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At least 973 records · Page 54Linked to original sources
PubMed1993

Natural course of endothelium-dependent and -independent responses in autogenous femoral veins grafted into the arterial circulation of the dog.

We examined the natural course of endothelium-dependent and -independent responses in reversed autogenous vein grafts during regeneration and tissue repair processes after vein grafting in dogs. Vein grafts implanted in the canine femoral artery were removed, cut into rings, and suspended in organ chambers for isometric tension recording at 3 days and 1, 2, 4, and 6 weeks after implantation. Endothelial cells were denuded from some rings. Control veins were taken from nonsurgically treated femoral veins. Acetylcholine caused endothelium-dependent relaxations in the control veins, whereas in the vein grafts there was no evidence of endothelium-dependent relaxations to acetylcholine 3 days after the operation. Acetylcholine caused endothelium-independent contractions throughout the study. The endothelium-dependent responses to ADP and calcium ionophore A23187 were constantly maintained. Three days after the operation, the amplitude of norepinephrine-induced contractions of the vein grafts was impaired, and at 1 week the amplitude was recovered, although it was significantly smaller than the amplitude of contractions of the control veins at any postoperative period. Endothelium-independent relaxations to sodium nitroprusside were maintained throughout the study. Thus, there was a selective loss of acetylcholine-mediated relaxation in vein grafts in the early postoperative stage, a time when the intima is not thickened. These altered responses in vein grafts in the early postoperative period may have a role in graft failure.

Animals↗
PubMed1998

Nitric oxide inhibits alpha2-adrenoceptor-mediated endothelium-dependent vasodilation.

This study was designed to investigate the interaction between the NO/L-arginine pathway and the alpha2-adrenoceptor-mediated endothelium-dependent vasorelaxation. Reactivity of isolated resistance mesenteric arterial segments from mice lacking the gene for constitutive endothelial NO synthase (eNOS- mice, n=14) and from their wild-type controls (WT mice, n=46) was studied in isometric conditions in the presence of indomethacin (blocker of cyclooxygenase). Oxymetazoline (OXY, 0.01 to 30 micromol/L; a selective alpha2-adrenoceptor agonist) induced an endothelium-dependent relaxation of eNOS- but not WT arteries preconstricted either with phenylephrine or serotonin. In the presence of Nomega-nitro-L-arginine (l-NNA, 100 micromol/L), an inhibitor of NOS, OXY induced an endothelium-dependent relaxation of WT mesenteric arteries. l-NNA had no effect on the relaxation caused by OXY in eNOS- arterial rings. Therefore, the relaxation caused by OXY was independent of NO formation. To demonstrate the inhibitory role of NO on the alpha2-adrenoceptor-mediated relaxation, subthreshold (0.1 nmol/L) to threshold (1 nmol/L) concentrations of sodium nitroprusside (donor of NO) were added to l-NNA-treated arteries before OXY challenges: in these conditions, the alpha2-adrenoceptor-mediated relaxation of eNOS- and WT arteries was inhibited. OXY-induced relaxation was restored on readdition of methylene blue (1 micromol/L, inhibitor of guanylate cyclase), suggesting that cGMP may be the mechanism of inhibition of the alpha2-adrenergic pathway in the presence of NO. Finally, OXY-mediated relaxation was blocked by tetraethylammonium (1 mmol/L) but not glibenclamide (1 micromol/L), suggesting the involvement of an endothelium-derived hyperpolarizing factor that activates Ca2+-activated K+ channels. In conclusion, alpha2-adrenoceptor activation caused relaxation of isolated murine mesenteric arteries that was functionally blocked by NO through a mechanism that may involve activation of the soluble guanylate cyclase and cGMP formation. The endothelium-dependent alpha2-adrenoceptor-mediated relaxation is likely to be due to an endothelium-derived hyperpolarizing factor, whose release and/or production is reduced by concurrent NO formation.

Animals↗
PubMed1999

Phospholamban is present in endothelial cells and modulates endothelium-dependent relaxation. Evidence from phospholamban gene-ablated mice.

Vascular endothelial cells regulate vascular smooth muscle tone through Ca2+-dependent production and release of vasoactive molecules. Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles. In the present study, we report the existence of PLB in the vascular endothelium, a nonmuscle tissue, and provide functional data on PLB regulation of vascular contractility through its actions in the endothelium. Endothelium-dependent relaxation to acetylcholine was attenuated in aorta of PLB-deficient (PLB-KO) mice compared with wild-type (WT) controls. This effect was not due to actions of nitric oxide on the smooth muscle, because sodium nitroprusside-mediated relaxation in either denuded or endothelium-intact aortas was unaffected by PLB ablation. Relative to denuded vessels, relaxation to forskolin was enhanced in WT endothelium-intact aortas. The endothelium-dependent component of this relaxation was attenuated in PLB-KO aortas. To investigate whether these changes were due to PLB, WT mouse aorta endothelial cells were isolated. Both reverse transcriptase-polymerase chain reaction and Western blot analyses revealed the presence of PLB in endothelial cells, which were shown to be >98% pure by diI-acetylated LDL uptake and nuclear counterstaining. These data indicate that PLB is present and modulates vascular function as a result of its actions in endothelial cells. The presence of PLB in endothelial cells opens new fields for investigation of Ca2+ regulatory pathways in nonmuscle cells and for modulation of endothelial-vascular interactions.

Animals↗
PubMedDate not supplied

Endothelium-dependent relaxation of canine basilar arteries. Part 1: Difference between acetylcholine- and A23187-induced relaxation and involvement of lipoxygenase metabolite(s).

Vascular responses to acetylcholine (ACh) and the calcium ionophore A23187 were studied in rings of canine basilar arteries. In preparations that were precontracted to a stable plateau by 3 X 10(-6) M prostaglandin F2 alpha (PGF2 alpha), 10(-9) to 10(-7) M A23187 elicited significant relaxation of the basilar arteries if the endothelium was intact. Judging from histologic findings, the ability of a ring to relax in this manner is due to the presence of the endothelium. The same concentration of A23187 did not relax vascular tissues in which the endothelium was purposely disrupted. Although 10(-7) to 10(-3) M ACh did not sufficiently produce endothelium-dependent relaxation of canine basilar artery rings, ACh in the same concentration did produce significant relaxation in canine femoral rings. Our results suggest that the sensitivity of the muscarinic receptor of cerebral arteries appears to be appreciably different from that of peripheral (femoral) arteries. Pretreatment with 1.5 X 10(-5) M indomethacin, a cyclooxygenase inhibitor, potentiated the contractile responses produced by PGF2 alpha in intact rings. Preincubation with the lipoxygenase inhibitors nordihydroguaiaretic acid at (NDGA) at 1.5 X 10(-5) M or AA861 at 10(-5) M prevented A23187-induced relaxation. The same concentration of NDGA and AA861 did not affect endothelium-independent relaxation induced by glyceryl trinitrate. We suggest that endothelium-dependent relaxation of the canine basilar artery by A23187 may be mediated by noncyclooxygenase metabolite(s).

Acetylcholine↗
PubMed1988

Endothelium-dependent contractions to calcium ionophore A23187, arachidonic acid, and acetylcholine in canine basilar arteries.

The effects of the calcium ionophore A23187, arachidonic acid, and acetylcholine were studied in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in physiological saline. In unstimulated rings, A23187, arachidonic acid, and acetylcholine caused endothelium-dependent contractions. The contractions of rings caused by uridine 5'-triphosphate were not affected by removal of the endothelium. An inhibitor of cyclooxygenase, indomethacin (10(-5) M), prevented excitatory responses to A23187, arachidonic acid, and acetylcholine but did not alter contractions caused by KCl. An inhibitor of thromboxane synthetase, dazoxiben (10(-4) M), significantly reduced endothelium-dependent contractions to A23187 and arachidonic acid but did not significantly affect contractions caused by acetylcholine. These results demonstrate that A23187, arachidonic acid, and acetylcholine cause excitatory endothelium-dependent responses in canine cerebral blood vessels by increasing the release of product(s) of cyclooxygenase from endothelial cells; in the case of A23187 and arachidonic acid, thromboxane A2 contributes to the endothelium-dependent contractions.

Acetylcholine↗
PubMed1992

Dietary omega-3 fatty acids and endothelium-dependent responses in porcine cerebral arteries.

PURPOSE: We sought to determine the effect of dietary omega-3 polyunsaturated fatty acids on cerebrovascular endothelium-dependent responses in studies performed on isolated porcine basilar arteries. METHODS: Male Yorkshire pigs (6-8 weeks old) were kept for 4 weeks on a standard diet (control group, n = 12) or on chow supplemented with polyunsaturated fatty acids (eicosapentaenoic acid, 3.5 g/day, or docosahexaenoic acid, 1.5 g/day; treated group, n = 12). Isometric tension recording of the basilar artery was carried out and responses were compared between the two groups. RESULTS: The regimen resulted in a decrease in the plasma arachidonic acid level and an increase in eicosapentaenoic acid. Endothelium-dependent relaxations induced by bradykinin and adenosine diphosphate were augmented in the basilar arteries of the treated group. Incubation with indomethacin (10(-5) M) prevented the augmentation of the relaxations induced by bradykinin, but not those caused by adenosine diphosphate. The indomethacin-sensitive, endothelium-dependent contractions to arachidonic acid remained comparable in the two groups, indicating that the activity of cyclooxygenase was not affected by the diet. CONCLUSIONS: Dietary supplementation with omega-3 polyunsaturated fatty acids enhances endothelium-dependent relaxations in the basilar artery by two mechanisms: 1) replacement of endogenous arachidonic acid and suppression of the concomitant release of vasoconstrictor prostaglandins from the endothelium, and 2) enhancement of the release of endothelium-derived relaxing factor.

Adenosine Diphosphate↗
PubMed2001

An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide.

Myogenic tone is an important determinant of vascular tone and blood flow in small resistance arteries of certain vascular beds. The role of the endothelium in myogenic responses is unclear. We hypothesized that endothelium-derived NO release modulates myogenic constriction in small resistance arteries and that mesenteric small arteries from mice with targeted disruption of the gene for endothelial NO synthase (eNOS) (knockout mice) demonstrate greater myogenic tone than do wild-type mice. Third-order mesenteric arteries (approximately 200 micrometer) were isolated and mounted in a pressure myograph. Internal diameter was recorded over a pressure range of 10 to 80 mm Hg. Removal of the endothelium significantly (P<0.05) enhanced the magnitude of myogenic constriction in wild-type mice. Similarly, pretreatment of arteries with N(G)-nitro-L-arginine methyl ester (L-NAME; 300 micromol/L) produced a comparable significant (P<0.05) increase in myogenic tone, whereas indomethacin (5 micromol/L) had no effect. eNOS knockout arteries also exhibited myogenic constriction. Neither L-NAME nor indomethacin had any effect on myogenic tone in the arteries of eNOS knockout mice. However, blockade of potential endothelium-derived hyperpolarizing factor-like mechanisms via inhibition of K(+) flux using either apamin (100 nmol/L) with charybdotoxin (100 nmol/L), Ba(2+) (30 micromol/L) with ouabain (1 mmol/L), or 18alpha-glycyrrhetinic acid (100 micromol/L) significantly (P<0.01) enhanced myogenic constriction. This study demonstrates that basal endothelium-derived NO modulates myogenic tone in mesenteric small arteries of wild-type mice. However, eNOS knockout arteries display normal myogenic responsiveness despite the absence of basal NO activity. The data suggest that this compensatory effect is due to the activity of an endothelium-derived hyperpolarizing factor to normalize vascular tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2000

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice.

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H(2)O(2)) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh. Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H(2)O(2) to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K(+) channel opener levcromakalim. Exogenous H(2)O(2) elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that the endothelium produced H(2)O(2) upon stimulation by ACh and that the H(2)O(2) production was markedly reduced in eNOS-KO mice. These results indicate that H(2)O(2) is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.

Acetylcholine↗
PubMed1983

Prostacyclin biosynthesis in cultured vascular endothelium is limited by deactivation of cyclooxygenase.

Primary monolayer cultures of human umbilical vein endothelium produce prostacyclin (PGI2) in response to stimulation by thrombin, ionophore A23187, arachidonic acid, and the prostaglandin endoperoxide, PGH2. None of these treatments had a significant effect on the capacity of the endothelium to produce PGI2 in response to subsequent stimulation by PGH2. By contrast, endothelium initially exposed to thrombin, A23187, or arachidonic acid produced approximately 37, 68, and 84% less PGI2, respectively, upon subsequent stimulation by arachidonic acid. These findings suggest that PGI2 biosynthesis in cultured endothelium results in deactivation of cyclooxygenase-hydroperoxidase but not PGI2 synthetase. To test the hypothesis that PGI2 biosynthesis alone causes deactivation of cyclooxygenase, thrombin, A23187, and arachidonic acid were added to monolayers that had been preincubated with ibuprofen (250 microM), a rapidly reversible, competitive inhibitor of this enzyme. After removal of the ibuprofen and the initial stimulus, PGI2 production in response to subsequent stimulation by arachidonic acid was maximal. These findings suggest that the metabolism of arachidonic acid itself causes a direct deactivation of cyclooxygenase. After an initial exposure to arachidonic acid, PGI2 production in response to a second stimulation by arachidonic acid was restored to approximately 34, 69, and 74% of maximal, after recovery periods of 1, 24, and 48 h, respectively. We conclude that the regulation of PGI2 biosynthesis in normal vascular endothelium may be in part a function of the activity and biosynthesis of cyclooxygenase-hydroperoxidase and the deactivation of this enzyme may be a primary factor limiting the capacity of the endothelium to produce PGI2.

Antioxidants↗
PubMed1986

Aggregating human platelets cause direct contraction and endothelium-dependent relaxation of isolated canine coronary arteries. Role of serotonin, thromboxane A2, and adenine nucleotides.

Aggregating human platelets contract isolated rings of canine coronary artery without endothelium, but relax rings with intact endothelium. We performed experiments to identify the substances released from platelets responsible for these effects. The contraction in rings without endothelium was reduced by treating the platelets with thromboxane synthetase inhibitor, dazoxiben, or treating the vessels with the thromboxane-receptor antagonist, SQ 29548. The serotonergic antagonist, methiothepin, also reduced the platelet-induced contraction. The combination of methiothepin plus dazoxiben or SQ 29548 caused a further inhibition. The endothelium-dependent relaxation to platelets during contractions evoked by prostaglandin F2 alpha was nearly abolished by the ADP- and ATP-scavenger, apyrase. It was not inhibited by methiothepin, which antagonizes endothelium-dependent relaxations to serotonin. Thus, both serotonin and thromboxane A2 contribute to the direct activation of coronary smooth muscle by aggregating human platelets, whereas adenine nucleotides are the principal mediators of the endothelium-dependent relaxation.

Adenine Nucleotides↗
PubMed1991

Elevated glucose impairs endothelium-dependent relaxation by activating protein kinase C.

A possible relationship between protein kinase C activation and impaired receptor-mediated endothelium-dependent relaxation in diabetes mellitus was examined in isolated aorta from normal rabbit exposed to elevated glucose. Aorta treated for 10 min with 4-phorbol 12-myristate 13-acetate (PMA), a protein kinase C activator, showed decreased relaxations to the endothelium-dependent vasodilator, acetylcholine, similar to normal aorta exposed to elevated glucose (22 and 44 mM) for 6 h. Relaxations to the receptor-independent endothelium-dependent vasodilator, A23187, and those caused by the direct smooth muscle vasodilator, sodium nitroprusside, were unaffected by treatment with PMA or exposure to elevated glucose. Indomethacin increased relaxations to acetylcholine of aorta treated with PMA indicating a role for vasoconstrictor prostanoids. PMA caused a significant increase in basal and acetylcholine-stimulated release of vasoconstrictor prostanoids including thromboxane A2 from aortic segments with, but not without endothelium. Protein kinase C inhibitors, H-7 or sphingosine, restored the abnormal acetylcholine-induced relaxations as well as suppressed the abnormal release of prostanoids in aorta exposed to elevated glucose. These findings suggest that the dysfunction of receptor-mediated endothelium-dependent relaxation associated with exposure to elevated glucose is due to increased production of vasoconstrictor prostanoids by the endothelium as a consequence of protein kinase C activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries.

The present study was designed to determine whether bradykinin induces endothelium-dependent hyperpolarization of vascular smooth muscle in human coronary arteries, and if so, to define the contribution of this hyperpolarization to endothelium-dependent relaxations. The membrane potential of arterial smooth muscle cells (measured by glass microelectrodes) and changes in isometric force were recorded in tissues from six patients undergoing heart transplantation. In the presence of indomethacin and NG-nitro-L-arginine (NLA), the membrane potential was -48.3 +/- 0.6 and -46.9 +/- 0.6 mV, in preparations with and without endothelium, respectively, and was not affected by treatment with perindoprilat, an angiotensin-converting enzyme inhibitor. In the presence of both indomethacin and NLA, bradykinin evoked transient and concentration-dependent hyperpolarizations only in tissues with endothelium, which were augmented by perindoprilat and mimicked by the calcium ionophore A23187. Glibenclamide did not inhibit membrane hyperpolarization to bradykinin. In rings contracted with prostaglandin F2 alpha, the cumulative addition of bradykinin caused a concentration-dependent relaxation during contractions evoked by prostaglandin F2 alpha, which was not abolished by NLA and indomethacin. The present findings demonstrate the occurrence of endothelium-dependent hyperpolarization, and its contribution to endothelium-dependent relaxations, in the human coronary artery.

Aged↗
PubMed1994

Endothelium dependency of contractile activity differs in infant and adult vertebral arteries.

Contractions to serotonin (5-HT) and endothelin-1 (ET-1) in infant (0-2 yr) and adult (38-71 yr) vertebral arteries were examined in the presence of either the cyclooxygenase inhibitor indomethacin or NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide production. In addition, endothelium-dependent relaxations to acetylcholine were characterized in arteries contracted with agonist. The results showed that: (a) Contractions of infant arteries to 5-HT or ET-1 decreased to 44 +/- 8% and 27 +/- 13%, respectively, within 10 min. Indomethacin or removal of endothelium abolished this decreased response, whereas L-NMMA had no effect. (b) Adult arteries produced sustained contractions to 5-HT or ET-1 that were unaffected by indomethacin, endothelium denudation, or L-NMMA. (c) Endothelium-dependent relaxations to acetylcholine were greater in infant than adult arteries and were abolished by indomethacin (but not L-NMMA) in infants and L-NMMA (but not indomethacin) in adults. Thus, endothelium-dependent responses in infant arteries are attenuated because of increased prostaglandin activity not observed in adult tissues. Additionally, there is an age-dependent change in the primary mechanism responsible for acetylcholine-induced vasodilation. Apparently, endothelium dependency of acetylcholine-induced relaxation is highly dependent on cyclooxygenase activity in the infant vertebral artery, but in the adult artery, nitric oxide is linked to the vasodilator response.

Adult↗
PubMed2000

Endothelium-dependent sensory non-adrenergic non-cholinergic vasodilatation in rat thoracic aorta: involvement of ATP and a role for NO.

The involvement of non-adrenergic non-cholinergic (NANC) transmitters, such as adenosine 5'-triphosphate (ATP) and nitric oxide (NO), in the neurogenic relaxation of rat thoracic aorta was investigated in vessel segments suspended for isometric tension recording by polygraph. Responses to electrical field stimulation (EFS) and exogenous vasodilator were investigated in vessels precontracted with 5-hydroxytryptamine. EFS (100 V, 2-16 Hz, for 10 s at 3-min intervals), in the presence of guanethidine (10 microM) and atropine (10 microM) produced frequency-dependent relaxations. Pretreatment with tetrodotoxin (1 microM) markedly reduced the relaxation and desensitization with capsaicin (10 microM) significantly inhibited the relaxation. Exogenously added ATP caused concentration-dependent relaxations. Mechanical removal of the endothelium significantly inhibited EFS- and ATP-induced relaxation by 30+/-3% and 37+/-2%, respectively. Pretreatment with a P1-purinoceptor antagonist, 8-phenyltheophylline (10 microM) or P2X-purinoceptor antagonist, Evans blue (10 microM) did not influence the relaxations to EFS and exogenously added ATP. In contrast, the P2Y-purinoceptor antagonist, basilen blue (100 microM) markedly reduced the relaxations to EFS by 52+/-4% in the endothelium-intact preparations. However, in the endothelium-denuded preparations and capsaicin-pretreated preparations, basilen blue did not change relaxations elicited by EFS. The NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) also significantly inhibited the relaxations to EFS and ATP by 40+/-6% and 30+/-2%, respectively, in the endothelium-intact preparations but had no effect on the relaxations in the endothelium-denuded preparations or capsaicin-pretreated preparations. In addition, the EFS-induced relaxations were also inhibited 43+/-7% by pretreatment with 1H-[1,2,4]-oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ; 1 microM), soluble guanylate cyclase inhibitor. This study suggests that the NANC nerve system is present in the thoracic aorta of rat, mediating vasodilatation by sensory nerves. ATP, as a neurotransmitter released from sensory nerves, activates P2Y-purinoceptors located on the endothelium and stimulates the NO/cyclic GMP pathway, resulting in vasodilatation.

Adenosine Triphosphate↗
PubMed2007

Endothelium-dependent vasodilatory and hypotensive effects of Crotalaria sessiliflora L. in rats.

The aim of the present study was to investigate the vasoactive effect of Crotalaria sessiliflora L. extract (CSE) on rats and its mechanism when combining in vivo and in vitro approaches. CSE (0.5-5 mg/ml) induced concentration-dependent relaxation on endothelium-intact thoracic aortic rings precontracted with phenylephrine (PE, 10(-5) M). This effect disappeared with the removal of functional endothelium. Pretreatment of the aortic strips with either N(G)-nitro-L-arginine (L-NNA, 10(-5) M) or methylene blue (10(-5) M) significantly reduced the relaxation induced by CSE. The endothelium-dependent relaxation caused by CSE was associated with production of cGMP. CSE (5 mg/ml) increased the production of cGMP in endothelium-intact aortic rings and this effect was significantly attenuated by L-NNA (10(-5) M) and methylene blue (10(-5) M). Relaxation in response to CSE in strips precontracted with PGF2alpha (3x10(-5) M) was eliminated by removing extracellular Ca2+ and significantly reduced by pretreatment with ruthenium red (10(-5) M). In in vivo tests, injection of 40 mg/kg of CSE induced an increase in plasma NO production, and this effect was blocked by L-NNA. Furthermore, CSE produced dose-dependent and transient decrease in blood pressure in normotensive rats and this effect was blocked by atropine as well as L-NNA. These findings suggest that CSE induces endothelium-dependent relaxation via NO/cGMP signaling by promoting extracellular Ca2+ influx and the release of Ca2+ from intracellular stores of endothelium, probably due to endothelial muscarinic receptor activation.

Animals↗
PubMed1986

Endothelium-dependent changes in the response to vasoconstrictor substances of isolated dog mesenteric veins.

In dog mesenteric vein strips, contractions induced by histamine relative to those induced by 5 mM Ba++ were potentiated by removal of endothelium. The induced contractions were potentiated by AA861, a lipoxygenase inhibitor, and methylene blue, a guanylate cyclase inhibitor, to an appreciably greater extent in the strips with endothelium than in those with damaged endothelium. Indomethacin did not potentiate the contraction induced by histamine. Cimetidine potentiated the contraction in control strips and those without endothelium to a similar extent whereas chlorpheniramine suppressed the contraction. Contractile responses to acetylcholine, norepinephrine, serotonin and prostaglandin (PG) F2 alpha were not potentiated by removal of endothelium. It may be concluded that histamine activates histaminergic receptors, possibly H1 but not H2, in endothelial cells and results in a release of vasodilator substance produced by lipoxygenase, which accumulates cellular cyclic GMP and relaxes mesenteric veins. The H1 and H2 receptors in smooth muscle cells appear to be responsible for contractions and relaxations, respectively. Acetylcholine, norepinephrine, serotonin and PGF2 alpha do not seem to release vasodilator substances from endothelium in an amount sufficient to cause significant relaxations of venous smooth muscle.

Animals↗
PubMed1999

The role of endothelium-derived nitric oxide in relaxations to levcromakalim in the rat aorta.

The present study was designed to examine the role of basally released nitric oxide in relaxations to an ATP-sensitive K+ channel opener. Whether relaxations to levcromakalim are modulated by endothelial removal or the inhibitors of vasodilator effects of endothelium-derived nitric oxide, were investigated in the rat aorta. During contractions to phenylephrine (3 x 10(-7) to 10(-6) M), levcromakalim (10(-8) to 10(-5) M) or a nitric oxide donor, 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7, 10(-9) to 10(-5) M), was added in a cumulative fashion. Relaxations to levcromakalim (10(-8) to 10(-5) M) were significantly reduced by the endothelium-removal. In aortas with endothelium, relaxations in response to levcromakalim were decreased by selective inhibitors of nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 10(-4) M) and soluble guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one; ODQ, 10(-5) M) and a scavenger of nitric oxide (carboxy-PTIO, 10(-3) M). Relaxations to levcromakalim in aortas treated with these inhibitors are comparable to those seen in aortas without endothelium. KCl (30 mM) and an ATP-sensitive K+ channel inhibitor, glibenclamide (10(-5) M), abolished relaxations to levcromakalim in aortas with or without endothelium, whereas glibenclamide did not alter relaxations to NOC-7 (10(-9) to 10(-5) M) in aortas without endothelium. These results suggest that in rat aortas, inhibition of vasodilator effects of basally released nitric oxide can reduce relaxations via ATP-sensitive K+ channels, although these channels do not mediate relaxations to exogenously applied nitric oxide.

ATP-Binding Cassette Transporters↗
PubMed2003

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans.

Vascular endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, such as prostacyclin, nitric oxide (NO), and a yet unidentified endothelium-derived hyperpolarizing factor (EDHF). Possible candidates for EDHF include epoxyeicosatrienoic acids, endothelium-derived K(+) ions, and as we have recently identified, hydrogen peroxide (H(2)O(2)). Electrical communication between endothelial and smooth muscle cells through gap junctions has also been suggested to be involved in endothelium-dependent hyperpolarization. Among the above candidates, the H(2)O(2) hypothesis well explains the pathophysiological interactions between NO and EDHF and re-highlights the physiological roles of the reactive oxygen species in endothelium-dependent vascular responses. This brief review summarizes our current knowledge about H(2)O(2) as an EDHF, with special reference to its production by the endothelium, its action on membrane potentials and its pathophysiological roles.

Animals↗