Biomedical subjects

I Fleming

Publications and source records attributed to I Fleming.

96 records · Page 6Linked to original sources

PubMedDate not supplied

Nitric oxide, nitric oxide synthase, and hypertensive vascular disease.

In normotension the endothelium produces mainly nitric oxide (NO) and prostacyclin, and the vasodilator and growth inhibitory influence predominates. Hypertension, however, is associated with a shift towards enhanced constriction and vascular hypertrophy. These effects are associated with an apparent decrease in the production of bioactive NO and concomitant increase in the generation of oxygen-derived free radicals, such as superoxide anions (O(2)-). While the enzymatic source of endothelial O(2)- has been debated intensely over the past few years, it may well turn out that the endothelial NO synthase is itself an important producer of O(2)-. Because the redox state of endothelial cells and, for example, the activation of redox-sensitive transcription factors is regulated by the balance between NO and O(2)- production, endothelial NO synthase may well be the most crucial enzyme determining the anti- or prohypertensive and eventually proatherogenic state of the vascular wall.

Animals↗

PubMedDate not supplied

Increase in fast hemoglobin concentration after incubation with acetaldehyde detected by an electrophoretic method.

Incubation of acetaldehyde with hemoglobin has been shown by chromatographic methods to result in an increase in fast hemoglobin. We have studied this increase in fast hemoglobin concentration by a gel electrophoretic method. Increases in fast hemoglobin concentration are detected following incubation with concentrations of 100 microM acetaldehyde and no further increase in yield occurs with concentrations greater than 7 mM acetaldehyde. The reaction is complete within 5 hr and the product is stable with a half-life of greater than 12 days.

Acetaldehyde↗

PubMedDate not supplied

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↗

PubMedDate not supplied

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↗

PubMedDate not supplied

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↗

PubMedDate not supplied

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↗