Endothelial Cells

Healthy Endothelium Neither spontaneous platelet aggregation nor clot formation occurs in the intact circulation because of the antithrombotic properties of healthy endothelium. Consequently, endothelial injury results in a loss of its antiplatelet antithrombotic properties and allows forlocal platelet adherence and thrombus formation that is sensitive to aspirin 282 . Aspirin also reduces prostacyclin (PGI2) production in vascular endothelial cells. In contrast to platelets, this is...

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Aspirin in the Cardiovascular System BleedingTimeand Platelet Function Aspirin wasin clinical use for about half a century, when the first reports about disturbed hemostasis were published. In 1945, Singer, an ETN specialist, reported late bleedings after tonsillectomies 38 . He attributed this to his prescription of aspirin for analgesic purposes. Withdrawal of aspirin or its replacement by metamizol (dipyrone) resulted in disappearance of bleeding. A relationship between aspirin intake and...

Oxidative Stress and Nitric Oxide

There are three isoforms of NO synthases (NOS) from which at least two are regulated by aspirin the iNOS in macrophages, other inflammatory cells, fibroblasts and smooth muscle cells, and the eNOS, which, by definition, is mainly located in endothe-lial cells. iNOS generates large amounts ofNO and oxygen-centered free radicals that amplify the inflammatory process whereas eNOS synthesizes small amounts of NO that regulate vessel tone via endothelium-dependent relaxation of vascular smooth...

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15-epi-Lipoxin-A4 (15-epi-LXA4) aspirin-triggered Lipoxin (ATL) Figure 2.12 Generation of 15-(R)-HETE in endothelial cells by acetylated COX-2 (COX-2-Ac) and its transcellular conversion to 15-epi-lipoxin A4 (15-epi-LXA4) or aspirin-triggered lipoxin by 5-lipoxygenase (5-LO) of polymorphonuclear cells (modified after 122 ). involved in endothelial protection (Section 2.3.1) and, possibly represents a new class of anti-inflammatory and proresolving lipid mediators 123 . The most recent finding...

Fever and Mediators of the Febrile Response

Febrile response is in most cases a part of a physiologic defense reaction and caused by cytokine-in- Figure 2.36 Effects of aspirin on pain rating, pain-related somatosensory evoked potentials (SEPs) and power density (PD) in response to pain-inducing stimuli in healthy volunteers. Encephalographic measurements (EEG) were taken before (pre) and 90min after (post) oral aspirin (1 g) intake. Note the aspirin-induced alterations, suggesting reduced signal transmission. No changes were seen with a...

Hemostasis and Thrombosis

Hemostasis The rapid cessation of bleeding after vessel injury is a vital function of the organism. To reach this goal, a variety of chemical factors have been developed that form together the functional unit of the clotting cascade. This system becomes activated within seconds after tissue injury to avoid life-threatening blood loss. In physiological conditions, hemostasis is well controlled and carefully balanced by a variety ofprocoagulant and anticoagulant factors. In arteries, clotting...

J R Vane

Department of Pharmacology, Institute of Basic Medical Sciences,Royal College of Surgeons of England, Lincoln's Inn Fields, London WC2A 3PN NATURE NEW BIOLOGY VOL. 231 JUNE 23 1971 Figure 1.4 First description of inhibition of prostaglandin biosynthesis by aspirin and salicylate and the reference compound indomethacin by John Vane. Note the dose dependency of this reaction by all compounds including aspirin (modified after 26 ). Figure 1.4 First description of inhibition of prostaglandin...

Toxic Actions of Salicylates on the Liver

Reye's syndrome is a hepathoencephalopathy that has been brought into connection with aspirin- induced alterations in fatty acid metabolism, glu-coneogenesis, and urea metabolism in the liver (Section 3.3.3). Serum of patients with clinical Reye-like symptoms stimulated oxygen consumption in isolated liver mitochondria, indicating uncoupling of oxidative phosphorylation 209 . In addition, there was the generation of dicarboxylic acids that corresponded directly to the reduction in ATP formation...

Summary

Salicylates exert a number of effects on energy metabolism that become most prominent in the liver. There is impaired -oxidation, in particular, of long-chain fatty acids, generation of dicarbox-ylic acids, and uncoupling of oxidative phos-phorylation. These effects are concentration-dependent and most prominent at high toxic concentrations of salicylates maintained in vitro over longer periods of time. Mechanistically, salicylate becomes activated by CoA to be able to penetrate the...

COXIndependent Actions on Cell Function

The most convincing evidence for prostaglandin-independent though biologically significant actions of salicylates is their biosynthesis by plants. Salicy-lates are natural plant constituents and part of a defense system that protects them from injury by exogenous noxes such as bacteria or viruses. Salicylate generation increases plant resistance and can be substantially upregulated at the transcriptional level in response to injury. The failure to do so, for example, after genetic manipulation,...

Salicylate Poisoning Chart

Chart For Metabolism Poisons

Salicylic acid 9 1 32 4 65 4 Salicyluric acid 75 1 47 34 22 4 Salicylic acid phenol glucuronide 11 1 23 2 15 4 Gentisicacid 5 1 10 2 7 2 Total salicylates mg salicylic acid equivalent 246 8 2999 374 8092 1470 Salicylic acid 9 1 32 4 65 4 Salicyluric acid 75 1 47 34 22 4 Salicylic acid phenol glucuronide 11 1 23 2 15 4 Gentisicacid 5 1 10 2 7 2 Total salicylates mg salicylic acid equivalent 246 8 2999 374 8092 1470 Note the increased excretion of nonmetabolized salicylic acid and the reduced...