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Biomedical subjects

R M Botting

Publications and source records attributed to R M Botting.

35 records · Page 2Linked to original sources
PubMed1992

The role of chemical mediators released by the endothelium in the control of the cardiovascular system.

The vascular endothelium is much more than just a lining for blood vessels. It inactivates many mediators and produces a host of active substances. The production of these substances is modulated by interactions between the endothelial cells and white blood cells, platelets or constituents of plasma. The endothelial cells can be activated by amines, peptides, proteins, nucleotides, arachidonic acid and its metabolites, as well as by physical changes such as pulse pressure. This activation of endothelial cells is often mediated by specific receptors which respond in a variety of ways including the generation of prostacyclin and endothelium-derived relaxing factor (EDRF). Both of these mediators inhibit platelet aggregation and cause vascular dilatation, prostacyclin through increasing cyclic AMP, and EDRF through increasing cyclic GMP. EDRF has been identified as nitric oxide (NO) derived from the guanidino group of L-arginine. Inhibitors of NO formation cause a strong increase in blood pressure, showing that under normal conditions there is a constant formation of NO to dilate the vasculature. Endothelin is another agent made by endothelial cells; characterized and synthesized in 1988, it is the most potent vasoconstrictor so far discovered. Three endothelin isomers have been identified; paradoxically, ET-1 strongly releases both prostacyclin and NO, thus modulating its own vasoconstrictor activities.

Animals↗
PubMed1992

Secretory functions of the vascular endothelium.

The endothelial cells which line the blood vessels as a monolayer exert a remarkable control over the vascular system. Indeed, the endothelium can be regarded as a highly active metabolic and endocrine organ in its own right. On the hand, vasoactive substances such as serotonin and bradykinin are inactivated and on the other the cells can enzymatically produce the vasoconstrictor, angiotensin II and secrete endothelin-1 ((ET-1). Perhaps more importantly, the cells also produce two unstable vasodilator substances, which potently inhibit platelet clumping: prostacyclin and endothelium-derived relaxing factor (EDRF) which has been identified as nitric oxide (NO; 1). Both substances seem well designated as local hormones, released to influence adjacent cells. The endothelial cell, therefore, exerts control over the cardiovascular system by elaborating dilator substances as well as vasconstrictors.

Endothelins↗
PubMed1990

The mode of action of anti-inflammatory drugs.

The history of the use of aspirin and salicylate is briefly reviewed, as are the many putative mediators of inflammation. The theory that aspirin-like drugs bring about their anti-inflammatory effects through inhibition of prostaglandin biosynthesis is presented, in the light of other arachidonic acid products such as the leukotrienes. The selective inhibition of cyclo-oxygenase by the large group of aspirin-like non-steroidal anti-inflammatory drugs explains their therapeutic activity. The elucidation of other pathways of oxidative metabolism of arachidonic acid has revealed new targets for the development of drugs with potentially greater therapeutic activity in the treatment of inflammation, cardio-thrombotic diseases and asthma.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Endothelins.

The endothelins (ETs) are a family of newly discovered peptides with potent vasoconstrictor properties. They were first discovered in cultured endothelial cells but ET expression has since been found in many other tissues such as brain and kidney. They are peptides with 21 amino acids formed by hydrolytic cleavage of a larger peptide, big ET. Release of ETs from cultured endothelial cells is modulated by a variety of chemical and physical stimuli and as no storage sites have been identified it is suggested that endothelin release is regulated at the level of transcription or translation. Both big ET and ET-1 are found circulating in the blood. The levels are elevated in shock, myocardial infarction and kidney failure indicative of enhanced formation in these diseases. The literature now abounds with reports on actions of the ETs in vitro and in vivo. The vasoconstrictor properties are powerful and long-lasting. Several studies also show a mitogenic effect, indicating a possible trophic role. It is likely that in the next few years the development of inhibitors of endothelin synthesis and/or action will be of importance in unravelling the role of the ETs.

Amino Acid Sequence↗
PubMed1988

Mediators produced by the endothelial cell.

This review discusses the role of three mediators, synthesized by vascular endothelial cells, that help to keep the surface of the normal endothelium nonthrombogenic. The first is prostacyclin, a product of arachidonic acid metabolism discovered in 1976. This labile prostanoid, with a half-life of approximately 3 minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Prostacyclin and its analogues are currently being tested clinically for use in cardiovascular diseases such as primary pulmonary hypertension. The second mediator discussed is endothelium-derived relaxing factor (EDRF), discovered in 1980, which also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Substances that stimulate the release of EDRF include acetylcholine, bradykinin, and adenosine 5'-diphosphate. EDRF is even more labile than prostacyclin, with a half-life of about 6 seconds, and it has recently been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. 13-Hydroxy-9,11-octadecadienoic acid, a third suggested mediator, is not released but acts from inside the cell to make the endothelial surface nonadhesive for circulating blood cells. It is proposed that these three mediators form the endothelial defense mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis.

Animals↗
PubMedDate not supplied

Endothelins: potent releasers of prostacyclin and EDRF.

The isopeptides endothelin-1 (ET-1) and endothelin-3 (ET-3) are potent vasoconstrictor substances in pithed or chemically-denervated rats. However, when injected into anesthetized rats with a high resting blood pressure, these peptides have vasodepressor actions. In addition, the pressor effects were potentiated by indomethacin indicating that release of endogenous eicosanoids modulated the pressor responses. Endothelin-1 released eicosanoids from a number of perfused isolated organ preparations. Prostacyclin and thromboxane A2 were released from perfused guinea-pig lungs, prostaglandin E2, prostacyclin and thromboxane A2 from rabbit spleen and prostacyclin and thromboxane A2 from rabbit kidneys. The eicosanoids were identified both by bioassay and by radioimmunoassay. Injection of ET-1 or ET-3 into the mesenteric artery of the rat isolated perfused mesentery preparation caused dose-related reductions in perfusion pressure. These depressor effects could be abolished by removing the endothelium with deoxycholate or by perfusing with oxyhaemoglobin, indicating that they were caused by release of EDRF. Endothelin-1 also released EDRF, identified by bioassay, from the endothelium of a perfused rabbit aorta. Endothelin-1 and ET-3 injected into anesthetized rabbits inhibited ex vivo platelet aggregation by increasing cyclic AMP, presumably through the release of prostacyclin into the circulation. Thus, endothelins release prostacyclin and EDRF both in vitro and in vivo.

Amino Acid Sequence↗
PubMedDate not supplied

Relationship between different isoforms of nitric oxide synthase and cyclooxygenase in various cell types.

Nitric oxide (NO) and prostacyclin (PGI2), formed by NO synthase (NOS) and cyclooxygenase (COX), respectively, are two potent anti-aggregatory vasodilators released from endothelial cells. Both NOS and COX exist as constitutive and inducible isoforms. We have shown that NOS and COX are co-induced in vitro and in vivo by bacterial endotoxin and that low amounts of NO increase whereas high amounts inhibit the activity and expression of inducible COX in vitro.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Regulatory mechanisms of the vascular endothelium: an update.

This review discusses recent experimental findings in prostacyclin, nitric oxide and endothelin research. Prostacyclin formation by endothelial cells in atherosclerosis and diabetes is reviewed and the synthesis of prostacyclin by cyclooxygenase 1 and 2 (COX-1 and COX-2) is discussed. Further work on nitric oxide describes its involvement in septic and haemorrhagic shock and its interactions with the cyclooxygenase pathway. Recent studies in endothelin research include the development of both selective and orally active receptor antagonists, characterization of endothelin converting enzymes and the involvement of endothelin-1 in inflammation and wound repair.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Formation by the endothelium of prostacyclin, nitric oxide and endothelin.

Prostacyclin and nitric oxide (NO) are two labile vasorelaxant and anti-aggregatory substances which are released by receptor activation and in response to shear forces acting on endothelial cells, whereas the potent constrictor peptide, endothelin-1 (ET-1) is probably slowly released and exerts long-term control over the cardiovascular system. This review deals with the synthesis, release and pharmacological actions of prostacyclin, NO and ET-1, as well as the diseases which might result from their under- or over-production.

Animals↗