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Biomedical subjects

J R Vane

Publications and source records attributed to J R Vane.

At least 199 records · Page 11Linked to original sources
PubMed1989

Endothelin-1 causes vasoconstriction and vasodilation in the blood perfused liver of the dog.

Endothelin-1 (ET-1; 1 pmol-1 nmol) was injected intra-arterially into the canine hepatic artery perfused, in situ, with arterial blood. The characteristic arterial vascular response to ET-1 was biphasic consisting of an initial increase in flow (vasodilatation) of short duration followed by a prolonged reduction in flow (vasoconstriction). The hepatic portal circuit was perfused at a constant flow with blood derived from the mesenteric circuit. Hepatic portal inflow pressure was continuously recorded. ET-1 injected intraportally increased the portal perfusion pressure indicating an increase in portal inflow resistance. This portal vasoconstrictor response to ET-1 was of much longer duration than that previously observed with other vasoactive agents in this vascular territory.

Animals↗
PubMed1989

Kinins act on B1 or B2 receptors to release conjointly endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells.

1. Bradykinin (Bk) induced the coupled release of endothelium-derived relaxing factor (EDRF) and prostacyclin (PGI2) from bovine aortic endothelial cells grown in culture. The B2 kinin receptor antagonist, [D-Arg0,Hyp3,Thi5,8,D-Phe7]-Bk, abolished this release by Bk. 2. Des-Arg9-Bk, a B1 kinin receptor agonist, also induced the release of EDRF and PGI2, but much higher concentrations were required to obtain a similar release to that induced by Bk. 3. [Leu8],des-Arg9-Bk, a B1 receptor antagonist, significantly reduced the response to des-Arg9-Bk without affecting the release induced by Bk. 4. The release of EDRF and PGI2 induced by arachidonic acid or ADP was not significantly affected by the B2 or the B1 antagonist. 5. We conclude, therefore, that Bk and des-Arg9-Bk were acting respectively on B2 and B1 bradykinin receptors. 6. The possible role of kinin receptors in the release of EDRF and PGI2 from endothelial cells is discussed.

Adenosine Diphosphate↗
PubMed1989

Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.

Animals↗
PubMed1989

Comparison of the survival of endothelium-derived relaxing factor and nitric oxide within the isolated perfused mesenteric arterial bed of the rat.

1. The survival of the endothelium-derived relaxing factor (EDRF) released by acetylcholine (ACh) in the rat isolated perfused mesenteric vascular bed was compared to that of exogenously applied nitric oxide (NO) by direct bioassay of the effluent from the mesenteric bed on rabbit aortic strips (RbAs). 2. NO (0.1-10 nmol) produced dose-related vasodilatations in the mesenteric vascular bed and also survived in the effluent in concentrations sufficient to provoke relaxations of the RbAs. ACh (1.7 pmol-300 nmol) caused dose-related vasodilatations in the mesenteric bed but no EDRF was detected in the effluent. This was true even when ACh provoked much larger vasodilatations in the mesenteric bed than those to doses of NO that survived passage through the bed. 3. Removal of the endothelial cells in the mesenteric vascular bed abolished vasodilatations in response to ACh but did not significantly affect those to NO. Survival of NO through the mesenteric bed was not increased. 4. Superoxide dismutase (SOD, 10 u ml-1) did not significantly affect the vasodilator effects of either ACh or NO. It did increase the survival of NO through the mesenteric vascular bed but native EDRF was still not detected in the effluent. 5. The absence of bioassayable EDRF in the effluent following ACh-induced vasodilatations might be explained by the volume into which EDRF is released abluminally being much smaller than that into which it is released luminally.

Animals↗
PubMed1989

Superoxide anions enhance platelet adhesion and aggregation.

1. Superoxide dismutase (SOD, 60 u ml-1) or ferricytochrome c (70 microM) significantly inhibited thrombin-stimulated platelet adhesion to gelatin-coated plastic, whereas catalase (1000 u ml-1) or mannitol (1 mM) had no effect. 2. The platelet aggregation induced by low concentrations of thrombin (causing less than 45% maximal change in light transmission) was inhibited by SOD. Catalase or mannitol had no effect on platelet aggregation. 3. Pyrogallol (an O2- generator) enhanced both platelet adhesion to gelatin-coated plastic and platelet aggregation induced by thrombin; this enhancement was neutralized by SOD. 4. These results indicate that O2- increase both platelet adhesion and aggregation, whereas other free radicals such as hydrogen peroxide or hydroxyl radicals are not involved.

Adenine↗
PubMed1989

Simultaneous measurement of endothelium-derived relaxing factor by bioassay and guanylate cyclase stimulation.

1. Endothelium-derived relaxing factor (EDRF) released by cultured endothelial cells (EC) from bovine aortae was measured by bioassay using pre-contracted strips of rabbit aorta and by radioimmunoassay of guanosine 3':5'-cyclic monophosphate (cyclic GMP) produced by stimulation of bovine lung soluble guanylate cyclase. 2. Bradykinin (Bk, 3 and 30 pmol) injected through a column of EC caused release of EDRF as detected by bioassay and increased cyclic GMP concentrations. Superoxide dismutase (SOD, 15 u ml-1) increased the amount of EDRF detected by the activation of soluble guanylate cyclase. 3. In the absence of endothelial cells, nitric oxide (NO, 1-2 microM), arachidonic acid (AA, 3-30 microM) or sodium nitroprusside (SNP, 1-100 microM) stimulated guanylate cyclase. Superoxide dismutase strongly increased the stimulation of guanylate cyclase induced by NO, but had little effect on the stimulation induced by SNP and no effect on the stimulation induced by AA. 4. Oxyhaemoglobin (10-300 microM) abolished the stimulation of guanylate cyclase by EDRF, NO or SNP but was much less effective as an inhibitor of AA-induced stimulation of guanylate cyclase. 5. These results demonstrate that measurement of guanylate cyclase stimulation by radioimmunoassay is a viable method for detecting EDRF release, especially useful when the drugs used interfere with bioassay tissues.

Animals↗
PubMed1989

Interactions of iloprost and sodium nitroprusside on vascular smooth muscle and platelet aggregation.

1. The aim of the study was to assess and quantify any synergism occurring between the stable analogues of prostacyclin (iloprost) and nitric oxide (sodium nitroprusside) with respect to both relaxation of vascular smooth muscle and inhibition of platelet aggregation in the rabbit. 2. Iloprost (0.3-3 ng ml-1) and sodium nitroprusside (0.3-3 ng ml-1) caused dose-dependent relaxation of the rabbit mesenteric and coeliac arteries. 3. Iloprost (0.3-30 ng ml-1) and sodium nitroprusside (0.03-30 micrograms ml-1) caused dose-dependent inhibition of rabbit platelet aggregation induced by adenosine diphosphate or collagen. 4. In combination, iloprost and sodium nitroprusside caused an inhibition of platelet aggregation that was 2-3 fold greater than would be expected by summation, while no such potentiation was observed on vascular smooth muscle. 5. Thus, our results indicate that under physiological conditions the mediators prostacyclin and endothelium-derived relaxing factor (NO) can exert a synergistic action on platelets, but have only an additive effect on vascular smooth muscle.

Animals↗
PubMed1989

Mediators and the anti-thrombotic properties of the vascular endothelium.

This review discusses the role of three mediators synthesized by the vascular endothelium, which are involved in maintaining the surface of the endothelial cells in a non-thrombogenic state. Prostacyclin, discovered in 1976, is a product of arachidonic acid metabolism. This labile prostanoid, with a chemical half life of approximately three minutes, relaxes vascular smooth muscle and inhibits the aggregation of blood platelets. Endothelium-derived relaxing factor (EDRF), discovered in 1980, is even more labile than prostacyclin with a half life counted in seconds. It also relaxes smooth muscle and inhibits the aggregation and adhesion of platelets. Recently, it has been identified as nitric oxide. Prostacyclin and EDRF are released together following stimulation of receptors on endothelial cells and cooperate to inhibit platelet aggregation and adhesion. 13-HODE, acts from inside the cell to make the endothelial surface less adhesive and is not released. These mediators act together to form the endothelial defence mechanism against adhering blood cells. Underproduction can lead to diseases such as hypertension or atherosclerosis. A mainly fish diet, rich in eicosapentaenoic acid alters the prostacyclin/thromboxane balance in favour of prostacyclin-like activity. This type of diet may provide protection against atherosclerosis and myocardial infarction.

Antithrombins↗
PubMed1989

Endothelin-1 releases prostacyclin and inhibits ex vivo platelet aggregation in the anesthetized rabbit.

The effects of porcine endothelin (endothelin-1, ET-1; 1 nmol/kg i.a.) on ex vivo platelet aggregation and platelet cAMP/cGMP levels were investigated in the anesthetized rabbit. ET-1 inhibited ADP-induced platelet aggregation by 83 +/- 9% within 5 min (p less than 0.01). This ET-1-induced inhibition of platelet aggregation lasted for 30 min and was associated with a significant (five- to sixfold) increase in platelet cAMP. However, platelet cGMP levels were unaffected. Indomethacin (5 mg/kg i.v., 20 min prior to ET-1) abolished the ET-1-induced inhibition of ex vivo platelet aggregation as well as the corresponding augmentation of platelet cAMP. Thus, ET-1 inhibits platelet function in vivo due to the release into the circulation of antiplatelet cyclo-oxygenase products, such as prostacyclin (or PGD2).

Anesthesia↗
PubMed1989

Pharmacology of endothelin-1 in isolated vessels: effect of nicardipine, methylene blue, hemoglobin, and gossypol.

Sensitive bioassay tissues for porcine endothelin-1 (ET-1) were developed in a cascade superfusion system and in organ baths. Venous preparations of the rabbit and rat were more sensitive than arterial preparations. ET-1 had a different pharmacological profile than Bay K 8644 on the various preparations. Nicardipine (0.1-1 microM) abolished the responses to Bay K 8644 without affecting those induced by ET-1. Thus, ET-1 contracts venous and some arterial vessels via specific receptors or channels that differ from dihydropyridine-sensitive calcium channels. Methylene blue and hemoglobin potentiated responses to ET-1 in endothelium-denuded venous vessels, whereas gossypol had no effect.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Vasoactive mediators derived from the endothelium.

Two of the many mediators synthesized by vascular endothelial cells (EC), are involved in maintaining the surface of the normal, healthy endothelium in a non-thrombogenic state. 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 in the clinic for cardiovascular diseases such as primary pulmonary hypertension. A number of drugs including defibrotide, nafazatrom, ronicol and cicletanine may exert their therapeutic effects by releasing prostacyclin from the EC. 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 which stimulate release of EDRF include acetylcholine, bradykinin and ADP. EDRF is even more labile than prostacyclin with a half life counted in seconds. It has recently been identified as nitric oxide formed from L-arginine by an unknown mechanism. Prostacyclin and EDRF are released together following stimulation of endothelial receptors and synergize to inhibit platelet aggregation. It is suggested that these mediators form the endothelial defence mechanism against blood-borne cells and chemicals and that breakdown of this barrier results in diseases such as hypertension and atherosclerosis. The peptide, endothelin is the third mediator under discussion. Characterised and synthesised in 1988, it is the most potent vasoconstrictor so far discovered. Three isomers of endothelin have been identified. Paradoxically, endothelin strongly releases both prostacyclin and EDRF thus modulating its own vasoconstrictor actions.

Endothelins↗
PubMed1988

Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor.

Endothelin releases prostacyclin and thromboxane A2 from guinea pig or rat isolated lungs and endothelium-derived relaxing factor in the perfused mesentery of the rat. Endothelin is also substantially removed by the pulmonary circulation of the rat in vitro and in vivo and by guinea pig lungs in vitro. In the rat, the effects of endothelin on the blood pressure vary from pressor (in pithed rats) to purely depressor in anesthetized rats where the resting blood pressure is high. It therefore has the characteristics of a local pressor hormone, rather than a circulating one.

Animals↗
PubMed1988

Receptor-mediated release of endothelium-derived relaxing factor and prostacyclin from bovine aortic endothelial cells is coupled.

Bovine aortic endothelial cells were grown on microcarrier beads and were perfused with Krebs-Ringer solution. Endothelium-derived relaxing factor (EDRF) was bioassayed on a cascade of four strips of rabbit aorta, and prostacyclin was analyzed by RIA of 6-oxo-prostaglandin F1 alpha. The endothelial cells released EDRF and prostacyclin when stimulated with bradykinin and its analogues, or with ADP, ATP, arachidonic acid, and phospholipase C (phosphatidylcholine cholinephosphohydrolase, EC 3.1.4.3). The detection of EDRF was potentiated by superoxide dismutase, and the relaxation of rabbit aortic strips induced by EDRF was antagonized by methylene blue. The release of EDRF and prostacyclin was inhibited by phorbol myristate acetate, R59022 (a diacylglycerol kinase inhibitor), and gentamycin. We suggest that the release of EDRF and prostacyclin is coupled and the initial common step is activation of a phospholipase C.

Animals↗
PubMed1988

Endothelium-derived relaxing factor reduces platelet adhesion to bovine endothelial cells.

The adhesion of thrombin-stimulated human blood platelets to either the endothelial surface of intact bovine aorta or cultured bovine aortic endothelial cells was studied to determine the role of endothelium-derived relaxing factor in the regulation of platelet adhesion. Endothelial cells and platelets were pretreated with indomethacin to prevent the formation of prostaglandins. The adhesion of thrombin-stimulated platelets to endothelial cells was reduced by superoxide dismutase and bradykinin. The inhibitory effect of both drugs was abolished by hemoglobin and was absent in strips of bovine aorta where the endothelial cells had been removed by scraping. It is suggested that the effects of bradykinin are mediated by the release of endothelium-derived relaxing factor, which is protected from destruction by superoxide dismutase, and that endothelium-derived relaxing factor contributes to the nonadhesive properties of the vascular endothelium.

Adenine↗
PubMed1988

Effect of captopril on the bradykinin-induced release of prostacyclin from guinea-pig lungs and bovine aortic endothelial cells.

1. In guinea-pig isolated lungs perfused with Krebs solution, captopril (10 microM) inhibited the metabolism of bradykinin (Bk) and the conversion of angiotensin I to angiotensin II, as measured by bioassay. Captopril significantly enhanced Bk-stimulated output of prostacyclin. 2. In bovine aortic endothelial cells grown on microcarrier beads, captopril (10 microM) did not affect the release of prostacyclin or of endothelium-derived relaxing factor (EDRF) induced by Bk. 3. Angiotensin I or angiotensin II did not release prostacyclin from guinea-pig isolated lungs or bovine aortic endothelial cells. They were also ineffective as releasers of EDRF from bovine aortic endothelial cells. 4. Thus, activation of angiotensin converting enzyme is not involved in the release of prostacyclin from guinea-pig isolated lungs or bovine aortic endothelial cells, or in release of EDRF from bovine aortic endothelial cells.

Angiotensin I↗