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PubMed2002

Direct assessment and diminished production of morphine stimulated NO by diabetic endothelium from saphenous vein.

AIM: To directly measure in real time basal and stimulated levels of NO released from human saphenous vein endothelium and to quantify the expression of the mu opiate receptor, which has been linked with NO release. METHODS: Saphenous vein segments from patients with type 2 diabetes (n=12) and patients without diabetes (n=8) were obtained. The release of NO was measured directly from the endothelium using a NO-specific amperometric probe. N(Omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 mmol/L), a NO synthase (NOS) inhibitor, or morphine (1 mumol/L), a stimulant, was administered and the measurements were repeated. Values were reported relative to the mean initial measurement of NO release from diabetic endothelium, which was defined as the relative zero level of NO release. A RT-PCR was then performed on the endothelium to measure mu opiate receptor expression. RESULTS: Diabetic patients (n=12) showed a relative and significantly diminished basal level of released NO, (0.049+/-0.012) nmol/L, compared with non diabetic patients (n=8), (0.42+/-0.12) nmol/L (P<0.05). Application of L-NAME to nonstimulated tissues resulted in no change in NO release from the diabetic group and a decrease in NO release of (0.21+/-0.09) nmol/L from the non diabetic group (P<0.05). Morphine stimulation of the diabetic endothelium resulted in a lower peak and shorter duration of NO release compared to the non-diabetic tissue, (21+/-6) nmol/L vs (38+/-4) nmol/L and (7.3+/-1.4) min vs (12.2+/-2.2) min, respectively (P<0.01). Lastly, evaluation of the mu opiate receptor expression was found to be diminished in the diabetics by 59.1 %. CONCLUSION: Maturity-onset diabetes attenuates both the constitutive basal and morphine stimulated NO release from human saphenous vein endothelium. In this study, after NOS inhibition, the actual basal NO release in diabetes was negligible. One explanation for the impaired capacity of diabetic endothelium to release NO was the diminished mu opiate receptor that was seen in diabetic endothelium.

Aged↗
PubMed2002

(-)epicatechin induces and modulates endothelium-dependent relaxation in isolated rat mesenteric artery rings.

AIM: The present study was aimed to examine the role of endothelial nitric oxide in the relaxant response to green tea (-)epicatechin and its modulation of endothelium-mediated relaxation in the isolated rat mesenteric artery rings. METHODS: Changes in the isometric tension were measured with Grass force-displacement transducers. RESULTS: The (-)epicatechin-induced relaxation was largely dependent on the presence of intact endothelium and was reversed by NG-nitro-L-arginine methyl ester 10 micromol/L or methylene blue 10 micromol/L, the inhibitors of nitric oxide-mediated relaxation. L-Arginine at 1 mmol/L antagonized the effect of L-NAME or methylene blue. Pretreatment of endothelium-intact rings with (-)epicatechin 10 micromol/L enhanced the relaxation induced by endothelium-dependent vasodilator, acetylcholine, while this concentration did not influence the endothelium-independent relaxation induced by sodium nitroprusside in the endothelium-denuded artery rings. CONCLUSION: The results indicate that the endothelium-dependent vasodilation by (-)epicatechin is mainly mediated through nitric oxide and low concentration of (-)epicatechin augments endothelium-dependent vasorelaxation in the rat mesenteric arteries.

Animals↗
PubMed2003

High-concentration tramadol-induced vasodilation in rabbit aorta is mediated by both endothelium-dependent and -independent mechanisms.

AIM: The mechanism of tramadol-induced vasodilation was investigated using isolated rabbit thoracic aortic rings. METHODS: Aortic rings from 8 rabbits were placed in organ bath and precontracted with phenylephrine (10(-5) mol/L) before addition of tramadol. Relaxation responses by tramadol were evaluated in the presence and absence of endothelium, indomethacin (an inhibitor of cyclooxygenase), NG-nitro-L-arginine methyl ester (L-NAME, a specific inhibitor of nitric oxide synthase), glibenclamide (an inhibitor of ATP-sensitive potassium channels), tetraethylammonium chloride (TEA, an inhibitor of calcium-sensitive potassium channels), and naloxone (an antagonist of opioid receptors). RESULTS: Tramadol (10(-4) mol/L and 3 x 10(-4) mol/L) caused significant vasodilation in endothelium-intact and endothelium-denuded aortic rings (P<0.05). The relaxation response to tramadol was significantly greater in endothelium-intact rings than in endothelium-denuded rings. Pretreatment of aortic rings with indomethacin (10(-5) mol/L), glibenclamide (10(-5) mol/L), TEA (10(-3) mol/L), and naloxone (10(-4) mol/L) had no effect on the tramadol-induced relaxation. In endothelium-intact rings, L-NAME (10(-4) mol/L) pretreatment caused marked inhibition of the relaxation induced by tramadol, but not endothelium-denuded rings. CONCLUSION: In the rabbit aorta, vascular relaxation induced by tramadol is due to both nitric oxide production from endothelium and a direct effect on smooth muscle.

Analgesics, Opioid↗
PubMedDate not supplied

Effect of the vascular endothelium on contractions induced by noradrenaline and phenylephrine in perforating branch of the human internal mammary artery.

The effects of noradrenaline (Nor) and phenylephrine (Phe) on the isolated, non-precontracted perforating branch of the human internal mammary artery (HIMA) were investigated. Nor and Phe induced concentration-dependent contractions of intact and endothelium-denuded arterial rings with no statistically significant differences between the pEC(30) and maximal response values. The pretreatment of arterial rings with indomethacin had no effect on Nor- and Phe-induced contractions of both, intact and endothelium-denuded preparations. The pre-addition of L-NMMA did not affect contractions of perforating branch of the HIMA evoked by Nor, but provoked significant potentiation of Phe-induced contractions of perforating branch of the HIMA both intact and denuded of endothelium only at Phe concentration higher than 3 x 10(-6)M. The effects of selective alpha1-adrenoceptor antagonist, prazosin and selective alpha2-adrenoceptor antagonist, rauwolscine were concentration-dependent, and they induced a significant shift to the right (for both studied antagonists) of the concentration-response curves for Nor in both preparations with or without endothelium. The effects of prazosin and rauwolscine on the concentration-response curves for Phe were similar. In conclusion, this study has shown that Nor and Phe induce concentration-dependent contractions of the perforating branch of the HIMA. Removal of the endothelium did not modify this effect. Products of cyclooxygenase pathway had no influence on Nor and Phe action. Endothelium derived nitric oxide (NO) had no modulatory effect of Nor-induced contractions, but inhibition of NO synthesis provoked potentiation of Phe-induced contractions either in intact or endothelium-denuded preparations. The mechanism of this effect remains still unclear. On the basis of differential affinity of the antagonists and affinities of Nor and Phe themselves, we suggest that alpha1-adrenoceptor subtype is probably involved in the Nor- and Phe-induced contraction of the perforating branch of the HIMA both intact or denuded of endothelium.

Adrenergic alpha-Antagonists↗
PubMed1992

Potassium channel openers dilate large epicardial coronary arteries in conscious dogs by an indirect, endothelium-dependent mechanism.

Cromakalim and pinacidil, two potassium channel openers, dilate both large and small coronary arteries in conscious dogs. Because flow-mediated dilation of large arteries is endothelium-dependent, the consequences of in vivo endothelium removal (balloon denudation) on the response of large epicardial coronary arteries to cromakalim (10 micrograms/kg) and pinacidil (30 micrograms/kg) were investigated in six dogs chronically instrumented for the measurement of arterial pressure, left circumflex coronary artery diameter and coronary blood flow. Endothelium removal abolished the dilation of large coronary arteries induced by acetylcholine (endothelium-dependent dilation) and reactive hyperemia (flow-mediated dilation), but only slightly reduced (-18%) that induced by nitroglycerin. Before endothelium removal, both cromakalim and pinacidil induced a significant decrease in coronary resistance (-71 +/- 2 and -63 +/- 2%, respectively) and a significant increase in coronary diameter (8.5 +/- 1.3 and 6.7 +/- 0.9%). After endothelium removal, the decreases in coronary resistance were unaffected, but the increases in coronary diameter were reduced by 93 and 98% as compared to predenudation responses with cromakalim and pinacidil, respectively (both P < .01). In contrast, in vitro studies performed in isolated large epicardial coronary arteries obtained from five additional dogs showed that cromakalim evoked relaxations that were not affected by prior in vivo endothelium removal. Thus, despite the presence of potassium channels in isolated denuded large coronary arteries, our data demonstrate that cromakalim- and pinacidil-induced dilation of large arteries in vivo is an indirect, flow-mediated effect which is entirely endothelium-dependent.

Acetylcholine↗
PubMed1992

Endothelium and atherosclerosis.

PURPOSE: To review the effect of damaged endothelium on the development of atherosclerotic disease. BACKGROUND: Atherosclerotic cardiovascular disease is a complex problem involving lipid deposition, blood pressure, rheologic forces, carbohydrate tolerance and thrombogenic factors. The loss of functional, if not structural, integrity of the vascular endothelium is closely related to the initiation of atherosclerosis. The endothelium contributes to local vascular regulation. Normal endothelial cells are thrombo-resistant; they prevent leukocyte adhesion and control vascular tone by converting angiotensin I into angiotensin II, inactivating bradykinin, norepinephrine, serotonin and ADP, and by secreting vasodilator substances, such as prostacyclin and endothelium-derived relaxing factor (EDRF), and contracting factors such as endothelin. Endothelin is a potent vasoconstrictor peptide that increases intracellular calcium, causing a rapid and transient increase in c-fos and c-myc messenger (m)RNA levels and DNA synthesis in rat vascular smooth muscle cells. In isolated vessel segments, altered endothelial vasoreactivity is usually demonstrated following mechanical trauma to the endothelium. METHODS AND RESULTS: We investigated the function of normal and damaged endothelium in pigs, following superficial balloon injury, which produces a significant alteration in endothelium-dependent coronary vasoreactivity. The anesthetized pigs were given an intracoronary (left anterior descending artery) infusion of acetylcholine. The balloon injury caused a local transient spasm while the distal uninjured vessel did not change. When acetylcholine was given before the balloon injury, the diameter of the left anterior descending artery did not change, even after preconstriction in vivo with prostaglandin (PG) F2 alpha, but acetylcholine given after the balloon angioplasty caused dose-dependent vasoconstriction. It is known that vasoconstriction in arteries can reduce blood flow and increase arterial wall-shear forces, which increase platelet deposition in injured arteries and may precipitate rupture of atherosclerotic plaques. CONCLUSION: The intact endothelium is one of the greatest sources of protection from arterial thrombosis, atherosclerosis and vasoconstriction.

Acetylcholine↗
PubMed1991

Time course and extent of recovery of endothelium-dependent contractions and relaxations after direct arterial injury.

To determine the time course of the return of endothelium-dependent relaxations and contractions during intimal regeneration, we performed balloon endothelial denudation of the thoracic and abdominal aorta of male Lewis rats and examined smooth muscle function and endothelium-dependent responses in vitro at 1, 2, 4, and 8 weeks after aortic injury. At each study interval during endothelial cell regeneration, vascular smooth muscle contracted and relaxed normally to direct stimulation with norepinephrine and sodium nitroprusside. Endothelium-dependent contractions to serotonin returned to normal at 1 week and developed into a hypercontractile response at 8 weeks. Endothelium-dependent relaxations to acetylcholine returned to normal at 8 weeks, but endothelium-dependent relaxations to adenosine diphosphate remained impaired. These experiments demonstrate that regenerating endothelium regains the ability to produce contracting factor before relaxing factor, and it even exhibits potentiated contractile activity 8 weeks after injury. Thus, after direct arterial injury, regenerating endothelium has abnormal endothelium-dependent function that predisposes the vessel to vasospasm and thrombosis.

Acetylcholine↗
PubMed1987

Affinity of binding of radiolabeled (125I) heparin and low molecular weight heparin fraction CY 222 to endothelium in culture.

Binding of radiolabeled (125I) heparin and its low molecular weight fraction CY 222 (Choay) to human and porcine cultured endothelium was investigated. The binding was measured over a wide range of heparin or CY 222 concentration in culture medium, from less than 20-time up to more than 30-times of the therapeutic heparin level. A relatively small fraction (less than 1%) of tested products was bound to endothelium. The process of binding was temperature-independent. A comparable number of endothelial binding sites (approx. 10(12)/cm2) for both 125I-heparin and 125I-CY 222 was calculated. About 40% totally bound 125I-heparin and 30% of 125I-CY 222 was found in extracellular matrix of cultured endothelium. The endothelium exhibited a 2.4-times lower affinity for 125I-CY 222 (Kd = 5.59 +/- 1.77 microM) than that for 125I-heparin (Kd = 2.35 +/- 0.78 microM). A similar affinity of human (venous) and porcine (aortic) endothelium for 125I-heparin was demonstrated. Cultured endothelium exhibited the same affinity for unlabeled heparin as for 125I-heparin. The endothelium depleted of sialic acid residues bound 1.5-times more of 125I-CY 222 than the control endothelium in culture.

Animals↗
PubMed1989

Konkurrenz zwischen endothelabhängiger und Nitroglygerin-induzierter koronarer Vasodilatation [Competition between endothelium-dependent and nitroglycerin-induced coronary vasodilation].

UNLABELLED: Intact vascular endothelium can relax the smooth muscle by liberation of EDRF (endothelium-derived relaxing factor) and thus induce vasodilation. We investigated to what extent functional integrity of the endothelium modifies the dilatory capacity of coronary arteries and which influence nitroglycerin exerts on endothelium-dependent relaxation mechanism. In 74 coronary segments from eight patients with coronary artery disease, coronary artery diameters were measured before (C1) and 90 s after intracoronary infusion of the endothelium-dependent vasodilator bradykinin (0.1 mM) by means of a computer-assisted contour assessment system (CAAS). The same segments were then measured before (C2; 10 min after C1) and 90 s after an intracoronary infusion of the endothelium-independent vasodilator nitroglycerin (0.29 mM). By dividing diameter increases after bradykinin in group I less than 0.15 mm, n = 42 segments and group II: greater than 0.45 mm, n = 32 segments, the following diameters were obtained (mean +/- SD): (table; see text) CONCLUSION: In atherosclerotic coronary segments with impaired endothelium and consecutively reduced endothelium-dependent dilation the vasodilatory capacity of nitroglycerin is enhanced. Due to a competitive effect on the final common biochemical pathway, i.e., stimulation of soluble guanylate cyclase and elevation of intracellular levels of cyclic guanosylmonophosphate (cGMP) nitrovasodilators can facilitate insufficient endogenous relaxation of vascular smooth muscle.

Bradykinin↗
PubMed1989

Granulocyte-mediated injury to herpes simplex virus-infected human endothelium.

Some endothelial-injury syndromes, including atherosclerosis, may involve herpes simplex virus (HSV) infection. Examining the mechanism of injury, we found adherence of unstimulated granulocytes to HSV infected endothelium to be twice that to uninfected endothelium (34.8 +/- 1.1 versus 18.8 +/- 0.5%; mean +/- SEM; p less than 0.001) which further increased in the presence of anti-HSV antibodies. Enhanced adhesion was accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled, HSV-infected endothelium (16.4 +/- 0.9%, HSV-infected versus 0.9 +/- 4.5% for uninfected endothelium; p less than 0.01). HSV infection also increased granulocyte-mediated endothelial cell detachment from its substratum (14.7 +/- 1.7% versus 3.3 +/- 0.3% for uninfected endothelium; p less than 0.001), which further increased (p less than 0.01) in the presence of immune complexes (IgG-sensitized erythrocytes). This suggests that neo-Fc receptors of infected endothelium bind IgG-coated particles, which, in turn, attract and stimulate granulocytes. In support, granulocyte-mediated detachment was not enhanced by immune complexes if endothelium was infected with a mutant HSV strain (E3/3) that does not produce glycoprotein E, the viral glycoprotein having Fc-receptor activity. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to the substratum matrix protein, fibronectin. Resuspended, virus-infected endothelial cells bound significantly less well to tissue-culture wells coated with both low (p less than 0.001) and high (p less than 0.05) concentrations of fibronectin as compared with uninfected endothelial cells, a dichotomy further worsened in the presence of granulocyte-released elastase. We conclude that HSV-infected human endothelium is vulnerable to granulocyte-mediated injury by opposing alterations in its adhesive properties: its increased binding of granulocytes and its weakened tethering to matrix fibronectin, particularly when exposed to secreted granulocyte proteases, such as elastase.

Cell Adhesion↗
PubMed1989

Endothelium-derived relaxing and contracting factors.

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.

Animals↗
PubMedDate not supplied

Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta.

Taking their lead from studies which have shown that endothelium-derived relaxing factor(s) (EDRF) mediates vasorelaxation by activating smooth muscle guanyl cyclase, the authors of the current article have examined the role of the endothelium in relation to the effects of the alpha-adrenoceptor antagonist prazosin. Prazosin acted as a non-competitive antagonist of norepinephrine- (NE-) induced contraction in rat aortic preparations with intact endothelium, but as a competitive antagonist in endothelium-denuded preparations. The affinity of NE for its smooth muscle receptor was the same in the presence or absence of endothelium, but its efficacy was 7 times lower in the presence than in the absence of endothelium. Other experiments showed that inhibition of guanyl cyclase by methylene blue in the presence of endothelium (like endothelium removal) led to competitive antagonism of NE responses by prazosin, and that increasing the tissue content of cyclic GMP by pre-incubating de-endothelialized preparations with 8-Br-cyclic GMP (as in intact preparations) led to non-competitive antagonism of NE responses by prazosin. The authors concluded that EDRF, by increasing the cyclic GMP content of vascular smooth muscle of rat aorta, can modify the efficacy of NE, and thereby alter the mode of antagonism of prazosin.

Animals↗
PubMed1986

Comparison of endothelium-dependent relaxation in bovine intrapulmonary artery and vein by acetylcholine and A23187.

This study was conducted to compare the influence of endothelium on mechanical responses of bovine intrapulmonary artery and vein to acetylcholine (ACh) and A23187 and to determine if a relationship exists between the responses and cyclic GMP (cGMP) accumulation. ACh and A23187 induced relaxation in artery and A23187 induced relaxation in vein. The relaxant responses in both vessels were abolished by rubbing the intimal surfaces, indicating that the relaxant responses depended upon the presence of a functionally intact endothelium. cGMP accumulation was temporally associated with both ACh- and A23187-induced endothelium-dependent relaxation. Both the relaxant responses and the accompanying cGMP accumulations were abolished or reduced markedly by intimal rubbing or pretreatment with methylene blue. Atropine abolished relaxation and cGMP accumulation induced by ACh in artery, but not relaxation and cGMP accumulation induced by A23187. Whereas indomethacin did not affect either ACh- or A23187-induced relaxation in artery, it slightly, but significantly, reduced A23187-induced relaxation in vein. In contrast to its effect in artery, ACh only induced contractile responses in vein and did not alter cGMP levels, whether or not functional venous endothelium was present. However, ACh did relax veins when arterial endothelium was present in crossover experiments using a modified sandwich technique. At concentrations which induced endothelium-dependent relaxation in artery, ACh similarly induced no, or only minimal, contraction in both artery and vein in which endothelium was functionally destroyed. These findings demonstrate that bovine intrapulmonary artery and vein exhibit endothelium-dependent relaxation in response to A23187, and similar to ACh-induced relaxation in the artery, A23187-induced relaxation is associated closely with accumulation of cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Tissue plasminogen activator in the trabecular endothelium.

By quantitative analysis of tissue plasminogen activator (TPA) in the trabecular endothelium, corneal endothelium, and iris in the eyes of monkeys and dogs, we found significant levels of TPA activity. In a [125I]fibrin-coated well assay, the levels for the dog and monkey were, respectively: trabecular endothelium, 0.2 and 0.5; corneal endothelium, 0.8 and 0.5 IU per mg protein. The iris tissue showed high TPA activity, but its protein content could not be measured with the techniques employed. Activity in the aqueous humor was not detectable. By the ELISA technique, the values (in ng TPA/mg tissue protein) for the dog and monkey were, respectively: trabecular endothelium, 0.16 and 0.44; corneal endothelium, 0.48 and 0.92. Again, iris tissue showed high TPA activity, whereas the aqueous humor showed low activity (0.86 ng/ml). The data obtained with the two methods showed a reasonable consistency, although a direct comparison was not possible because two separate standards were used. The presence of TPA in the trabecular endothelium, corneal endothelium, and iris may be important in modulating the resistance to aqueous outflow under normal conditions as well as those of hyphema.

Animals↗
PubMed1977

The endothelium: roles in thrombosis and hemostasis.

The renewed interest in endothelial function is based partly on success with tissue culture of endothelial cells. Endothelium functions primarily in the control of blood vessel wall permeability and in the provision of a blood-compatible lining surface. Recent findings indicate that endothelial cells are active metabolically in ways that may help prevent thrombosis. Endothelium actively degrades several different vasoactive compounds that circulate in blood and that can serve as platelet-aggregating agents. Endothelium also contains an inhibitor of platelet function and an activator of plasminogen, both of which can be released from the cell in response to appropriate stimuli. While intact endothelium functions primarily in prevention of thrombosis, damaged endothelium can contribute greatly to thrombus formation. Release of prostaglandins, adenine nucleotides, and other intracellular components from damaged endothelium can enhance platelet aggregation. Damaged endothelium may not function effectively in removal of vasoactive agents and may not release effective quantities of the inhibitor of platelet function or the activator of plasminogen. Altered endothelium exhibits tissue-factor activity, which can activate the extrinsic blood coagulation-system cascade. Finally, altered endothelial cells may contract and expose basement membrane to blood, thus enhancing thrombosis.

Blood Coagulation↗
PubMedDate not supplied

Endothelium-dependent and nitrovasodilator-induced activation of cyclic GMP-dependent protein kinase in rat aorta.

Cyclic GMP-dependent protein kinase (cyclic GMP-kinase) activity in isolated strips of rat aorta was measured in the absence and presence of exogenous cyclic GMP (2 microM) and expressed as a ratio. This activity ratio represented an estimate of the endogenous activation state of the enzyme. Acetylcholine [10 microM), an endothelium-dependent vasodilator, increased the activity ratio from a control value of 0.42 to 0.71 in aorta with endothelium intact. With endothelium removed, acetylcholine had no effect on cyclic GMP-kinase activity. The nitrovasodilator sodium nitroprusside (50 nM) increased activity ratios in aorta both with (0.42 to 0.54) and without (0.29 to 0.40) endothelium. Since activity ratios were higher in aortas with an intact endothelium, a tonic influence of the endothelium on aorta cyclic GMP-kinase is suggested. The vasodilator isoproterenol (3 microM) had no effect on cyclic GMP-kinase activity ratios. The increases in cyclic GMP-kinase activity caused by sodium nitroprusside and acetylcholine were preserved when aortas were homogenized in buffer containing 3 mg/ml charcoal. Thus, most of the cyclic GMP-kinase activation occurred in the intact tissue and not because of endogenous cyclic nucleotides present during homogenization or assay. The increases in the activity ratio to sodium nitroprusside and acetylcholine correlate with increases in cyclic GMP concentration and with smooth muscle relaxation. It is concluded that cyclic GMP-kinase in rat aorta is activated by acetylcholine in an endothelium-dependent manner and by sodium nitroprusside in an endothelium-independent manner. These data are consistent with the hypothesis that cyclic GMP mediates relaxation of vascular smooth muscle to acetylcholine and sodium nitroprusside by activating cyclic GMP-kinase and consequent protein phosphorylation. The data further illustrate the importance of endothelial cells in vascular responses to acetylcholine.

Acetylcholine↗
PubMed1994

The endothelium of the rat renal artery plays an obligatory role in A2 adenosine receptor-mediated relaxation induced by 5'-N-ethylcarboxamidoadenosine and N6-cyclopentyladenosine.

Studies were undertaken in the rat isolated renal artery in order to determine if adenosine receptor agonists were capable of inducing the release of nitric oxide from the renovascular endothelium. N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamidoadenosine (NECA) produced concentration-dependent relaxations in endothelium intact renal artery rings. The NECA curve was biphasic with a first phase pA50 of 6.05. The CPA curve was monophasic with a pA50 of 4.35. In the absence of endothelium the curves to both NECA and CPA were monophasic with pA50 values of 3.37 and 3.50, respectively. The A2a adenosine receptor-selective agonist CGS21680 (2-[p-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenos ine) was inactive in endothelium intact tissues. Relaxant responses to CPA and NECA in the presence of endothelium were antagonized by 8-p-sulfophenyltheophylline and by 1,3-dipropyl-8-cyclopentylxanthine only at a nonselective concentration (3 x 10(-6) M) suggesting activation of A2 adenosine receptors. The responses to CPA and NECA in the absence of endothelium are not due to activation of A1 or A2 adenosine receptor subtypes because they are resistant to blockade by these xanthines. CPA and NECA responses in the presence of endothelium were inhibited by NG-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, but not by the cyclooxygenase inhibitor indomethacin or the K+ATP channel antagonist glibenclamide. These results suggest that the rat renal artery contains A2b adenosine receptors that are located exclusively on the endothelium and cause the release of nitric oxide.

Adenosine↗
PubMed1994

The endothelium in health and disease.

The early observations of an apparent anomalous action of acetylcholine on the regulation of vascular tone in vivo and in vitro were found to be a reflection of the intactness of the endothelium in vivo. An intact endothelium mediates relaxation of smooth muscle in response to acetylcholine, whereas endothelium-denuded blood vessels exposed to this agonist often exhibit vasoconstriction. The vasodilation is mediated by the actions of the endothelium-derived relaxing factors nitric oxide and prostacyclin. In addition, endothelial cells release endothelium-derived hyperpolarizing factor, which regulates potassium-channel opening in vascular smooth muscle. The chemical nature of this molecule remains to be elucidated. Many of the physiologic stimulants for endothelium-derived relaxing factor production are released by aggregating platelets, and the significance of the endothelium's vasoprotective role becomes apparent when the mechanisms and consequences of platelet agglutination are studied. Damage to the endothelium, however minor, results in the loss of this protective function and is associated with an impaired response to serotonin of G-protein coupled receptors. In the presence of risk factors such as elevated serum cholesterol, the consequences of an impaired endothelial function are greatly enhanced. Age-related changes in endothelial responsiveness may account for the prevalence of cardiovascular disease in human beings over the age of 30 years.

Blood Platelets↗