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J R Vane

Publications and source records attributed to J R Vane.

At least 217 records · Page 12Linked to original sources
PubMed1988

The effects of endothelium-dependent vasodilators on cardiac output and their distribution in the anaesthetized rat: a comparison with sodium nitroprusside.

1. The effects of sodium nitroprusside, acetylcholine and bradykinin on cardiac output and its distribution were studied in the anaesthetized, vagotomised rat preparation by use of 113Sn-labelled microspheres. 2. All three vasodilators lowered peripheral arterial blood pressure, but only bradykinin significantly reduced total peripheral resistance without reducing cardiac output. Bradykinin caused tachycardia, but this was offset by a reduction in stroke volume. These effects of bradykinin were not altered by indomethacin (4 mg kg-1). Acetylcholine and sodium nitroprusside both caused significant (P less than 0.05) reductions in stroke volume and cardiac output. 3. Bradykinin reduced vascular resistance in the liver, stomach, small intestine, large intestine, pancreas/mesentery, epididimides, skeletal muscle and fat. These responses were not affected by indomethacin, whereas, the reduction in vascular resistance in the brain induced by bradykinin was abolished by indomethacin. 4. Acetylcholine caused a reduction in renal vascular resistance, where bradykinin had no effect. However, acetylcholine did not cause any haemodynamic changes in the bradykinin-sensitive intestinal vasculature. 5. Acetylcholine caused vasoconstriction in the coronary and epididymal vasculature. Bradykinin in the presence of indomethacin induced vasoconstriction in the skin. 6. In conclusion, the data show that, with the possible exception of the brain and the skin, the vasodilator actions of bradykinin can adequately be transduced (presumably by endothelium-derived relaxing factor, EDRF) in the absence of prostacyclin synthesis. Additionally, these results indicate that the vasculature of the stomach, pancreas/mesentery, epididimides and skeletal muscle are equally sensitive to both acetylcholine and bradykinin, whereas the kidneys showed selectivity towards acetylcholine and the intestines towards bradykinin. These results may indicate differential receptor populations.

Acetylcholine↗
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↗
PubMed1987

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity. One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30- to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.

Animals↗
PubMed1987

Antiinflammatory drugs and the many mediators of inflammation.

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 antiinflammatory effects through inhibition of prostaglandin biosynthesis is presented, in the light of other arachidonic acid products such as the leukotrienes. Evidence is presented that aspirin brings about its antiinflammatory effects (at least in the rat) after its conversion into salicylate. The selective inhibition of cyclooxygenase by the large group of aspirin-like non-steroid antiinflammatory 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.

Animals↗
PubMed1984

Prostacyclin-sensitive adenylate cyclase in cultured myocytes: differences between rabbit aorta and mesenteric artery.

Prostacyclin relaxes isolated strips of rabbit mesenteric artery and stimulates cholesteryl ester hydrolysis in rabbit aortic smooth muscle cells. Both effects are considered to be mediated by an increase in intracellular cAMP levels. Here we report that prostacyclin, prostaglandin E1 and two stable analogues of prostacyclin (5,6-dihydroprostacyclin and carbacyclin) dose dependently stimulate adenylate cyclase activity in membranes of cultured myocytes from both rabbit aorta and mesenteric artery. The rank order of potency in both systems was prostacyclin greater than carbacyclin greater than prostaglandin E1 greater than 5,6-dihydroprostacyclin, which parallels the order of potency observed for the vasodilator actions. Three other prostanoids, with limited vasoactive properties, prostaglandin D2, BW245C and 6-keto-prostaglandin F1 alpha failed to stimulate significantly adenylate cyclase activity. The two cell types differ in that the enzyme activation in aortic cell involves the interaction of each prostaglandin with one component of the adenylate cyclase system, while in mesenteric arterial cells the activation is brought about by the interaction with a higher and a lower affinity class of components.

Adenylyl Cyclases↗
PubMed1984

A biochemical basis for the gastrointestinal toxicity of non-steroid antirheumatoid drugs.

The non-steroid anti-inflammatory drugs inhibit cyclo-oxygenase and therefore the biosynthesis of prostaglandins, and it has been proposed that this biochemical intervention is the basis not only of their therapeutic activity but also contributes to their gastrointestinal side-effects. Since endogenous prostaglandins may exert mucosal protective actions, inhibition of cyclo-oxygenase by aspirin-like drugs would be expected to lead to gastric damage. The clinically-used anti-inflammatory compounds reduce prostaglandin levels in the experimental inflammatory exudate, but also inhibit prostacyclin formation in gastric tissue and induce gastric damage. In contrast, anti-inflammatory doses of sodium salicylate and an experimental drug BW755C (3-amino-1m-(trifluoromethyl)-phenyl-2-pyrazoline) fail to inhibit gastric mucosal prostacyclin formation (but do reduce prostaglandin levels in the inflammatory exudate) and cause only minimal gastric damage, supporting the relationship between production of gastric erosions and the inhibition of mucosal prostacyclin production. Anti-inflammatory doses of BW755C also fail to inhibit prostaglandin formation in the small intestine. Furthermore, studies on homogenates of gastric mucosa and ileum show that sodium salicylate, paracetamol and BW755C are only weak inhibitors of gastric mucosal cyclo-oxygenase in vitro. The development of nonsteroid anti-rheumatic drugs which have minimal action on prostaglandin production by the gastro-intestinal tract and exhibit reduced gastrointestinal toxicity, thus appears to be a feasible proposition.

Animals↗
PubMed1984

The use of stable prostaglandins to investigate prostacyclin (PGI2)-binding sites and PGI2-sensitive adenylate cyclase in human platelet membranes.

Prostacyclin, (PGI2) is a potent but unstable inhibitor of platelet aggregation, probably acting through stimulation of adenylate cyclase. A stable analogue of prostacyclin with antiaggregatory properties, 5,6-dihydro-PGI2 (6 beta-PGI1), and PGE1 can compete for the binding sites labelled by 3H-PGI2 in human platelet membranes (the affinity being PGI2 greater than PGE1 greater than 6 beta-PGI1). Both 6 beta-PGI1 and PGE1, as well as PGI2, bind to two classes of binding sites. 6 beta-PGI1 and PGE1 activate adenylate cyclase to the same extent as PGI2, with a rank order of potency which parallels that observed in binding experiments. The stimulation of this enzyme is brought about by interaction of each of these prostanoids with two different classes of components. The comparison of binding and adenylate cyclase data suggests that the sites to which PGI2, 6 beta-PGI1 and PGE1 bind might be coupled to the activation of adenylate cyclase. Since 6 beta-PGI1 seems to act through the same molecular mechanisms as PGI2, because of its stability it is an useful tool to investigate the mode of action of prostacyclin in platelets.

Adenylyl Cyclases↗
PubMed1984

Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C.

The effects of three anti-inflammatory drugs, which interfere with arachidonic acid transformation by three different enzymes, have been compared by using a simple model of tissue damage and foreign body rejection. In groups of control rats, subcutaneously implanted polyester sponges were rejected after a mean of 12 days. Indomethacin, which selectively inhibits prostaglandin synthesis, did not significantly change time to rejection but BW755C (3-amino-1-[m-(trifluoromethyl) phenyl]-2-pyrazoline), which is a dual inhibitor of prostaglandin and leukotriene synthesis, prolonged time to rejection to a mean of 22 days. The anti-inflammatory steroid dexamethasone, which reduces arachidonic acid metabolism by stimulating the formation of a phospholipase inhibitor, prolonged time to sponge rejection as BW755C did. Treatment with BW755C or dexamethasone was also accompanied by a reduction in total leukocyte numbers in inflammatory exudates collected at 1-14 days, whereas indomethacin increased leukocyte migration on days 1 and 2 and had no effect at later times. These results suggest that the inhibition of the leukotriene-forming lipoxygenase suppresses leukocyte activation and that this leads to a reduced rate of tissue damage in experimental inflammation.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Platelet and cardiovascular activity of the hydantoin BW245C, a potent prostaglandin analogue.

The platelet anti-aggregating, cardiovascular and gastro-intestinal actions of a hydantoin prostaglandin analogue, BW245C have been compared with prostacyclin and PGD2 in several species. In human plasma in vitro, BW245C was 0.2 times as active as prostacyclin and 8 times as active as PGD2 in inhibiting platelet aggregation. In rat and rabbit plasma, BW245C was only weakly active but was more potent in sheep and horse plasma. Since the activity of PGD2 varied in a parallel fashion, BW245C may interact with PGD2 binding sites on platelets. The potency of BW245C as a vasodepressor also varied between species, being 0.5, 0.1, 0.06 and less than 0.02 times as active as prostacyclin in the anaesthetised dog, monkey, rat and rabbit respectively. The relative activity of BW245C as an inhibitor of platelet aggregation ex vivo was more comparable, being 0.08, 0.04 and 0.05 times as active as prostacyclin following intravenous infusion in the rabbit dog and monkey respectively. In the rabbit, BW245C was a highly selective platelet inhibitor with minimal cardiovascular actions, whereas in the dog and monkey, BW245C lowered BP in anti-aggregating doses. The potent platelet anti-aggregating actions of BW245C following parenteral or oral administration makes this hydantoin a potentially-useful anti-thrombotic prostaglandin analogue.

Animals↗