderate-frequency (8 MHz) ultrasound, and forearm blood flow was measured by strain gauge plethysmography. The endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), increased brachial artery diameter by 7.6 +/- 1.3% and 12.2 +/- 1.5% in normal subjects as compared to 6.9 +/- 2.1% and 10.4 +/- 2.4% in patients with heart failure (P = NS, normal vs heart failure). The endothelium-independent vasodilator, nitroglycerin (0.15 microgram), also produced similar increases in brachial artery diameter in the two groups (8.2 +/- 1.3% in normal subjects vs 11.1 +/- 1.4% in patients with heart failure, P = NS). In contrast, forearm blood flow responses to methacholine were significantly (P < .05) greater in normal subjects (4.1 +/- 0.5 and 9.2 +/- 1.4 mL/min/100 mL forearm volume) than in patients with heart failure (2.0 +/- 0.8 and 5.1 +/- 1.3 mL/min/100 mL forearm volume). Forearm blood flow responses to the endothelium-independent vasodilator, sodium nitroprusside, were similar between the two groups. This study suggests that endothelium-dependent and endothelium-independent vasodilation of the brachial artery is not impaired in patients with class II-III heart failure. This finding contrasts with abnormal endothelium-dependent vasodilation of forearm resistance vessels. These data suggest that there are regional differences in endothelial function in patients with heart failure.

Adult↗
PubMed1998

Interactions between endothelium-derived relaxing factors in the rat hepatic artery: focus on regulation of EDHF.

1. In rat isolated hepatic arteries contracted with phenylephrine, acetylcholine and the calcium ionophore A23187 each elicit endothelium-dependent relaxations, which involve both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). However, the contribution of prostanoids to these responses, and the potential interaction between EDHF and other endothelium-derived relaxing factors have not been examined. 2. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG, 0.3 mM) and a mixture of charybdotoxin (0.3 microM) and apamin (0.3 microM), inhibitors of the target potassium (K) channel(s) for EDHF, acetylcholine and A23187 each induced a concentration-dependent and almost complete relaxation, which was abolished in the additional presence of indomethacin (10 microM). Thus, in addition to EDHF and NO, a relaxing factor(s) generated by cyclo-oxygenase (COX) contributes to endothelium-dependent relaxation in the rat hepatic artery. 3. The resting membrane potentials of endothelium-intact and endothelium-denuded vascular segments were -57 mV and -52 mV, respectively (P>0.05). In intact arteries, the resting membrane potential was not affected by L-NOARG plus indomethacin, but reduced to -47 mV in the presence of charybdotoxin plus apamin. Acetylcholine and A23187 (10 microM each) elicited a hyperpolarization of 13 mV and 15 mV, respectively. The hyperpolarization induced by these agents was not affected by L-NOARG plus indomethacin (12 mV and 14 mV, respectively), but reduced in the presence of charybdotoxin plus apamin (7 mV and 10 mV, respectively), and abolished in the combined presence of charybdotoxin, apamin and indomethacin. 4. The NO donor 3-morpholino-sydnonimine (SIN-1) induced a concentration-dependent relaxation, which was unaffected by charybdotoxin plus apamin, but abolished by the selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 microM). SIN-1 (10 microM) did not alter the resting membrane potential in endothelium-denuded vascular segments. 5. The COX-dependent relaxation induced by acetylcholine was abolished following exposure to 30 mM KCl, but unaffected by glibenclamide (10 microM). The prostacyclin analogue iloprost induced a concentration-dependent relaxation, which was also abolished in 30 mM KCl and unaffected by the combined treatment with glibenclamide, charybdotoxin and apamin. Iloprost (10 microM) induced a glibenclamide-resistant hyperpolarization (8 mV with and 9 mV without glibenclamide) in endothelium-denuded vascular segments. 6. Exposure to SIN-1 or iloprost did not affect the EDHF-mediated relaxation induced by acetylcholine (i.e. in the presence of L-NOARG and indomethacin). Replacement of L-NOARG with the NO scavenger oxyhaemoglobin (10 microM) or the soluble guanylate cyclase inhibitor ODQ (10 microM) or methylene blue (10 microM), which all significantly inhibited responses to endothelium-derived NO, did not affect the acetylcholine-induced relaxation in the presence of indomethacin, indicating that endogenous NO also does not suppress EDHF-mediated responses. 7. These results show that, in addition to EDHF and NO, an endothelium-derived hyperpolarizing factor(s) generated by COX contributes significantly to endothelium-dependent relaxation in the rat heptic artery. Neither this factor nor NO seems to regulate EDHF-mediated responses. Thus, EDHF does not serve simply as a 'back-up' system for NO and prostacyclin in this artery. However, whether EDHF modulates the NO and COX pathways remains to be determined.

Animals↗
PubMed1990

Endothelium-dependent vasorelaxations in response to aggregating platelets are impaired in reversed vein grafts.

The endothelium releases factor(s) that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses to aggregating platelets are altered in vein grafts. Segments of jugular veins were grafted in the reverse position into the carotid arteries in 16 rabbits. After 4 weeks the patent grafts (14 of 16) were removed, and the endothelium-dependent responses were examined in vitro. In control veins aggregating platelets, adenosine diphosphate, and serotonin caused endothelium-dependent relaxations. The platelet-induced relaxations were attenuated by apyrase (adenosine diphosphatase and adenosine triphosphatase) but not by methiothepin (serotonergic blocker). In vein grafts, endothelium-dependent relaxations in response to aggregating platelets were absent, and only contractions that could be attenuated by methiothepin were observed. In vein grafts, endothelium-dependent relaxations in response to adenosine diphosphate were reduced, and only endothelium-independent contractions were observed in response to serotonin. These contractions were attenuated by methiothepin. These results suggest that (1) the endothelium exerts an inhibitory effects mediated mainly by adenosine diphosphate in response to aggregating platelets in rabbit jugular veins and (2) endothelium-dependent relaxations in response to aggregating platelets are impaired in vein grafts because of reduced endothelium-independent contractions in response to serotonin. This impairment of endothelium-dependent responses in vein grafts may contribute to failure of the grafts.

Adenosine Diphosphate↗