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PubMed1995

Endothelium-dependent relaxation of rat aorta by butein, a novel cyclic AMP-specific phosphodiesterase inhibitor.

Butein, isolated from Dalbergia odorifera T. Chen, caused endothelium-dependent relaxation of rat aorta precontracted with phenylephrine. This effect was abolished in endothelium-denuded aorta and in endothelium-intact aorta in the presence of NG-monomethyl-L-arginine, oxyhemoglobin and methylene blue, whereas the effect was unaltered by indomethacin or charybdotoxin. These results indicate that the vasorelaxant effect of butein depended on the endothelium and was mediated by endothelium-derived relaxing factor (EDRF). Incubation of endothelium-intact aorta with butein increased not only cAMP but also cGMP content. Four phosphodiesterase forms were isolated by diethylaminoethyl (DEAE)-Sephacel chromatography from rat aorta. cAMP-specific phosphodiesterase (type IV) activity was potently inhibited by butein with an IC50 of 10.4 +/- 0.4 microM. In contrast, phosphodiesterase I, III and V activities were inhibited by butein above 100 microM. Adenylate cyclase and guanylate cyclase activities were unchanged by butein. These results suggest that the increase of cAMP formation elicited by butein is due to the inhibition of cAMP-specific phosphodiesterase. The specific phosphodiesterase IV inhibitor (rolipram) and V inhibitor (zaprinast) both produced endothelium-dependent relaxations, whereas the phosphodiesterase III inhibitor (trequinsin) produced relaxation of rat aorta independent of the endothelium. In the presence of a functional endothelium, relaxations produced by butein were significantly potentiated by isoprenaline, forskolin, trequinsin and sodium nitroprusside. It is concluded that butein, a novel cAMP-specific phosphodiesterase inhibitor, produced relaxation of rat aorta, an effect dependent on an intact endothelium. The relaxant effect of butein was markedly enhanced by cGMP-elevating agents.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

The role of the endothelium on enhanced contractile response of non-insulin-dependent diabetic rat aortae: effects of insulin treatment.

1. The role of the endothelium on the constrictor effect of noradrenaline (NA), and endothelium-dependent and endothelium-independent vasodilator effects of different agonists were determined in rings of aortae obtained from nondiabetic (control), non-insulin-dependent (NID-) diabetic and NID-diabetic rats treated with insulin. 2. The NA-induced contractions are markedly increased with no change in agonist potency (pD2 value) in aortae with intact endothelium obtained from NID-diabetic rats when compared to those from age-matched controls. Mechanical removal of the endothelium resulted in a significant increase in maximum contractile response of control aortae but not NID-diabetic aortae to NA relative to presence of endothelium. No significant difference was observed between the contractile responses of NID-diabetic and control aortae to NA after the removal of endothelium. 3. Endothelium-dependent relaxations elicited by acetylcholine (ACh), histamine, ATP and insulin strongly depressed in NID-diabetic aortae but the relaxations stimulated by sodium nitroprusside (SNP) did not change when compared to corresponding controls. There was no significant changes in the pD2 values calculated by agonist-induced relaxations of aortae from either untreated or insulin-treated NID-diabetic rats compared with controls. 4. NID-diabetes-induced alterations on the reactivity of aortae were significantly restored by in vivo insulin treatment. 5. These data indicate that impaired endothelium-dependent vasodilatory responses of aortae from NID-diabetic rats results in increased NA-induced contractions. It is possible that, impaired endothelium-dependent vasodilatory modulation of vasoconstriction may play a important role in development of vasospasm and hypertension in NID-diabetics.

Adenosine Triphosphate↗
PubMedDate not supplied

The effects of chronic ethanol treatment on endothelium-dependent responses in rat thoracic aorta.

The purpose of this study was to investigate the effects of chronic ethanol consumption on blood pressure and vascular responses, specifically, the possible alterations in endothelium-dependent relaxation which are associated with ethanol-induced hypertension in the rat model. Male rats received ethanol in drinking water for 13 weeks. Systolic pressure was recorded weekly. Following treatment, segments of thoracic aorta with and without intact endothelium were used to generate relaxation-response curves to the endothelium-dependent agents, acetylcholine, ATP and bradykinin, as well as the endothelium-independent agents, adenosine and sodium nitroprusside. Mean systolic pressures at the end of the treatment period were: 127.8 +/- 1.2 and 151.1 +/- 1.3 mmHg for controls and ethanol-treated rats, respectively. Ethanol treatment did not affect the relaxation produced by either acetylcholine, ATP or sodium nitroprusside in aorta with or without endothelium. In contrast, ring segments with intact endothelium from ethanol-treated rats exhibited augmented relaxation in response to both adenosine and bradykinin compared to controls. Removal of the endothelium abolished the relaxation produced by bradykinin in both groups. Although removal of the endothelium had no effect on the relaxation produced by adenosine in the control group, it attenuated the adenosine-induced relaxation in the ethanol-treated group back to control levels. These data suggest that chronic ingestion of ethanol causes elevated blood pressure and augments the endothelium-dependent relaxation to bradykinin. These findings also suggest that chronic ethanol treatment can cause the appearance of an endothelium-dependent component in the relaxation produced by adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed2006

Endothelium-dependent inhibition of the contractile response is decreased in aorta from aged and spontaneously hypertensive rats.

BACKGROUND: Stimulation of vascular 5-hydroxytryptamine-2C (5-HT(2c)) receptors produces contraction in rat aorta. We investigated the effect of aging on endothelium-dependent inhibition of contractile responses in thoracic aorta from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). METHODS: Endothelium-intact and denuded aortic rings were prepared from young (7-9 weeks old) and senescent (65-70 weeks old) WKY and SHR rats. Changes in isometric tension elicited by 5-HT, in the absence or in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin were recorded. RESULTS: In aorta from WKY and SHR, 5-HT elicited concentration-dependent contractions, which were increased by endothelium removal. The ability of endothelium to depress contractile response to 5-HT was found to be reduced in vessels from senescent animals, mainly in SHR. L-NAME increased the sensitivity and maximal effect to 5-HT in endothelium-intact but not in denuded aortic rings from young WKY rats. The effect of L-NAME was lower in young SHR compared with age-matched WKY rats, but it did not modify the response to 5-HT in senescent rats. Indomethacin did not affect contraction in arteries from young WKY or in denuded aortic rings from young SHR and aged WKY. In contrast, the inhibitor attenuated the response in endothelium-intact vessels from young SHR and aged WKY, and this effect was more marked in arteries with and without endothelium from senescent SHR. Thus, inhibition of cyclooxygenases by indomethacin revealed an enhanced endothelium-dependent modulation of contraction in senescent and hypertensive rats. CONCLUSIONS: Results indicate that hypertension and aging decrease the negative modulator role of endothelium, in 5-HT-induced vasoconstriction in aorta from WKY and SHR. Data also point out that endothelial dysfunction involves an increased formation of vasoconstrictor prostanoids, which counteract nitric oxide effects. In addition, SHR endothelium releases contractile prostanoids at an early stage of hypertension, whereas in old SHR vascular smooth muscle also releases prostanoids, which contribute to 5-HT-induced contraction.

Aging↗
PubMed2004

Damaged DNA-binding protein 2 accelerates UV-damaged DNA repair in human corneal endothelium.

PURPOSE: To determine damaged DNA-binding protein 2-gene expression levels in vitro and ex vivo, and the degree of DNA repair in damaged DNA-binding protein 2-overexpressing cultured human corneal endothelium after ultraviolet irradiation. METHODS: Constitutive damaged DNA-binding protein 2-gene expression levels in various human tissues were determined by semi-quantitative reverse transcription-polymerase chain reactions. The dynamics of nucleotide excision repair-related gene expression in cultured human corneal endothelium were investigated in a ribonuclease protection assay after ultraviolet-irradiation. The effect of damaged DNA-binding protein 2 on DNA repair was studied after ultraviolet-irradiation in cultured human corneal endothelium infected with adenovirus carrying damaged DNA-binding protein 2. RESULTS: Human corneal endothelium and epithelium in the donor cornea had the highest constitutive damaged DNA-binding protein 2-gene expression of the various human tissues studied. Gene expression level dynamics associated with nucleotide excision repair factors after ultraviolet-irradiation showed that the increase in the rate of damaged DNA-binding protein 2-gene expression in cultured human corneal endothelium was highest of the nucleotide excision repair-related genes studied. An in vivo DNA repair assay showed that DNA repair efficiency in damaged DNA-binding protein 2-overexpressing cultured human corneal endothelium after ultraviolet-irradiation was significantly improved as compared with that in the control human corneal endothelium. CONCLUSION: The human corneal endothelium abundantly expresses the damaged DNA-binding protein 2-gene that is produced efficiently on ultraviolet exposure. This overexpressed damaged DNA-binding protein 2 in the human corneal endothelium contributes to the protection system against DNA damage after ultraviolet-irradiation. Our findings show a critical role for damaged DNA-binding protein 2 in DNA repair to maintain the human corneal endothelium function.

Adult↗
PubMed1997

Surgical preparation abolishes endothelium-derived hyperpolarizing factor-mediated hyperpolarization in the human saphenous vein.

BACKGROUND: The impairment of the synthesis and release of endothelium-derived relaxing factors may be related to the high incidence of atherosclerosis and occlusion in saphenous vein grafts. This study focused on the effect of surgical preparation on one of the endothelium-derived relaxing factors, endothelium-derived hyperpolarizing factor, in the human saphenous vein. METHODS: Human saphenous vein segments taken from patients undergoing coronary bypass were placed in an organ bath. A glass microelectrode was inserted into a smooth muscle cell. The membrane potential in response to acetylcholine (-9 to -5 log M) was measured in normal or surgically prepared saphenous vein with presence or absence of NG-nitro-L-arginine (300 mumol/L) and indomethacin (7 mumol/L). RESULTS: The resting membrane potential was -71.28 +/- 1.91 mV (n = 7) with intact endothelium and -65.5 +/- 2.92 mV (n = 6, p > 0.05) without endothelium. Acetylcholine hyperpolarized membrane potential with intact endothelium (-90.57 +/- 1.48 mV, n = 7, p < 0.001), but not without endothelium (-69.67 +/- 2.93 mV, n = 6, p > 0.05). In the surgically prepared saphenous vein, acetylcholine did not hyperpolarize membrane potential (-71.83 +/- 3.84 mV versus the resting membrane potential of -69.50 +/- 3.53 mV, n = 6, p > 0.05). CONCLUSIONS: The endothelium-derived hyperpolarizing factor plays a role in the human saphenous vein. The surgical preparation abolishes the endothelium-derived hyperpolarizing factor-mediated hyperpolarization in the saphenous vein. This study provides evidence of functional changes of endothelium by traditional surgical preparation from another point of view, and it may be related to the high incidence of occlusion in saphenous vein grafts.

Biological Factors↗
PubMed1997

Studies on endothelium-dependent vasorelaxation by hydralazine in porcine coronary artery.

Hydralazine relaxed porcine coronary artery strips in a concentration-dependent manner by distinct endothelium-dependent and endothelium-independent actions. With lower doses (< or = 10(-6) M), the hydralazine-induced relaxation appears to be completely endothelium-dependent and we designed the present study to elucidate the mechanisms of this endothelium-dependent relaxation. Hydralazine (10(-6) M)-induced endothelium-dependent relaxation was not affected by the presence of 10(-5) M indomethacin, 10(-3) M L-NG-nitro-arginine (L-NOARG) or 10(-5) M haemoglobin, and was accompanied by accumulation of cGMP but not of cAMP in artery strips. There was a close time-dependent parallel relationship between endothelium-dependent relaxation and accumulation of cGMP induced by hydralazine (10(-6) M). The endothelium-dependent relaxation and accumulation of cGMP induced by hydralazine showed much slower kinetics than those induced by ionomycin (10(-7) M). Pretreatment of the strips with actinomycin D (10 micrograms/ml) significantly inhibited not the endothelium-dependent relaxation and accumulation of cGMP induced by ionomycin (10(-7) M) but those induced by hydralazine (10(-6) M). These results suggest that hydralazine induces endothelium-dependent vasorelaxation via the slow accumulation of cGMP in the strips. This does not occur through the release of nitric oxide or prostaglandin I2 but through immediate transcription and probably expression of a molecule in the endothelium.

Animals↗
PubMed2001

A triglyceride-rich fat emulsion and free fatty acids but not very low density lipoproteins impair endothelium-dependent vasorelaxation.

OBJECTIVE: To investigate the effects of triglycerides and free fatty acids on endothelium-dependent and endothelium-independent vasorelaxation. METHODS: Femoral arterial rings from rats were studied in organ baths. The vascular segments were constricted with phenylephrine after 20 min of preincubation with the triglyceride-rich fat emulsion Intralipid, free fatty acids (16:0, 18:1, 18:3) bound to bovine serum albumin, or very low density lipoproteins. Endothelium-dependent and endothelium-independent relaxations were determined after administration of acetylcholine and nitric oxide donors, respectively. RESULTS: Preincubation with Intralipid caused a concentration-dependent impairment of endothelium-dependent but not endothelium-independent relaxation. Very low density lipoproteins did not affect vascular function. All free fatty acids impaired endothelium-dependent relaxation, whereas endothelium-independent relaxation was unaffected. Administration of the antioxidant vitamin C partly reversed the impairment of the endothelium-dependent relaxation induced by Intralipid and free fatty acids. CONCLUSIONS: The present study demonstrates that the triglyceride-rich fat emulsion Intralipid and individual FFAs impair endothelium-dependent relaxation of arterial rings from rat, whereas triglycerides in the form of VLDL do not affect endothelial function. The finding that the antioxidant vitamin C partly reverses this impairment indicates the involvement of oxidative mechanisms.

Acetylcholine↗
PubMed1998

Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.

OBJECTIVES: We sought to determine whether the antioxidant vitamin C improves endothelium-dependent vasodilation of forearm resistance vessels in patients with insulin-dependent diabetes mellitus. BACKGROUND: Endothelium-dependent vasodilation is impaired in patients with diabetes mellitus. Oxidatively mediated degradation of endothelium-derived nitric oxide contributes to abnormal endothelium-dependent vasodilation in animal models of diabetes mellitus. METHODS: The study group included 10 patients with insulin-dependent diabetes mellitus and 10 age-matched control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3 to 10 microg/min). Endothelium-independent vasodilation was assessed by intraarterial infusion of nitroprusside (0.3 to 10 microg/min). Forearm blood flow dose-response curves were determined for each drug infusion before and during concomitant infusion of vitamin C (24 mg/min). RESULTS: In diabetic subjects, endothelium-dependent vasodilation was augmented by the concomitant infusion of vitamin C (p = 0.001). Endothelium-independent vasodilation was not affected by the concomitant infusion of vitamin C (p = NS). In control subjects, vitamin C infusion did not affect endothelium-dependent vasodilation (p = NS). CONCLUSIONS: Vitamin C selectively restores the impaired endothelium-dependent vasodilation in the forearm resistance vessels of patients with insulin-dependent diabetes mellitus. These findings indicate that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in humans with insulin-dependent diabetes mellitus.

Adult↗
PubMedDate not supplied

Murine Lewis lung carcinoma-derived endothelium expresses markers of endothelial activation and requires tumor-specific extracellular matrix in vitro.

The purpose of the study was to identify characteristics specific to tumor-derived endothelium that may be important in tumor biology, or for the development of targeted therapeutics or imaging agents. Normal C57Bl/6 murine heart or lung endothelium, or C57Bl/6 murine Lewis lung carcinoma tumor-derived endothelium was isolated from excised tissues using specific antibodies. The endothelium was cultured using either native fibronectin, or the oncofetal form of fibronectin. Cell surface adhesion molecule expression was analyzed by flow cytometry, and the cellular distribution of specific molecules was examined using indirect immunofluorescence staining. Oncofetal fibronectin was critical for maintaining the phenotype of tumor-derived endothelium, which demonstrated an elongated morphology in vitro, with few cell-cell contacts. They expressed high levels of CD31, CD102, and vascular endothelial cadherin, and constitutively expressed CD62E, CD54, and CD106, indicating an "activated" phenotype. Moreover, they expressed significantly greater levels of Sca-1 and Flk-1 than normal murine endothelium. Cellular distribution of CD31, beta-catenin, and CD106 in tumor-derived endothelium was not continuous at cell borders, as observed in cultures of murine heart endothelium. In conclusion, Lewis lung carcinoma-derived tumor endothelium exhibits a specific phenotype in vitro, distinct from normal endothelium, and could be used as an in vitro tool for developing targeted agents.

Animals↗
PubMed1998

Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides: evidence for receptor heterogeneity.

1. The vascular actions of the proteinase-activated receptor-2-activating peptides (PAR2APs), SLIGRL-NH2 (SL-NH2) and SLIGKV-NH2 (KV-NH2) as well as the reverse-sequence peptide, LSIGRL-NH2 (LS-NH2) and an N-acylated PAR2AP derivative, trans-cinnamoyl-LIGRLO-NH2 (tcLI-NH2), were studied in rat intact and endothelium-denuded artery ring preparations, primarily from the pulmonary artery (RPA). 2. In RPA rings with but not without a functional endothelium, SL-NH2 (but not LS-NH2) caused either an endothelium-dependent relaxation (at concentrations: < 10 microM) or (at higher concentrations: > 10 microM), an endothelium-dependent contraction. No contractile response was observed in endothelium-denuded preparations, that otherwise contracted in response to the PAR1AP, TFLLR-NH2. 3. The endothelium-dependent contractile response to SL-NH2 was not blocked by the alpha-adrenoceptor antagonist prazosin, the endothelin antagonist BQ123, the angiotensin II antagonist DuP753, by tetrodotoxin; nor by the enzyme inhibitors, N(omega)-nitro-L-arginine-methylester (NO-synthase), indomethacin (cyclo-oxygenase), SKF-525A (epoxygenase) and MK886 (leukotriene synthesis inhibitor). 4. In the relaxation assay, KV-NH2 was 5 fold less potent than SL-NH2, whereas in the contractile assay KV-NH2 was about equipotent with SL-NH2. However, the maximal contractile response to KV-NH2 was lower than that of SL-NH2. 5. The PAR2AP analogue, tcLI-NH2, was as active as SL-NH2 in the relaxation assay but was inactive as a contractile agonist in the endothelium-intact RPA. 6. The relaxant responses caused by SL-NH2 and trypsin, as well as the contractile response caused by SL-NH2, did not desensitize in the course of repeated exposures of the tissue to agonist; whereas the contractile response to trypsin, only observed at concentrations greater than 30 u ml(-1), was desensitized by previous exposure of the tissue to either thrombin or trypsin. 7. In a contractile assay, where the tissue was desensitized to a concentration of trypsin that would otherwise cause a relaxant response, the preparation still contracted in response to SL-NH2. However, the trypsin-desensitized preparations were no longer contracted by thrombin. 8. From the cross-desensitization by thrombin of the contractile response to trypsin (and vice versa), we concluded that the contractile effect of trypsin was due to activation of the thrombin receptor and not PAR2. 9. We concluded that the endothelium-dependent contraction caused by high concentrations of SL-NH2 is due to an as yet unidentified contracting factor; whereas the endothelium-dependent relaxation response observed at low concentrations of SL-NH2 (< or = 10 microM) is mediated by nitric oxide. 10. The distinct structure activity profiles for the contractile response (potency of KV-NH2 < or = SL-NH2) compared with the relaxant response (potency of KV-NH2 << SL-NH2); the contractile responsiveness to SL-NH2 of an endothelium-intact RPA preparation, that did not contract in response to trypsin; and the lack of contractile activity of the PAR2AP analogue tcLI-NH2, that was as active as SL-NH2 in the relaxation assay all argue in favour of receptor heterogeneity in the vasculature for the PAR2APs. It remains to be determined if the distinct endothelial receptor responsible for the contractile action of SL-NH2 can be proteolytically activated, like PAR1 and PAR2.

Animals↗
PubMed2000

Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries.

The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC(50)=3.5+/-1.1 nM, R(max)=103+/-10% of control contraction induced by 60 mM KCl and 1 microM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 microM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC(50)=1.3+/-0.8 nM, R(max)=20.1+/-4.9% of control contraction induced by 10 microM 5-HT). The contractile response was significantly enhanced by removal of the endothelium (R(max)=55.4+/-16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HT-precontracted arteries, which was abolished by L-NAME or removal of the endothelium. No contractile effects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration- and endothelium-dependent relaxations of methoxamine-precontracted vessels. The relaxant responses were potentiated by L-NAME (300 microM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). The present study is the first to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.

Animals↗
PubMed2002

Urocortin-induced endothelium-dependent relaxation of rat coronary artery: role of nitric oxide and K+ channels.

1. The mechanisms underlying the vasodilator response to urocortin are incompletely understood. The present study was designed to examine the role of endothelial nitric oxide and Ba(2+)-sensitive K(+) channels in the endothelium-dependent component of urocortin-induced relaxation in the rat left anterior descending coronary artery. 2. Urocortin induced both endothelium-dependent and -independent relaxation with respective pD(2) of 8.64+/-0.03 and 7.90+/-0.10. Removal of endothelium reduced the relaxing potency of urocortin. In rings pretreated with 10(-4) M N(G)-nitro-L-arginine methyl ester, 10(-5) M methylene blue or 10(-5) M ODQ, the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. L-Arginine (5x10(-4) M) antagonized the effect of N(G)-nitro-L-arginine methyl ester. 3. The relaxant response to urocortin was reduced in endothelium-intact rings preconstricted by 3.5x10(-2) M K(+) and abolished when extracellular K(+) was raised to 5x10(-2) M. Pretreatment with 10(-4) M BaCl(2) significantly inhibited urocortin-induced relaxation. Combined treatment with 10(-4) M BaCl(2) plus 10(-4) M N(G)-nitro-L-arginine methyl ester did not cause further inhibition. In urocortin (10(-8) M)-relaxed rings, BaCl(2) induced concentration-dependent reversal in vessel tone. Tertiapin-Q (10(-6) M) also attenuated urocortin-induced relaxation. In contrast, BaCl(2) did not alter urocortin-induced relaxation in endothelium-denuded rings. 4. In endothelium-denuded rings, hydroxylamine- and nitroprusside-induced relaxation was inhibited by 10(-4) M BaCl(2), but not by 10(-6) M tertiapin-Q. 5. The endothelium of the coronary artery was moderately stained with the antiserum against urocortin. 6. Taken together, the present results indicate that the urocortin-induced endothelium-dependent relaxation of rat coronary arteries is likely attributable to endothelial nitric oxide and subsequent activation of Ba(2+)- or tertiapin-Q-sensitive K(+) channels. The urocortin-induced endothelium-dependent relaxation appears to be mediated by cyclic GMP-dependent mechanisms.

Animals↗
PubMed1996

Effect of the vascular endothelium on contractions induced by prostaglandin F2 alpha in isolated pregnant guinea pig uterine artery.

The purpose of this study was to examine the influence of endothelium on prostaglandin F2 alpha-mediated contractions in pregnant guinea pig uterine artery. Consequently, the effects of prostaglandin F2 alpha on pregnant guinea pig uterine arterial rings with both intact and denuded endothelium were studied. In vessels with denuded endothelium prostaglandin F2 alpha (0.1-10 microM) induced contraction (pD2 = 6.17) with greater potency than in vessels with intact endothelium (pD2 = 5.68). NG-Monomethyl-L-arginine (10 microM) did not affect the concentration-response curve for prostaglandin F2 alpha, regardless of endothelial condition. In contrast, in both types of preparation, indomethacin (10 microM) increased the maximal response value obtained with prostaglandin F2 alpha, but this effect was significantly greater in preparations with intact than in those with denuded endothelium (128.3 versus 206.5%). Moreover, indomethacin shifted the concentration-response curve for prostaglandin F2 alpha to the left only in preparations with intact endothelium. The pKA values for prostaglandin F2 alpha itself did not differ between preparations: 5.41 and 5.52 for pregnant guinea pig uterine artery with and without endothelium, respectively. The receptor reserve expressed as KA/EC50 was significantly greater in rings with denuded (4.44) compared to those in rings with intact endothelium (1.86). We conclude that prostaglandin-F2 alpha-induced contraction in pregnant guinea pig uterine artery is modulated by the vascular endothelium. It is probable that cyclooxygenase products relating to vasodilatation and derived from endothelium mediate this effect, acting as a functional endogenous antagonist and thereby reducing the apparent efficacy and potency of prostaglandin F2 alpha.

Animals↗
PubMed1990

Release of endothelium-derived relaxing factors from canine cardiac valves.

In the present study, the ability of intact cardiac valvular endothelial cells to release vasodilatory prostanoids and endothelium-derived relaxing factor was investigated. Endothelium-denuded canine coronary arteries were used for bioassay and contractile force recording. Insertion of small segments of cardiac valve (20-30 mm2) with intact endothelium into endothelium-denuded coronary arterial rings did not markedly alter the sensitivity nor magnitude of the coronary artery contractile response to KCl. In contrast, the prostaglandin F2 alpha (PGF2 alpha)-induced contraction was significantly depressed (70% decrease in magnitude and 216% increase in ED50), compared with contraction in the absence of valvular endothelium (5.52 +/- 0.49 g and ED50 of 1.18 +/- 0.02 microM, respectively). These alterations in PGF2 alpha-induced contractions were reduced to 38% decrease in magnitude and +66% in ED50 in the presence of 5 microM indomethacin. Addition of acetylcholine (0.1-30 microM) into these endothelium-denuded coronary artery/valve preparations resulted in a dose-dependent relaxation, reaching a maximum of -59.9 +/- 1.6% (mean +/- SEM of seven vessels). Preincubation of valvular endothelium with 5 microM indomethacin also reduced these acetylcholine-induced valvular endothelium-dependent relaxations to 40.4 +/- 5.5% (mean +/- SEM of 13 vessels). Addition of hemoglobin (3 microM) further attenuated relaxation to -16.0 +/- 7.7% (mean +/- SEM of 14 vessels), while superoxide dismutase (20 units/ml) potentiated the relaxant response to -81.3 +/- 9.4% (mean +/- SEM of 11 vessels) in the presence of indomethacin. These findings suggest that there is a continuous basal release of vasodilatory prostanoids and endothelium-derived relaxing factor from the valvular endothelium, which can be further stimulated with acetylcholine and superoxide dismutase, and inhibited by indomethacin and hemoglobin.

Acetylcholine↗
PubMed1994

Effects of the Ca2+ antagonist RO 40-5967 on endothelium-dependent responses of isolated arteries.

Experiments were designed to determine whether the Ca2+ channel inhibitor RO 40-5967 [(1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamine]ethyl]-6- fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride] causes endothelium-dependent relaxations or inhibits endothelium-dependent contractions of isolated blood vessels. Rings of dog femoral, carotid, and basilar arteries and of rat aorta, with and without endothelium, were suspended in conventional organ chambers for measurement of isometric force. During contractions evoked by phenylephrine (full alpha 1-adrenergic agonist), St 587 (partial alpha 1-adrenergic agonist) and endothelin-1 (ET), RO 40-5967 caused concentration-dependent relaxations of rings of dog femoral arteries; the relaxations to RO 40-5967 were greater in rings with endothelium than in those without endothelium. Nitro-L-arginine (NLA) and methylene blue (MB) inhibited the endothelium-dependent component of the response to RO 40-5967 during contractions to phenylephrine (PE) St 587 and ET. The endothelium-dependent relaxations evoked by RO 40-5967 during contractions to PE were not affected by diltiazem in the femoral artery, suggesting that this effect of the compound may not be related to its calcium channel inhibitor properties. Under bioassay conditions, RO 40-5967 stimulated release of relaxing factors from the endothelium of canine carotid arteries; the response of the detector tissues was inhibited by MB. In strips of canine femoral artery with endothelium, in which membrane potential of vascular smooth muscle cells (VSMC) was recorded with glass microelectrodes, RQ 40-5967 did not cause endothelium-dependent hyperpolarizations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1992

Endothelium-dependent and -independent relaxation by dopamine in the rabbit pulmonary artery.

1. The relaxing response of dopamine (DA) was studied in the rabbit pulmonary artery. DA caused concentration-related relaxation in helically cut strips of the artery contracted with prostaglandin F2 alpha in the presence of prazosin. 2. The DA-induced relaxation in endothelium-denuded strips was reduced to about 40% compared with that in endothelium-intact strips. 3. Methylene blue and haemoglobin, inhibitors of endothelium-dependent relaxation, reduced the DA-induced relaxations in endothelium-intact strips to the level of endothelium-denuded strips. These results indicate that the DA-induced relaxation is partially mediated or modified by the release of endothelium-derived relaxing factor (EDRF). 4. Apomorphine, as a DA agonist, caused concentration-dependent relaxation in endothelium-intact strips. Bromocriptine, a DA2 agonist, produced only a little relaxation at higher concentration. 5. In endothelium-intact strips, haloperidol, a DA antagonist, and the DA1 antagonists, fluphenazine and SCH 23390 inhibited DA-induced relaxations. On the other hand spiperone and domperidone, DA2 antagonists, were inactive. 6. In endothelium-denuded strips, fluphenazine and SCH 23390 inhibited DA-induced relaxations, but domperidone was inactive. 7. These results indicate that the DA-induced relaxation is mediated by DA receptors, and that DA1 receptors are involved in both endothelium-dependent and -independent relaxation in the rabbit pulmonary artery.

Animals↗
PubMed1993

Influence of the endothelium on Ca2+ dependency of angiotensin II-induced contractions of rat aortic rings.

Endothelium-dependent relaxation has been demonstrated to be involved in the regulation of vascular tone and extracellular Ca2+ was found to play a prominent role in this process. Since the dependency on extracellular Ca2+ appeared to differ considerably within the arterial tree, possibly as a consequence of vessel-related endothelium-dependent mechanisms, we investigated the effects of different compounds affecting Ca2+ entry (nifedipine, CoCl2) on angiotensin II-induced contractions of rat aortic rings with and without endothelium as well as the responses in a Ca(2+)-"free" solution. For this purpose, rat aortic rings were either undone from their endothelial layer by gentle mechanical rubbing or care was taken to keep the intima intact in case rings where endothelium were required. The presence of an intact endothelium was confirmed by acetylcholine-induced relaxation. A stronger responsiveness towards angiotensin I, both after a complete concentration-response curve and after a single maximal concentration of angiotensin II was observed in arterial segments without endothelium. The maximal contraction to a single concentration of angiotensin II (0.1 microM) in the rings without endothelium amounted to 75.8 +/- 3.8% of the preceding response to a supramaximal concentration of noradrenaline (= Emax). In rings without the endothelial layer, the contraction was 34.8 +/- 3.7% of Emax. This indicates an endothelium-induced relaxation in aortic rings with endothelium. After incubation with the Ca2+ entry blocker nifedipine (1 microM) both rings with and without endothelium were inhibited to the same extent, contractions amounted to 30.7 +/- 1.8% and 19.6 +/- 1.3% of Emax, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗