Endothelial modulation of coronary tone.
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Animals↗
Biomedical subjects
R Busse
Publications and source records attributed to R Busse.
Endothelium-mediated dilations contribute to the polarity of the arterial wall in vasomotion induced by alpha 2-adrenergic agonists.
We tested whether or not an endothelium-mediated dilation is involved in the response of intact arteries to alpha-adrenergic stimulation, by separately applying agonists to the luminal or adventitial side of the arterial wall. Cumulative dose-response curves of the alpha 1-agonists l-phenylephrine or cirazoline applied luminally in rat tail arteries and in side branches of canine femoral arteries were identical to those obtained by adventitial application in the intact arteries, and were not modified by removal of the endothelium (eliminating acetylcholine-induced dilations). Constrictions induced by the alpha 2-agonists UK-14,304 or azepexole applied luminally were significantly lower than those induced by adventitial application, and were augmented significantly by removal of the endothelium. Half-maximally precontracted arteries were dilated by addition of alpha 2-agonists to the luminal perfusate; these dilations were abolished by removal of the endothelium. It is concluded that the functional polarity of the vascular wall of these arteries in response to alpha 2-agonists results from the release of a dilatory signal from the endothelial cells, counteracting the direct contractile activation of the adjacent smooth muscle cells by the agonists.
6-Ketoprostaglandin F1 alpha↗
Pulsatile stretch and shear stress: physical stimuli determining the production of endothelium-derived relaxing factors.
Mechanical forces generated at the endothelium by fluid shear stress and pulsatile stretch are important in ensuring the continuous release of vasoactive endothelial autacoids. Although the mechanism by which endothelial cells are able to detect and convert these physical stimuli into chemical signals is unclear, this process involves the activation of integrins, G proteins and cascades of protein kinases. The constitutive endothelial nitric oxide synthase (NOS III), classified as a Ca2+/calmodulin-dependent isoform, can be activated by shear stress and isometric contraction in the absence of a maintained increase in [Ca2+]i via a mechanism involving its redistribution within the cytoskeleton/caveolae and the activation of one or more regulatory NOS-associated proteins. Thus it would appear that the intracellular cascades activated by Ca2+-elevating receptor-dependent agonists, such as bradykinin, and hemodynamic stimuli are distinct. Rhythmic vessel distension is also able to elicit the synthesis of superoxide anions and the endothelium-derived hyperpolarizing factor which play a role in modulating arterial compliance in certain vascular beds.
Animals↗
Significance of nitric oxide and peroxynitrite in permeability changes of the retinal microvascular endothelial cell monolayer induced by vascular endothelial growth factor.
Reactive oxygen species (ROS) play an important role in signaling pathways stimulated by growth factors in vascular cells. We investigated whether vascular endothelial growth factor (VEGF), which is upregulated in diabetic retinopathy and atherosclerosis, is able to enhance production of ROS, and if so, whether ROS modulate endothelial permeability. ROS levels in bovine retinal microvascular endothelial cells (BMEC) were measured by the oxidation of 2', 7'-dichlorodihydrofluorescein (DCHF), and permeability was examined by monitoring the passage of albumin through BMEC monolayers. VEGF stimulated oxidation of DCHF in BMEC, an effect which was inhibited by superoxide dismutase (SOD) and the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), but not by D-NAME. Urate, a scavenger of peroxynitrite, attenuated the VEGF-induced oxidation of DCHF. VEGF elicited a significant increase in the macromolecule permeability of BMEC monolayers within 30 min. SOD did not modify the basal or the VEGF-stimulated hyperpermeability, but the combination of SOD and VEGF induced a transient reduction in permeability after 10 min. L-NAME, but not D-NAME, enhanced VEGF-induced hyperpermeability without affecting basal values. Urate did not modify the VEGF-induced changes in permeability. In conclusion, VEGF stimulates oxidation of DCHF, which most likely represents peroxynitrite formation, and induces an increase in permeability of BMEC monolayers. Activation of NO synthase seems to counteract this stimulatory effect of VEGF on endothelial permeability.
Animals↗
Relaxation of isolated coronary arteries by angiotensin-converting enzyme inhibitors: role of endothelium-derived kinins.
In the presence of indomethacin (10 microM) and without previous exposure to bradykinin, two angiotensin-converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat (0.1 microM), elicited distinct relaxation responses from preconstricted endothelium-intact but not from denuded bovine coronary artery rings, and enhanced the relaxation response to bradykinin (3 nM). All of these responses were strongly reduced by the selective B2-kinin receptor antagonist Hoe 140 (0.1 microM). Bradykinin (30 nM), moexiprilat or ramiprilat (0.3 microM) also significantly increased the cyclic GMP content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA; 30 microM) or by removal of the endothelium. L-NNA also strongly reduced the relaxation response to moexiprilat but only partially inhibited that to bradykinin, demonstrating that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part through another endothelium-dependent mechanism. These findings suggest that ACE inhibitors induce endothelium-dependent relaxation presumably by facilitating the accumulation of endothelium-derived vasoactive kinins in or at the vessel wall. This local mechanism may significantly contribute to the dilator action of these compounds in vivo.
Angiotensin-Converting Enzyme Inhibitors↗
Endothelial dysfunction in atherosclerosis.
Endothelial injury or dysfunction has been proposed to be one of the initiating events of atherosclerosis and is associated with an apparent decrease in the production of the vasodilator autacoid nitric oxide (NO). The nature of the endothelial dysfunction resulting in an attenuation of NO-mediated responses is unknown although possibilities include decreased substrate availability, decreased expression of the NO synthase, imbalance between the production of endothelium-derived constricting and relaxing factors, production of an endogenous NO synthase inhibitor and overproduction of oxygen-derived free radicals. While experimental evidence has been provided to support almost all of these possibilities, increased production of superoxide anions within the vascular wall is currently favoured as an explanation for the observed changes in vascular responsiveness and the characteristic loss of the anti-adhesive properties of the endothelium in the early stages of atherosclerosis. The altered ratio of NO/superoxide anion (O2-) production has been proposed to alleviate intrinsic inhibition of the transcription factor NF kappa B and lead to enhanced expression of adhesion molecules and chemotactic factors at the endothelial surface. The aim of this short review is to summarise recent findings which suggest that an imbalance in the production of NO and O2- within the vascular wall is one of the earliest events to occur in the atherogenic process.
Animals↗
Calcium signalling and autacoid production in endothelial cells are modulated by changes in tyrosine kinase and phosphatase activity.
The vascular endothelium is the source of a number of vasodilator and vasoconstrictor autacoids and is thus a key regulator of vascular homeostasis. We studied the effects of altering the balance between protein tyrosine kinase and phosphatase activity on Ca2+ signalling and phosphotyrosine levels in cultured human endothelial cells, as well as on autacoid production in native endothelial cells. In isolated segments of rabbit aorta and carotid artery, as well as in bovine coronary arteries, the tyrosine phosphatase inhibitors phenylarsine oxide (PAO) and sodium orthovanadate initiated endothelium-dependent relaxations which could be attributed to the release of nitric oxide and the endothelium-derived hyperpolarizing factor. In cultured endothelial cells incubation with PAO resulted in a time-dependent accumulation in 6-keto prostaglandin F1 alpha, the stable metabolite of prostacyclin, as well as in an increase in the intracellular concentration of free Ca2+ ([Ca2+]i). Inhibition of tyrosine kinases attenuated both the PAO-induced relaxation and the increase in endothelial [Ca2+]i. Western blot analysis of endothelial cells treated with the tyrosine phosphatase inhibitors revealed a time-dependent increase in the tyrosine phosphorylation of a series of bands in both the Triton X-100-soluble and Triton X-100-insoluble (cytoskeletal) fractions. These observations suggest that alterations in cellular levels of phosphotyrosine may have profound effects on vascular homeostasis by modulating Ca2+ signalling and autacoid production in endothelial cells.
Animals↗
Calcium-dependent and calcium-independent activation of the endothelial NO synthase.
Largely assumed to be a Ca2(+)-/calmodulin-dependent enzyme, the endothelial constitutive nitric oxide (NO) synthase (NOS III) can be activated by agonists as a consequence of an increase in the intracellular concentration of free Ca2+ ([Ca2+]i). This increase in [Ca2+]i is elicited by an increase in inositol 1,4,5-trisphosphate which is the consequence of tyrosine phosphorylation and activation of phospholipase C-gamma1 as well as protein tyrosine phosphatases. Following the mobilization of intracellular Ca2+, the depleted Ca2+ stores signal to cation channels in the plasma membrane by a pathway which appears to involve activation of both tyrosine and serine/threonine kinases since this portion of the Ca2+ response is attenuated by both tyrosine kinase inhibitors and serine phosphatase inhibitors. In response to fluid shear stress the continuous production of NO by native and cultured endothelial cells is associated with only a transient and minimal increase in [Ca2+]i. In the absence of extracellular Ca2+ and in the presence of the calmodulin antagonist, shear stress stimulates a continuous production of NO which is sensitive to the nonspecific kinase inhibitor staurosporine and the tyrosine kinase inhibitor erbstatin A. A pharmacologically identical activation of NOS III can be induced by protein phosphatase inhibitors suggesting that the tyrosine phosphorylation of NOS III or an associated regulatory protein is crucial for its Ca2(+)-independent activation. Thus in a departure from widely held beliefs, we propose that the endothelial cells are able to respond to mechanical and humoral stimuli activating NOS III by at least two separate pathways.
Calcium↗
Effects of native and oxidized low density lipoproteins on formation and inactivation of endothelium-derived relaxing factor.
The influence of native (N-) and oxidized (Ox-) low density lipoproteins (LDLs) on endothelium-dependent vasomotion is still controversial. We investigated the short-term effects of N-LDL and Ox-LDL on the formation of endothelium-derived relaxing factor (EDRF) in native and cultured endothelial cells and on its inactivation after release from the cells. N-LDL was isolated from fresh human plasma via sequential ultracentrifugation and oxidized by incubation with Cu2+. EDRF released from cultured endothelial cells was inactivated by both N-LDL and Ox-LDL (1 mg/ml) as detected in a bioassay system. N-LDL reduced the EDRF-mediated vasodilations of the detector segments by 38.5 +/- 5.3%, and Ox-LDL, by 55.5 +/- 4.6%. The effects of lipoproteins on EDRF formation were studied in cultured endothelial cells preincubated with either N-LDL or Ox-LDL (1 mg/ml for 1 hour) and stimulated for EDRF release with bradykinin after washout of the lipoproteins. EDRF was assessed by measuring its stimulatory effect on the activity of a purified, soluble guanylate cyclase. Both N-LDL and Ox-LDL did not reduce the bradykinin-induced EDRF formation. Consistent with this finding, acetylcholine-induced, EDRF-mediated dilations of intact rabbit femoral artery segments were not impaired by luminal exposure to N-LDL or Ox-LDL (1 mg/ml for 1 hour). However, these relaxations were significantly reduced by preincubation of aortic ring preparations with the same concentrations of the same charges of N-LDL and Ox-LDL. In conclusion, neither N-LDL nor Ox-LDL acutely impairs the formation of EDRF but does inactivate EDRF after its release from endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Hypercholesterolemia and atherosclerosis change vascular reactivity in rabbits by different mechanisms.
Vasomotor reactivity was assessed in vitro in arterial segments obtained from rabbits with different stages of atherosclerosis. Rabbits were fed a standard chow diet (controls) or a cholesterol-enriched diet to induce hypercholesterolemia and atherosclerosis. A third group received the hydroxymethylglutaryl coenzyme A reductase inhibitor, lovastatin, simultaneously with the cholesterol diet. Contractile responses of thoracic aortas to norepinephrine, serotonin, and potassium-rich solution, as well as endothelium-dependent dilations to acetylcholine, were compared after 2 and 4 months on the respective diet. Additionally, plasma cholesterol levels and the amount of plaques covering the intimal surface (as a percentage of the intimal surface) were determined; transmission electron microscopy of atherosclerotic arteries was also performed. After 2 months, the only difference was an enhancement of contractile responses to serotonin in the cholesterol-fed versus the control group. After 4 months on the diet, contractile responses to serotonin were further enhanced, and norepinephrine- and potassium-induced vasoconstrictions were now also significantly enhanced in cholesterol-fed animals versus controls. Endothelium-dependent vasodilations were simultaneously reduced in cholesterol-fed animals. These alterations were partly prevented in cholesterol-fed and lovastatin-treated animals. Suppression of nitric oxide synthesis in control aortas by NG-nitro-L-arginine did not reveal any significant increases in contractile responses. Contractile responses to serotonin were enhanced after 2 months on the diet but before the appearance of intimal plaques, whereas attenuation of endothelium-dependent dilations, as well as the further enhancement of contractile responses to serotonin and to other agonists, were closely correlated with the degree of intimal plaques after 4 months on the diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Animal Feed↗
Nurses' reports on hospital care in five countries.
The current nursing shortage, high hospital nurse job dissatisfaction, and reports of uneven quality of hospital care are not uniquely American phenomena. This paper presents reports from 43,000 nurses from more than 700 hospitals in the United States, Canada, England, Scotland, and Germany in 1998-1999. Nurses in countries with distinctly different health care systems report similar shortcomings in their work environments and the quality of hospital care. While the competence of and relation between nurses and physicians appear satisfactory, core problems in work design and workforce management threaten the provision of care. Resolving these issues, which are amenable to managerial intervention, is essential to preserving patient safety and care of consistently high quality.
Attitude of Health Personnel↗
Inflammatory mediators induce the production of nitric oxide in vascular smooth muscle.
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Amino Acid Oxidoreductases↗