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Biomedical subjects

R H Bourgain

Publications and source records attributed to R H Bourgain.

At least 19 recordsLinked to original sources
PubMed1994

An optoelectronic registration method as applied to PAF-mediated hydrogen peroxide induced arterial thrombosis.

In the present paper, a standardized method for the induction and registration of platelet thrombi in arterioles (500 microns diameter) of small laboratory animals is described in full detail. Using an optoelectronic analogue computer device, different discriminating parameters characteristic for the thrombotic phenomenon are presented. As the topical application of exogenous PAF-acether induces the generation of endogenous PAF-acether according to previous investigations (Bourgain et al. (1985) Prostaglandins 30, 185) it was deemed interesting to investigate the effect of hydrogen peroxide using the described methodology. It was found that the latter substance not only primes the effect of PAF-acether-induced thrombosis, but also can trigger by itself PAF-acether modulated arterial thrombus formation. Experimental evidence is adduced that these thrombotic phenomena can be most efficiently down regulated by specific PAF-acether antagonists.

Adenosine Diphosphate↗
PubMed1992

PAF-acether induced arterial thrombosis and the effect of specific antagonists.

Platelet-vessel wall interactions and local thrombosis are investigated in vivo in a branch of the mesenteric artery of the guinea pig, using optoelectronic registration and ultrastructural control. Following an electrical challenge resulting in changes of cell membrane polarization, subsequent superfusion by PAF-acether or a stable analogue, (1-O-alkyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine, 10(-8) M focal concentration (f.c.)) for a restricted period results in endothelial cell retraction and bleb formation followed by platelet adhesion and the development of a thrombus which over time becomes invaded by leukocytes and eventually occludes the vascular lumen. It was demonstrated in a previous investigation that these phenomena are triggered by the generation of endogenous PAF-acether by the endothelial cells. Specific PAF-acether-antagonists, such as BN 52021 a ginkgolide, but also synthetic molecules, derivatives of the triazolo-pyridino-diazepine group (BN 50727, BN 50755 and BN 50789), significantly inhibit platelet-vessel wall interactions and thrombosis, but not the formation of blebs in the endothelial cells. Hydrogen peroxide (10(-5)M f.c.) not only primes the effect of PAF-acether, but is by itself capable of inducing thrombosis through a PAF-acether-mediated mechanism. Inhibition of acetyl hydrolase by PMSF (phenyl-methyl-sulfonyl-fluoride, 10(-5)M f.c.) invariably results in a significant enhancement of thrombosis, while conversely, inhibition of acetyl transferase by 27584 RP (4-(naphtylvinyl)pyridine hydrochloride, 10(-6)M f.c.) inhibits thromboformation indicating that the remodeling pathway is involved.

Acetyltransferases↗
PubMed1990

Endotoxin, PAF and arterial thrombosis.

Using an optoelectronic device, we demonstrated that endotoxin modulates platelet-activating factor (PAF)-induced arterial thrombosis in a mesenteric artery of the guinea-pig. Indeed, topical superfusion by PAF induces the generation of platelet-vessel wall interactions, invariably followed by thrombus formation. A low dose of endotoxin markedly increased, while a high dose significantly reduced thrombus formation. The reducing effect of the high dose can be completely offset by indometacin, indicating the involvement of prostaglandin I2.

Animals↗
PubMed1989

[Effect of cicletanine on prostacyclin generation in vivo].

The administration of arachidonic acid to live rabbits if followed by the generation of prostacyclin and/or thromboxane. Cicletanine increased the production of prostacyclin in a first group of rabbits and amplified the prostacyclin/thromboxane ratio in a second group of the thromboxane type. The most probable mechanism for this action is activation of prostacyclin synthase by cicletanine. This was confirmed in the in vivo model by a study of the platelet-vascular wall interaction: tranylcyprominE, a prostacyclin synthase inhibitor, increased the interaction. Under these experimental conditions, cicletanine inhibited the effect of tranylcypromine and completely restored the enzymatic activity of prostacyclin synthase.

Animals↗
PubMed1989

[Arterial thrombosis--an experimental approach].

In this study description is given of a method developed in our laboratory for the investigation of platelet-vessel wall interaction and in vivo thrombus formation. The development of this method is based on the recording of the optical density of an arteriole. Following a standardized challenge by an electrical current onto the arterial wall and subsequent topical superfusion by adenosine diphosphate (ADP), endothelial cells demonstrate specific lesions and platelets start to adhere onto the site of lesion, they aggregate and a platelet thrombus develops. Using an optoelectronic device, which functions as an analogue computer, the generation and the growth of the thrombus in the arteriole can be followed and recorded over time. This continuous on-line recording of the thrombotic phenomenon made it possible to develop discriminating parameters. As such it was possible to study thromboformation in relation to the effect of the metabolites of the arachidonate cascade. Because it is possible to register the thrombotic phenomenon over time, ultrastructural analysis using transmission and scanning electronmicroscopy was performed and allowed us to investigate the interaction of the platelets, the involvement of leukocytes and the onset of fibrin deposition in the thrombus. In further investigations it was demonstrated that as a result of an appropriate challenge of the arterial wall, Paf-acether was generated within the arterial endothelial cells, inducing local thromboformation which perpetuated itself. As such, it could be demonstrated that as a result of the local generation of endogenous Paf-acether thromboformation by an inflammatory process was maintained, leading eventually to complete obstruction of the artery.

Adenosine Diphosphate↗
PubMed1988

Exchange of cyclooxygenase dependent metabolites between vessel wall and platelets in arterial thrombosis.

In this investigation, transport of endoperoxides from the vessel wall to the platelets in an in vivo model for the induction and quantification of platelet thrombosis is described. Thrombi are induced in a branch of the mesenteric artery of the male white Wistar rat through topical superfusion of adenosine diphosphate solutions following focal de-endothelialization by means of a small electrical current in two groups, comparing untreated rats to acetylsalicylic acid (ASA) treated ones. In the latter group the cyclooxygenase activity of the platelets is completely inhibited but not so that of the endothelial cells. In both groups arachidonic acid enhances adenosine diphosphate induced arterial platelet thrombosis most likely through the conveyance of endoperoxides generated in the vessel wall to the platelets as thromboxane synthetase antagonists as well as thromboxane receptor blocking agents completely inhibit this enhancement in both groups. Furthermore it is demonstrated that ASA treated animals show an increased propensity to thrombosis induced by adenosine diphosphate.

Adenosine Diphosphate↗
PubMed1988

Modulation of prostacyclin synthetase by cicletanine and drugs which affect ion transport.

Cicletanine, a drug which affects membrane ion transport, induces a marked increase of the liberation of PGI2 as demonstrated by the increase of the stable metabolites in the plasma following intravenous administration of arachidonic acid. Furthermore, the inhibiting effect of tranylcypromine on prostacyclin synthetase is completely removed by this pharmacon. These observations are suggestive that this drug presents a scope for treatment of thrombotic disorders as well as hypertension.

Animals↗
PubMed1988

Modulation of in vivo generation of prostanoids by drugs affecting membrane ion transport.

An in vivo animal model was developed in the rabbit for the study of the mechanisms involved in the generation and release of prostanoids. Following heparinization and, if required, further sensitization of the animals by intravenous administration of haemolysed blood, injection of doses of arachidonic acid not exceeding 180 micrograms/kg induced a marked fall in arterial blood pressure on condition that the plasma anti-inflammatory protein levels were within the normal range. Cicletanine, certain diuretics (furosemide and bumetanide), as well as calcium-entry blockers such as verapamil and the association of insulin and potassium ions, all markedly decreased the AA50 value and were accompanied by a significant increase in the plasma levels of 6-oxo-PGF1 alpha, enhancing as such the ratio of 6-oxo-PGF1 alpha versus TXB2 in plasma. The infusion of insulin in association with potassium ions induced a similar but less sustained effect. Drugs which affect membrane ion transport were investigated in relation to an enhancing effect on the generation and release of prostanoids following the administration of arachidonic acid.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Enhancement of prostacyclin generation by cicletanine (an in vivo investigation).

The effect of cicletanine, an antihypertensive drug, was studied in two in vivo models. It was demonstrated that the drug markedly affected the response of intravenously administered arachidonic acid in the rabbit. In this model a marked increase of 6-oxo-PGF1 alpha was observed when challenged by the intravenous injection of 50 micrograms/kg b.w. of arachidonic acid. In the rat model used for the study of platelet-vessel wall interaction, it was demonstrated that the inhibition of prostacyclin synthetase could be offset by cicletanine. These results indicate that the drug modulates the generation of prostacyclin and as such is capable of affecting the peripheral resistances which determine the level of the blood pressure.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Effect of ginkgolide PAF-acether antagonists on arterial thrombosis.

Topical superfusion by PAF-acether over a branch of the mesenteric artery of the guinea pig invariably results in the formation of a platelet thrombus, adhering onto a denuded area of the vessel wall, or at sites where local retraction of the endothelial cells has occurred. It is demonstrated that the application of exogenous PAF-acether triggers a process of local autogeneration and release of endogenous PAF-acether (or PAF-like substances), maintaining a long phase of sequential regrowth and embolization of thrombi, eventually leading to a complete occlusion of the arterial lumen. Extracts of Ginkgo biloba, administered intravenously or in topical superfusion, inhibit both exogenous- and endogenous-induced thromboformation.

Animals↗
PubMed1986

Standardization of a device for continuous observation of local flow in tissue.

As our experimental set-up for continuous recording of local blood flow in the cerebral cortex of a laboratory animal with chronically implanted miniature thermistors (based on the heat clearance principle) gave satisfactory results for routine tests of pharmacological agents during anoxia, hypoxia, hypercapnia, etc., experiments, we intended to standardize the apparatus, to increase accuracy, to facilitate calibration and to enhance flexibility with respect to the operator. The exponential aspect in the thermistor resistance/temperature characteristic is linearized by applying a logarithmic converter in the thermistor amplifier. Calibration to the centigrade temperature scale is performed by a three digit numerical adaptation of two thermistor constants determined in a thermostatic-cryostatic bath (zero and slope). A heating power measuring circuit is provided so that the dissipation constant of the thermistor implanted in tissue can be obtained and the thermal conductivity of the tissue can be estimated. Linearity of the relation between cooling of the heated thermistor and local flow, for small cooling values as they are registered in vivo, is still being investigated.

Animals↗
PubMed1986

Endogenic PAF-acether production by guinea pig endothelial cells in experimental arterial thrombosis.

Superfusion of PAF-acether over a branch of the mesenteric artery in the guinea pig invariably results in local endothelial injury and thrombus formation within 3-10 minutes. The thrombotic phenomena do not disappear when PAF-acether superfusion is discontinued, and even when forced embolization is induced. Within a very short interval renewal of thrombosis occurs at the same site. Several data point to a mechanism involving generation and release of endogenic PAF-acether. Recents findings on PAF-acether release by cultured endothelial cells indicate that in the in vivo situation this phenomenon could well be responsible for maintaining the thrombotic status as demonstrated by ultrastructural analysis. In a later stadium polymorphonuclear leukocytes are also involved in total thromboformation.

Animals↗
PubMed1986

Thrombus induction by endogenic paf-acether and its inhibition by Ginkgo Biloba extracts in the guinea pig.

The anti-thrombotic effects of specific paf-acether antagonist BN 52021 were compared to the effects of Ginkgo Biloba extracts A, B, (A + B), and C. Local superfusion of BN 52021 over an experimentally injured arterial segment embolizes an existent paf-acether induced platelet thrombus. When applied before paf-acether, BN 52021 prevents local thromboformation in this model. Applied intravenously, BN 52021 reduces local thromboformation in a significant way. As compared to this BN 52021 standard, only Ginkgo Biloba B and the (A + B)-mixture present major thromboreductive activity.

Animals↗