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PubMed2000

Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium.

Increased adherence of sickle red blood cells (RBC) to endothelium is implicated as an initiating event of vaso-occlusion in sickle cell disease. Although much is known about the humoral influences of this interaction, there has been little investigation regarding endothelial contributions. Endothelial derived nitric oxide (NO) inhibits adhesion of platelets and leukocytes to endothelium and decreases expression of VCAM-1, an endothelial adhesion site implicated in sickle RBC/endothelial adherence. However, whether NO inhibits RBC adherence to endothelium is unexplored. We tested this hypothesis with endothelial monolayers exposed to RBC from normal (Hb AA) and sickle cell (Hb SS) volunteers in a parallel plate flow chamber. To decrease NO production, endothelial monolayers were exposed to 100 microM nitro-L-arginine (NLA), an inhibitor of nitric oxide synthase, resulting in an 87% increase in normal RBC adherence (P = 0.002). Because adherence of normal RBC to endothelium was low, the effect of DETA-NO, an NO donor, was tested after activation of endothelium with TNF-alpha increased adherence by 130% (P < 0.001). Subsequent addition of 2 mM DETA-NO produced a 75% decrease in adherence of normal RBC to endothelium (P = 0.03). At baseline, sickle RBC were significantly more adherent than normal RBC (P < 0.001) and DETA-NO decreased sickle RBC adherence by 54% (P = 0.04). Thus, NO inhibits both normal and sickle RBC adherence to endothelium. Strategies that enhance NO activity may be therapeutic in sickle cell disease.

Adolescent↗
PubMed1997

Transforming growth factor-beta enhances adhesion of melanoma cells to the endothelium in vitro.

Melanoma invasion requires migration through the vascular barrier. An early event in this process is the adhesion of metastatic cells to the endothelium. To elucidate the role of TGF-beta in the regulation of this process, human melanoma SK-MEL24 cells were labelled with [5'-(3)H]-thymidine and co-cultured with bovine pulmonary artery endothelial-cell monolayers. Radioactivity was assumed to be proportional to the number of SK-MEL24 cells bound to the endothelium. A low number of melanoma cells adhered to endothelial cells in a time-related manner. Pretreatment for 24 hr with 0.001 to 10 ng/ml TGF-beta1 or TGF-beta2 of both cell types enhanced melanoma-endothelium adhesion in a dose-dependent manner. Both melanoma and endothelial cells expressed RI- and RII-type TGF-beta receptors. The effect of TGF-beta was abolished by co-incubation with the proteoglycan decorin. Conditioned media from melanoma-endothelium co-cultures contained latent TGF-beta and failed to affect cell-cell adhesion. However, activation of TGF-beta by heating the medium or reducing the pH, increased melanoma-endothelium adhesion to an extent similar to that of the TGF-beta administered to the cultures. Zimography demonstrated that both cell types expressed urokinase-type plasminogen activator (uPA). Addition of plasminogen to the co-cultures, which was likely to be activated to plasmin by uPA, resulted in activation of TGF-beta and parallel stimulation of melanoma-endothelium adhesion. In conclusion, TGF-beta may enhance adhesion of melanoma cells to the endothelium, playing a relevant autocrine/paracrine role in the progression of invasive melanoma.

Activin Receptors, Type I↗
PubMed1993

Human neutrophil adhesion to bovine aortic endothelium. Evidence for endothelial lipoxygenase activity.

We examined the effect of phorbol myristate acetate on cultured bovine aortic endothelial cells to determine the role of endothelial cells in neutrophil-endothelial cell adhesive interactions. Confluent endothelial cells were preincubated with phorbol myristate acetate and other inflammatory signals including N-formylmethionyl-leucyl-phenylalanine (f-Met-Leu-Phe), the ionophore A23187, and thrombin; washed extensively; and incubated with 51Cr-labeled neutrophils. Preincubation of endothelium with A23187, phorbol ester, or thrombin increased adherence of neutrophils by 3.1-, 5.7-, and 3.7-fold over baseline. In contrast, f-Met-Leu-Phe preincubation failed to increase adhesion over baseline. Supernatants from endothelium preincubated with phorbol failed to augment adherence of untreated endothelial cells. Preincubation of endothelium with lipoxygenase inhibitors nordihydroguaiaretic acid (50 microM), 5,8,11,14-eicosatetraenoic acid (50 microM), and BW755C (50 microM) inhibited the effect of phorbol preincubation of endothelium significantly by 55, 27, and 22%, respectively. In contrast, inhibitors of cyclooxygenase and thromboxane synthase or thromboxane receptor antagonists had no effect on phorbol-induced adhesion. Specific desensitization of neutrophil adhesion to phorbol-treated endothelium could be demonstrated by prior exposure of neutrophils to low concentrations of leukotriene B4 (3.8 x 10(-10) M). Endothelium preincubated with phorbol but not f-Met-Leu-Phe or thrombin produced several fatty acid peaks at 280 nm, one of which comigrated with authentic leukotriene B4 (LTB4). This peak, isolated and purified, increased endothelial cell adherence in a temporal fashion in the same way as LTB4 and was demonstrated to be LTB4 by ultraviolet spectroscopy, high-performance liquid chromatography, and mass spectroscopy. These data demonstrate that endothelial cell-derived lipoxygenase metabolites, in particular LTB4, are involved, in part, in the acute regulation of neutrophil adhesion to endothelium induced by inflammatory signals such as phorbol ester.

Animals↗
PubMed1993

Intercellular adhesion molecule-1 on rat corneal endothelium in experimental uveitis.

We studied the expression of the intercellular adhesion molecule-1 (ICAM-1) on the corneal endothelium of the rat in the experimental uveitis induced by interphotoreceptor peptides (R-4) as an immunogen using immunohistochemical methods. ICAM-1, which was not detected in eyes without inflammation, was expressed on the corneal endothelium, vascular endothelium and inflammatory cells, such as monocytes and lymphocytes, in R-4 induced uveitis. The ocular inflammation in the iris, ciliary body and anterior chamber associated with the adherence of inflammatory cells to the corneal endothelium (keratic precipitates) first appeared on the 11th day and were most remarkable on the 14th day and then gradually subsided after 18th day. The expression of ICAM-1 on the corneal endothelium was noticed from the 12th day of immunization to the 16th day and was most prominent on the 14th day but disappeared after the 18th day. The present study proved that ICAM-1 was expressed on the corneal endothelium in anterior uveitis and further indicated that the corneal endothelium modulates the inflammation of the anterior ocular segment by expressing ICAM-1 and forming keratic precipitates.

Animals↗
PubMed1995

Endothelium-dependent relaxation in response to adenosine diphosphate is impaired under poor runoff conditions in the canine femoral artery.

To examine whether poor distal runoff conditions of the canine femoral artery modulates endothelium-dependent relaxations, we developed a poor distal runoff limb in the canine right femoral artery (poor runoff group). The left femoral artery was used as a control. Endothelium-dependent responses were examined in vitro. The rings of femoral artery were obtained from dogs pretreated with 6 weeks of poor distal runoff. In the control, flow rate and tau-variation were 79.1 ml/min and 214.2 dynes/cm2, respectively. In the poor runoff group, the flow rate and tau-variation were 27.4 ml/min and 52.7 dynes/cm2. There were significant differences between the two groups. In the rings taken from the control group contracted with norepinephrine, adenosine diphosphate (ADP) and A23187 caused endothelium-dependent relaxations. In the poor runoff group, the endothelium-dependent relaxations in response to ADP were impaired, while A23187 caused comparable endothelium-dependent relaxations. Direct relaxations in response to sodium nitroprusside were comparable between the two groups. These experiments indicate that under poor runoff conditions, the endothelium-dependent relaxations to ADP are impaired without changing the properties of the smooth muscle cells. This dysfunction of the endothelium under conditions of abnormal flow may accelerate a loss of late patency of the reconstructed arteries.

Adenosine Diphosphate↗
PubMed2002

Hepatic sinusoidal endothelium upregulates IL-1alpha, IFN-gamma, and iNOS in response to discordant xenogeneic islets in an in vitro model of xenoislet transplantation.

BACKGROUND: Data indicate that early islet graft failure is due to nonspecific inflammatory mechanisms that occur prior to T-cell-mediated rejection. The role of the host hepatic endothelium in mediating this immediate islet injury has not been elucidated. The endothelial cell may be important in this process because it is essentially the first cellular barrier encountered by intraportally introduced islets. We have characterized the initial response of hepatic endothelium to xenogeneic islets by measuring the expression of Il-1alpha, TNF-alpha, IFN-gamma, and iNOS in an in vitro dog-to-pig model of xenoislet transplantation. MATERIALS AND METHODS: Dog islets (500 islet equivalents) were cocultured with either porcine hepatic endothelium or porcine aortic endothelium over a 24-h period in serum-free medium. RNA was extracted at eight time points (0, 1, 2, 4, 6, 8, 12, and 24 h). Reverse-transcriptase polymerase chain reaction was performed on each sample. Polymerase chain reaction was done on the cDNA in order to visualize Il-1alpha, TNF-alpha, IFN-gamma, and iNOS expression. Bands were semiquantitated by comparison to an external standard (GAPDH) using band densitometry. RESULTS: Hepatic endothelium had early (1 h) expression of IL-1alpha, IFN-gamma, and iNOS. IL-1alpha peaked at 2 h, IFN-gamma at 12 h, and iNOS at 1 and 12 h. Aortic endothelium expressed low levels of IL-1alpha and TNF-alpha, but not IFN-gamma or iNOS. CONCLUSIONS: We have demonstrated that xenogeneic islets are able to activate host endothelial cells without serum or immune cells. The observed endothelial response corresponds with known islet toxic substances. Furthermore, the response differs between hepatic and aortic endothelial cells, suggesting that these differences may be important in choosing suitable implantation sites for islets. Our findings suggest that host endothelium may play an important part in early injury of islet xenotransplants.

Animals↗
PubMed1992

HN-10200 causes endothelium-independent relaxations in isolated canine arteries.

HN-10200, a nonselective inhibitor of phosphodiesterase, has positive inotropic and vasodilator activity. The present study was designed to determine the role of endothelium in causing relaxation to HN-10200 in isolated canine femoral and basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in Krebs-Ringer bicarbonate solution bubbled with 94% O2, 6% CO2 (t = 37 degrees C; pH = 7.4). HN-10200 and another nonselective phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), caused similar concentration-dependent relaxations in femoral arteries with and without endothelium. In femoral arteries without endothelium, HN-10200 and IBMX significantly augmented relaxations to prostacyclin, but did not affect relaxations to a nitric oxide donor 3-morpholinosydnonimine (SIN-1) or endothelium-derived relaxing factor (EDRF) released by bradykinin. In basilar arteries, relaxations to HN-10200 were augmented by the removal of endothelium, whereas relaxations to IBMX were not affected. Relaxations to prostacyclin, SIN-1, and EDRF were not affected by the presence of phosphodiesterase inhibitors. The results of the present study suggest that HN-10200 causes endothelium-independent relaxations. In addition, it may augment relaxations to prostacyclin but does not affect relaxations to EDRF.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Effect of endothelium and carbachol on alpha-adrenoceptor agonist stimulated uptake and efflux of 45Ca in rat isolated aorta.

Preincubation with carbachol (10 microM) did not affect basal 45Ca accumulation by rat isolated aortic segments complete with endothelium, although 45Ca accumulation was enhanced by removal of endothelium. This confirms the observation that in the presence of endothelium Ca2+ influx in rat aorta is antagonized, and indicates that the basal release of an endothelial derived factor might be sufficient to maximally antagonize basal Ca2+ influx, or alternatively that EDRF released as a result of muscarinic stimulation does not have identical effects to the factor released under basal conditions. Accumulation of 45Ca stimulated by B-HT 920 but not that stimulated by phenylephrine was antagonized in the presence of endothelium. Contractions elicited by B-HT 920 were abolished in the presence of endothelium while contractions evoked by phenylephrine were reduced by about 50%. Preincubation with 10 microM carbachol antagonized both phenylephrine (1 microM) stimulated 45Ca accumulation and contractile responses in the presence of endothelium to about the same extent. Therefore, it might be concluded that the inhibitory effect of EDRF in this tissue is due to an inhibition of stimulated Ca2+ influx. However, while addition of carbachol to tissues precontracted with phenylephrine elicited an immediate relaxation in the presence of endothelium, this relaxation could not be correlated with a reduction in tissue accumulation of 45Ca. Carbachol also antagonized the phenylephrine-induced reduction of tissue 45Ca content (i.e. efflux of Ca2+), in tissues preloaded with 45Ca. This implies that the initial endothelial-mediated relaxant effect of carbachol in precontracted tissues cannot be explained either by reduced influx or by an enhanced efflux of Ca2+ from the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1990

Human cerebral endothelium: isolation and characterization of cells derived from microvessels of non-neoplastic and malignant glial tissue.

Human microvessels were isolated and cultured from non-neoplastic cerebral tissue specimens resected for the treatment of seizure disorders and from malignant glial tumors. After 1-2 weeks, cobblestone patterned plaques of cells were isolated and cultured from these microvessels. Cell lines positive for Factor VIII antigen and negative for glial fibrillary acidic protein were designated as endothelium. Endothelium from both tissue sources produced gamma-glutamyl transpeptidase in response to glial cell conditioned media. Tumor derived microvessel endothelium had decreased longevity in culture when compared to normal microvessel endothelium. Tumor derived endothelium also formed less extensive intercellular junctional complexes in vitro. The isolation and characterization of human cerebral microvessel endothelium derived from non-neoplastic tissue and glial tumors may lead to a further understanding of the role of endothelium in tumor growth and vascular permeability alterations.

Adolescent↗
PubMed1993

Arterial size determines the enhancement of contractile responses after suppression of endothelium-derived relaxing factor formation.

We studied the effect of endothelium-derived relaxing factor (EDRF) on norepinephrine-induced contractile responses and on the tissue guanosine-3',5'-phosphate (cGMP) concentration of isolated rabbit arteries with an increasing endothelium to smooth muscle cell ratio (aorta, femoral and mesenteric arteries). After suppression of EDRF formation (either by NG-nitro-L-arginine or, in mesenteric arteries, by saponin), contractions elicited by cumulative doses of norepinephrine were unaltered in aorta but were enhanced by 22.5% in femoral arteries and by 44.3% in mesenteric arteries (at the highest norepinephrine concentration). The cGMP concentration (pmol/mg protein) of unstimulated, endothelium-intact vessels decreased after suppression of EDRF formation from 1.09 +/- 0.24 to 0.74 +/- 0.28 in aortic, from 2.86 +/- 0.4 to 0.61 +/- 0.19 in femoral and from 6.3 +/- 0.9 to 0.7 +/- 0.15 in mesenteric arterial segments. The basal cGMP concentration did not differ in endothelium-denuded segments of these arteries, suggesting a similar basal activity of soluble guanylate cyclase (sGC). A higher sensitivity of sGC may have contributed to the higher cGMP concentration observed in the smaller arteries, since in the presence of sodium nitroprusside the cGMP concentration of endothelium-denuded segments increased 1.8-fold in aortic, 2.9-fold in femoral and 2.4-fold in mesenteric arterial segments. However, these differences in sGC activation cannot be solely responsible for the high basal cGMP concentration in endothelium-intact mesenteric arteries. The greater ratio of endothelium to smooth muscle cell layers in the smaller arteries might result in a higher EDRF concentration in the vascular wall and subsequently in a higher cGMP concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Adhesion molecule expression on murine cerebral endothelium following the injection of a proinflammagen or during acute neuronal degeneration.

The acute inflammatory response in the murine CNS is different from that observed in other tissues. Few polymorphonuclear leukocytes are recruited to the brain parenchyma and there is a delay in the recruitment of monocytes. Leukocyte recruitment to sites of inflammation is dependent on adhesion molecules expressed on the endothelium. The atypical kinetics of leukocyte recruitment to the CNS may be the result of deficient or delayed adhesion molecule expression on the cerebral endothelium. Using immunohistochemistry, the present study demonstrates that following the intracranial injection of a proinflammagen, lipopolysaccharide, or following acute neuronal degeneration elicited with kainic acid, the adhesion molecules ICAM-1 and VCAM were readily upregulated on cerebral endothelium in a time course comparable with that demonstrated on non-CNS endothelium. Both molecules were expressed on vessels, irrespective of their size, at 24 h after kainic acid or 6 h after lipopolysaccharide injection but leukocyte recruitment was negligible. The expression of ICAM-1 was demonstrated not only on endothelium but also on microglia especially in response to nerve terminal degeneration. PECAM was constitutively expressed at high levels on cerebral endothelium and did not change during brain injury. However, PECAM was induced on astrocytes after lipopolysaccharide injection or during acute neuronal degeneration, the latter providing a particularly strong stimulus. This study indicates that the expression of these adhesion molecules on CNS endothelium is neither deficient or delayed and that they are unlikely to be limiting factors in leukocyte recruitment to the CNS.

Animals↗
PubMed1993

Involvement of cyclo-oxygenase-generated vasodilating eicosanoid(s) in addition to nitric oxide in endothelin-1-induced endothelium-dependent vasorelaxation in guinea pig aorta.

This study investigates the vasodilatory effects of endothelin-1 (ET-1) in isolated guinea pig aortic rings in vitro. Cumulative dose-response curves to ET-1 were constructed and ET-1 actions on prostaglandin F2 alpha (PGF2 alpha)-precontraction were studied in both endothelium-intact and endothelium-denuded preparations, in the presence or absence of a cyclooxygenase inhibitor (indomethacin) and/or nitric oxide inhibitors (NG-nitro-L-arginine methyl ester and hemoglobin). In endothelium-intact preparations, pretreatment with indomethacin (10(-5) M, 30 min), alone or in combination with NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), significantly augmented the constrictive responses to ET-1, whereas indomethacin, L-NAME, and hemoglobin (10(-5) M) had no significant effects in the endothelium-denuded preparations. Furthermore, in PGF2 alpha-precontracted, endothelium-intact preparations, ET-1, at a dose of 10(-9) M, induced initial relaxation followed by subsequent contraction, while it only contracted the endothelium-denuded preparations. The initial relaxation was abolished by indomethacin, but not by L-NAME or hemoglobin. In addition, this relaxation was not inhibited by a specific ETA receptor antagonist, BQ-123 (6 x 10(-6) M). In addition to the involvement of nitric oxide, these results show the involvement of cyclo-oxygenase-generated vasodilating eicosanoid(s) derived from endothelium in ET-1-induced vasorelaxation in guinea pig aorta in vitro. The results also indicate that this vasorelaxation is mediated by ETB receptor activation.

Animals↗
PubMedDate not supplied

The role of endothelium in the control of vascular tone.

In the last few years, experimental evidence has accumulated which suggests a substantial role for the endothelium in the control of vascular tone. Endothelium-dependent dilatations have been demonstrated in various arteries of numerous mammalian species including man. Among the stimuli which elicit endothelium-dependent dilatation are such varying stimuli as increases in blood flow and hypoxia, as well as endogenous (acetylcholine, ATP, ADP, bradykinin, substance P) and pharmacological agents (calcium ionophore A 23187, ergometrine, hydralazine, melittin). The functional importance of endothelium-dependent dilatation is emphasized by the fact that the direct vasoconstrictor effects of some of these substances (acetylcholine, histamine, norepinephrine, serotonin) on vascular smooth muscle is attenuated or even reversed by their simultaneous stimulatory effect on endothelial cells, resulting in the release of a vasodilator signal. Bioassay experiments have shown that a humoral vasodilator agent with a biological half-life in the range of seconds is released from the endothelium (native or cultured) during stimulation with acetylcholine, ATP and calcium ionophore. Experimental data are presented, which suggest that EDRF may act by direct stimulation of guanylate cyclase, resulting in smooth muscle relaxation due to increased smooth muscle cyclic GMP levels. The chemical nature of this nonprostaglandin endothelium-derived relaxant factor (EDRF) is still not known. The possible physiological and pathophysiological significance of endothelium-dependent dilatation in situ is discussed. Special attention is paid in this context to the potential role of EDRF activity in coronary vasomotor control.

Acetylcholine↗
PubMed2000

The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin--induced diabetic rats is restored by 5-methyltetrahydrofolate.

AIMS/HYPOTHESIS: Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. METHODS: Endothelium-dependent and endothelium-independent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor L-NG-nitroarginine methylester HCI (L-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. RESULTS: The L-NAME- and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-i um-1,2-diolate (DETA-NONOate) and to the K+-channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. CONCLUSION-INTERPRETATION: Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes.

Acetylcholine↗
PubMed1993

Role of endothelium in ischemic coronary syndromes.

The recent discovery that the endothelium synthesizes several powerful vasodilators, including prostacyclin and endothelium-derived relaxing factor, has substantially changed our view of the importance of the vascular endothelium and the perspective from which we consider the mechanisms of vascular control. It is now known that the vascular endothelium plays a key role in circulatory homeostasis through its ability to sense the local vascular milieu and respond to it by the synthesis and release of a variety of biologically active substances. The endothelium influences not only vascular tone, but also vascular remodeling via the production of growth-promoting and growth-inhibiting substances; hemostasis and thrombosis through antiplatelet, anticoagulant, and fibrinolytic effects; and inflammation through the expression of chemotactic and adhesion molecules on the cell membrane. In diseases such as atherosclerosis, however, these functions of the endothelium are impaired and may even become counterproductive and disease-promoting. The "activated" or injured endothelial cells paradoxically become prothrombotic, growth-promoting, and leukocyte-adhesive. The endothelium also loses its vasodilating ability, rendering the underlying vascular smooth muscle susceptible to a preponderance of vasoconstrictive forces. It is now recognized that these disturbances in endothelial function are principal players in the ischemic manifestations of coronary artery disease. Endeavors to modify or reverse endothelial dysfunction may therefore be of significant therapeutic benefit in the treatment of myocardial ischemia. This review outlines several important insights into the biology of the arterial wall that are currently being applied to the study of coronary artery disease in humans.

Animals↗
PubMed1991

Hypertension, endothelium, and cardiovascular risk factors.

The functions of the endothelium and the effects of hypertension, atherosclerosis, and diabetes on the endothelium are reviewed. The endothelium affects vascular tone by releasing vasodilators and modulating the effects of vasoactive substances such as catecholamines, bradykinin, serotonin, and angiotensin II. Relaxation of vascular smooth muscle depends upon a functionally intact endothelium and the release of the endothelium-derived relaxing factor nitric oxide. Endothelial cells also appear to release a hyperpolarizing factor that relaxes smooth muscle through activation of the sodium-potassium pump, and of the endothelium-dependent contracting factors. Similarities are found in the vascular injury resulting from hypertension, atherosclerosis, and diabetes. When these risk factors coexist, they can act synergistically and magnify the vascular injury. The endothelium appears to be one of the major targets for these forms of injury. Future therapeutic strategies will focus on ways to prevent, arrest, or reverse endothelial injury.

Animals↗
PubMed1994

Impaired endothelium-dependent relaxation after coronary reperfusion injury: evidence for G-protein dysfunction.

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.

Acetylcholine↗
PubMed1994

Endothelium-dependent relaxation after short-term preservation of vascular grafts.

As the integrity of graft endothelium seems to be essential to successful long-term patency in coronary operations, its preservation demands the utmost care. The aim of the present study was to investigate the effects of currently used solutions on endothelium-dependent relaxation after short-term storage of vessels at room temperature or at 4 degrees C. The infrarenal rat aorta was selected for study because its use enabled standardization of the investigation, which was performed in organ baths on 672 vessel segments from 112 Sprague-Dawley rats. Stable vasoconstriction was obtained with the thromboxane analogue U-46619. Acetylcholine was used to elicit endothelium-dependent relaxation. The results obtained for vessels preserved for 2 hours were compared with those for autologous vessels studied immediately after harvesting. Vessel contractility was unaffected by the preservation solutions, except in the Ringer's acetate group, where it was reduced by 50% (p < 0.05). Endothelium-independent relaxation, tested with papaverine, was unaffected in all groups. Ringer's lactate, Krebs solution, and Perfadex (a low-potassium-dextran-glucose solution) did not significantly affect endothelium-dependent relaxation either at room temperature or at 4 degrees C, although a tendency to impaired relaxation was seen in these three groups after cold storage. Standard Ringer's solution and fresh heparinized blood each significantly reduced endothelium-dependent relaxation in vessels stored at room temperature (p < 0.05), but not in those stored at 4 degrees C. Endothelium-dependent relaxation was significantly reduced after storage in normal saline solution (p < 0.05) and in Ringer's acetate (p < 0.01), both at room temperature and at 4 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗