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Biomedical subjects

J R Vane

Publications and source records attributed to J R Vane.

At least 181 records · Page 10Linked to original sources
PubMed1990

Sodium nitroprusside modulates the fibrinolytic system in the rabbit.

1. We have investigated the effect of sodium nitroprusside (NP) and glyceryl trinitrate (GTN) on fibrinolysis in anaesthetized rabbits ex vivo and in vitro by measurement of euglobulin clot lysis time (ECLT), plasma levels of tissue plasminogen activator (t-PA) activity, plasma t-PA antigen levels and plasminogen activator inhibitor (PAI-1) activity. 2. In vivo, NP (30 micrograms kg-1), GTN (30 micrograms kg-1) and prostacyclin (3 micrograms kg-1) caused similar transient decreases in left ventricular systolic pressure. However, while prostacyclin induced near-maximal inhibition of ex vivo platelet aggregation, NP or GTN had no effect. 3. Ex vivo, NP caused a significant decrease in ECLT and an increase in plasma t-PA activity. 4. Intravenous co-administration of t-PA (30 micrograms kg-1) with NP caused substantial prolongation of plasma t-PA activity, without affecting t-PA antigen levels. 5. In whole blood in vitro, NP (30 micrograms kg-1) prevented the time-dependent increase in PAI-1 activity and inhibited inactivation of added t-PA (10 ng ml-1). 6. We propose that NP exhibited fibrinolytic activity through increased t-PA activity as a result of inhibition of PAI-1 release from platelets. These results could have important therapeutic consequences when t-PA and nitrate treatments are combined.

Animals↗
PubMed1990

Endothelin-1 inhibits platelet aggregation in vivo: a study with 111indium-labelled platelets.

1. A non-invasive technique for the scintigraphic determination of 111indium-labelled platelet aggregation stimulated with submaximal doses of adenosine diphosphate (ADP, 56 micrograms kg-1 i.v.), collagen (100 micrograms kg-1 i.v.), platelet-activating factor (PAF, 0.1 microgram kg-1 i.v.) or thrombin (18 iu kg-1 i.v.) was used to investigate the platelet-inhibitory effects of endothelin 1 (ET-1) in anaesthetized rabbits in vivo. 2. ET-1 (1 nmol kg-1 i.v.) inhibited ADP-stimulated platelet aggregation in vivo; a maximum inhibition of 78% of the control value was reached at 3 min, with 45% inhibition at 15 min, and a return to control values at 30 min after injection of the peptide. 3. ET-1 (1 nmol kg-1 i.v.) inhibited in vivo platelet aggregation in response to collagen or PAF by 86% and 52%, respectively, but had no effect on thrombin-induced platelet aggregation. 4. Indomethacin (5 mg kg-1 i.v.) abolished the ET-1-induced inhibition of ADP-stimulated platelet aggregation and significantly potentiated and prolonged the pressor response brought about by ET-1. 5. In conclusion, the data demonstrate that ET-1 potently inhibits platelet aggregation in the anaesthetized rabbit in vivo by releasing a hypotensive and anti-aggregatory cyclo-oxygenase product, presumably prostacyclin, into the circulation.

Adenosine Diphosphate↗
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↗
PubMed1989

Endothelin-3: selectivity as an anti-aggregatory peptide in vivo.

Endothelin-3 (1 nmol/kg) given i.v. to anaesthetised rabbits significantly inhibited ADP-induced ex vivo platelet aggregation, while causing only a transient decrease in blood pressure and no change in heart rate. Pretreatment with piroxicam (14 mumol/kg) abolished the anti-aggregatory effect. Thus, endothelin-3, while not inhibiting rabbit platelets in vitro, can induce the release of a cyclo-oxygenase produce, probably prostacyclin, which inhibits ex vivo aggregation. Unlike endothelin-1, this was achieved with minimal effect on the haemodynamics.

Animals↗
PubMed1989

Endothelin-1 contracts isolated vessels independently of dihydropyridine-sensitive Ca2+ channel activation.

Spirally cut strips of arteries and veins were prepared from the rabbit or the dog and superfused in cascade. Venous strips were more sensitive to endothelin-1 (ET-1) than arterial ones and, in particular, the rabbit jugular and the rabbit mesenteric veins were contracted by as little as 0.5-2.5 pmol of ET-1 in a reproducible and dose-dependent way. The calcium agonist Bay K 8644 had a different profile of activity on the vascular strips, being more potent on the rabbit mesenteric artery than on the rabbit jugular or mesenteric veins. Nicardipine (10(-7) M) did not affect the ET-1-induced vascular contractions but abolished the contractile activity of Bay K 8644. Contractions induced by ET-1 were not affected by the kininase II inhibitor captopril in the rabbit jugular veins but were potentiated by methylene blue in both veins of the rabbit. Our results indicate that ET-1 potently contracts venous and arterial isolated vessels via the activation of specific receptors or channels that differ from the dihydropyridine-sensitive calcium channels. The fact that ET-1 is more active on venous than on arterial smooth muscle may have important pathophysiological implications.

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

Personality theory and personality assessment measures: how helpful to the clinician?

One of the most important role-defining functions of the clinical psychologist is personality assessment. Because of the wide range of personality assessment instruments available, there is a need for the clinician to be aware of their relative strengths and weaknesses. This article discusses the extent to which our present-day tests of personality and theories of personality are helpful in guiding the clinician to meaningful conclusions and predictions. Indirect methods of assessment, such as the Rorschach and TAT, encourage the subject's free and open-ended response to a small number of ambiguous stimuli so as to circumvent the subject's censorship of responses. To varying degrees, indirect methods have suffered from difficulties in establishing acceptable scoring systems and standardized norms. Direct measures, such as the MMPI, limit freedom of expression and assess fewer, but more clearly defined variables. Well-defined and objective scoring and interpretation are considered major advantages of direct over indirect methods. However, direct methods are not without disadvantages. Some important concerns are limitations in subject's self-knowledge, falsification of responses, and the development of response sets.

Humans↗
PubMed1989

Inhibition of platelet-derived mitogen release by nitric oxide (EDRF).

Platelets exposed to thrombogenic surfaces adhere, aggregate and release mitogenic substances from their alpha-granules. Endothelium-derived relaxing factor (EDRF) which has been identified as nitric oxide (NO) has been reported to inhibit platelet aggregation. We now report that NO inhibits mitogen release from stimulated human platelets. Mitogenic activity was assayed on mouse fibroblast 3T3 cells using incorporation of 3H-thymidine. Serum from collagen-aggregated platelets significantly increased 3H-thymidine incorporation by 3T3 cells above that of serum from control platelets. Both this increase and platelet aggregation were blocked by NO and prostacyclin in a dose related manner. The inhibitory activity of NO decayed with time when incubated in platelet-free plasma at 37 degrees C, but was still detectable after 2 minutes.

Blood Platelets↗
PubMed1989

Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor.

Incubation of neutrophils or mononuclear cells with washed platelets (all prepared from human venous blood) resulted in an inhibition of thrombin-induced platelet aggregation that was dependent on the number of nucleated cells added. The inhibition was potentiated by superoxide dismutase and reversed by oxyhemoglobin. In the case of neutrophils the inhibition was associated with an increase in cGMP, whereas with mononuclear cells both cAMP and cGMP were increased. The inhibitory activity of neutrophils or mononuclear cells was prevented by their preincubation with NG-monomethyl-L-arginine methyl ester. L-Arginine reversed the action of NG-monomethyl-L-arginine methyl ester, whereas D-arginine was ineffective. Preincubation of the cells with catalase or mannitol did not prevent their inhibitory action on platelet aggregation. The inhibition of platelet aggregation was not due to platelet damage or to uptake of thrombin by neutrophils or mononuclear cells. It was overcome by increasing the concentration of thrombin and was absent in cell-free supernatants obtained from a suspension of neutrophils or mononuclear cells or from mixtures of platelets with neutrophils or platelets with mononuclear cells. These data provide evidence for the release of a nitric oxide-like factor from human neutrophils and mononuclear cells. In addition, evidence is provided that, as in stimulated murine macrophages and endothelial cells, the precursor of this factor is L-arginine.

Cyclic AMP↗
PubMed1989

The fate of radioiodinated endothelin-1 and endothelin-3 in the rat.

Endothelin-1 (ET-1) has been isolated from cultured endothelial cells and might have a role in cardiovascular regulation. To study the fate of labeled ET-1, we prepared [125I]-labeled ET-1 (formerly porcine and human ET) and ET-3 (formerly rat ET). Approximately 0.2 microCi (0.2 pmol) was injected into the left ventricle of anesthetized rats and blood samples analyzed for radioactivity for up to 40 min. The animals were then killed and the distribution of radioactivity determined in various organs. Both ET-1 and ET-3 were rapidly removed from the circulation, with more than 60% of the removal occurring in the first minute. Removal of ET-1 was somewhat faster than that of ET-3. The highest uptake of radioactivity was seen in lung, kidney, and liver. When ET-1 was infused into the isolated perfused lung of the guinea pig, 64 +/- 1.9% of the label was retained. Subcellular fractionation of the lung homogenate following infusion of labeled ET-1 showed that 93% of the label was associated with membranes and intracellular organelles, suggesting internalization of the bound ET-1. Together, the results indicate a high density of ET-1 binding sites in the lung, liver, and kidney and that these organs may be important in removing circulating ET-1.

Animals↗
PubMed1989

Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit.

We have previously shown that porcine endothelin (ET-1) releases endothelium-derived relaxing factor (EDRF) in the rat isolated perfused mesentery. Here we show that both ET-1 (1-100 pmol) and rat endothelin (ET-3, 1-300 pmol) release EDRF in this preparation and that ET-1 releases EDRF from the luminally perfused aorta of the rabbit. Furthermore, we confirm that, as a pressor agent, ET-1 is greater than 10 times more potent than ET-3. Vasodilatations in the rat isolated perfused mesentery in response to ET-1 and ET-3 were due to the release of EDRF since they were inhibited by removal of the endothelium, methylene blue (100 microM), or hemoglobin (30 microM). ET-3 was more selective than ET-1 as a vasodilator because ET-1 induced vasodilatations were limited and in the higher doses overwhelmed by concurrent vasoconstrictions. Release of EDRF from the rabbit aorta in response to ET-1 but not to other agonists (acetylcholine, substance P, or adenosine diphosphate) was potentiated by infusion of potassium chloride (3 mM). Bay K 8644 failed to release EDRF in either system or to constrict the nondepolarized rat mesentery. Thus, both ET-1 and ET-3 release EDRF by activation of receptors or channels that differ from dihydropyridine-sensitive calcium channels.

Animals↗
PubMed1989

Endothelin-1 releases eicosanoids from rabbit isolated perfused kidney and spleen.

This study analyzes the effects of porcine endothelin-1 (ET-1) on perfusion pressure and eicosanoid release from rabbit isolated spleen and kidney. Bolus injections (2.5-50 pmol) or infusions (1, 5, and 10 nM) of ET-1 into either organ caused dose-related increases of perfusion pressure. Pressor responses were potentiated following infusion of indomethacin (5.6 microM) for 30 min. ET-1 triggered the release of cyclo-oxygenase products as revealed by bioassay and radioimmunoassay (RIA) analysis of the effluent. In the spleen, ET-1 stimulated the release of PGE2 mainly and, to a lesser extent, of PGI2 and TXA2. In the kidney, ET-1 stimulated a greater release of PGI2 than PGE2, but not TXA2. These results demonstrate that in the isolated rabbit spleen and kidney, ET-1 is a potent vasoconstrictor and triggers the generation of vasodilator eicosanoids that limit the pressor effects of the peptide.

Animals↗
PubMed1989

The hemodynamic effects of endothelin-1 in the pithed rat.

The pressor effects of porcine (ET-1) and rat (ET-3) endothelins were studied in the pithed rat along with the actions of cyclo-oxygenase inhibitors upon these responses. Indomethacin (15 mumol/kg i.v.) when given prior to endothelin had no effect on the pressor responses to ET-1 or ET-3. However, when indomethacin or piroxicam was administered between two doses of ET-1 or ET-3, the second response was significantly potentiated. This potentiation was abolished when the adrenal glands were excluded from the circulation but partially restored when neuropeptide Y (NPY) (1 nmol/kg i.v.) was administered. Radiolabeled microspheres were used to measure regional blood flow and from these measurements, regional vascular resistance was calculated. From these data, it is evident that ET-1 caused a generalized increase in vascular resistance, and only in the large intestine and epididymal fat pad was this attenuated by indomethacin. In the gastric vasculature, the effects of ET-1 were potentiated by indomethacin. In the bronchial vasculature, ET-1 caused a reduction in vascular resistance possibly due to the bronchoconstrictor actions of ET-1 and the concomitant release of vasodilators such as histamine. When the fraction of the cardiac output received by each vascular bed is taken into account, the gastrointestinal tract, kidneys, and skeletal muscle account for most of the increase in total peripheral resistance induced by ET-1. Prostanoids have a role in the pressor response to ET-1 and ET-3 that is more complex than one of simple physiological antagonism or potentiation at the level of the vascular smooth muscle and possibly act as modulators of other regulatory factors such as NPY.

Animals↗