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G V Born

Publications and source records attributed to G V Born.

At least 19 recordsLinked to original sources
PubMed1998

[Factors affecting the trans-endothelial accumulation of atherogenic plasma proteins in artery walls].

Our experiments were done to find out whether there are factors which influence the passage of the two major "risk factor proteins" LDL and fibrinogen, other than their plasma concentrations, from the blood into the arterial walls, where their accumulation is associated with atherogenesis. The results suggest that administration of a remarkable variety of pressor agents over a few days accelerate the uptake of both proteins by arterial walls, and that, in contrast, the process is no faster in rats that have been spontaneously, i.e., genetically, hypertensive for about 3 months. Considering our experimental findings in relation to human atherosclerotic disease, it is interesting that the risk of coronary heart disease and stroke is increased more than additively when both LDL or fibrinogen levels and systolic or diastolic blood pressures are high (18,46). If our work should point to some mechanistic connection between blood pressure and the accumulation of atherogenic plasma proteins in arterial walls, it would provide, at least in principle, an explanation for the epidemiological facts.

Animals↗
PubMed1997

Effect of deoxycorticosterone acetate on blood pressure in relation to accumulation of low-density lipoprotein and fibrinogen by aorta and other tissues of normotensive Wistar rats.

OBJECTIVE: To evaluate the effect of different 4-week doses of deoxycorticosterone acetate (DOCA), together with 0.9% sodium chloride in the drinking water (DOCA-salt) on the blood pressure and on the accumulation of low-density lipoprotein (LDL) and fibrinogen in artery walls ad other tissues in conscious, unrestrained, normotensive Wistar-Kyoto rats. METHODS: The accumulation of LDL labelled with 125I via the adduct tyramine cellobiose ([125I]-TC-LDL) and of fibrinogen similarly labelled with 131I ([131I]-TC-fibrinogen) was compared in aortic walls, heart, liver, kidney, lung. skeletal muscle, and adrenal gland tissues during the final 24 h of a 4-week administration of DOCA-salt, with vehicle-salt and saline as controls. RESULTS: In control and vehicle rats the blood pressure did not change significantly during the last 5 days of treatment. Administration of DOCA-salt produced a dose-dependent increase in blood pressure during the same period. DOCA-salt administration increased LDL accumulation in the aorta and the heart and decreased LDL accumulation in the adrenal gland compared with those in rats of the control and vehicle groups. DOCA-salt administration did not affect fibrinogen accumulation significantly. CONCLUSION: DOCA-salt treatment produces an increase in arterial blood pressure accompanied by an increase in LDL accumulation by the aortic wall and heart and a decrease in LDL accumulation by the adrenal gland. These observations raise the possibility that one mechanism by which hypertension affects atherosclerosis is through increased LDL accumulation in arterial walls.

Adrenal Glands↗
PubMed1997

Effect of captopril and losartan on blood pressure and accumulation of LDL and fibrinogen by aortic wall and other tissues in normotensive and hypertensive rats.

Hypertension, low-density lipoprotein (LDL), and fibrinogen are risk factors for atherosclerosis. We investigated the effect of reducing blood pressure, by blocking the renin-angiotensin system (RAS), on the accumulation of these atherogenic proteins in arterial walls and other tissues in conscious, unrestrained, normotensive and hypertensive rats. The accumulation of LDL and fibrinogen, labeled respectively with 125I and 131I via the adduct tyramine cellobiose ([125I]-TC-LDL and [131I]-TC-fibrinogen) was compared in aortic walls, heart, lung, skeletal muscle, liver, kidney, and adrenal gland during the final 24 h of treatment with either the angiotensin-converting enzyme (ACE) inhibitor captopril or the angiotensin II-receptor I (AT1) antagonist losartan. In normotensive rats, the blood pressure was decreased only by losartan. In spontaneously hypertensive rats (SHRs), the blood pressure was decreased by both losartan and captopril. Captopril had no significant effect on the accumulation of LDL or fibrinogen by the aortic wall. Losartan significantly increased the accumulation of LDL by the aortic wall of SHRs. Neither agent produced any change in LDL or fibrinogen accumulation in any of the other tissues. These results indicate that although blocking the RAS at either the enzymic or receptor level produces significant decrease of blood pressure in hypertensive animals, only losartan has any affect on LDL accumulation by the aortic wall.

Angiotensin Receptor Antagonists↗
PubMed1996

Increase by adrenaline or angiotensin II of the accumulation of low density lipoprotein and fibrinogen by aortic walls in unrestrained conscious rats.

1. Earlier experiments of ours with anaesthetized rabbits showed that infusions of catecholamines into the carotoid blood stream significantly increased the uptake of radioiodinated low density lipoprotein (LDL) by the artery wall after as little as 2 h. This observation has now been extended to much longer time periods, i.e., 6 days, and another species, viz. conscious and unrestrained rats; also to another pressor agent, angiotensin II, as well as to another plasma protein, fibrinogen. 2. Groups of rats were infused from subcutaneously implanted osmotic minipumps for 6 days. The infusions were either into a carotid artery or into the surrounding tissues, with essentially the same effects. Control animals were infused with saline, and test animals with either adrenaline or angiotensin II. The minipump concentration of adrenaline of 4-5 microM, which gave blood concentrations of 25-41 nM, increased the blood pressure significantly after 3 days. The minipump concentration of angiotensin II of 9.9 mg ml-1 was chosen to produce similar increases in blood pressure. 3. Five days after starting the infusion, rats were injected i.v. with either homologous or human LDL labelled with [125I]-tyramine cellobiose (TC), or with [131I]-TC labelled human fibrinogen. Twenty-four hours later, the animals were killed and the radioactivities determined in the whole aorta. The labelled TC radioactivities represent primarily metabolised protein (because TC is trapped intracellularly), but also include the fraction of intact, i.e., non-metabolized protein in transit through the vessel wall. To determine the contribution of the latter, in some experiments we injected double-labelled [131I]-[125TC]-LDL only. These experiments showed that the [131I]-LDL counts representing protein in transit accounted for approx. 20% of the total 125TC counts, and that this percentage was not significantly affected by adrenaline or angiotensin II. Therefore, the bulk of the experiments was carried out with single labelled proteins, using 125I to label TC-LDL and 131I to label TC-fibrinogen. In these experiments, the radioactivity of the arterial wall thus provides a cumulative measure of the uptake and degradation of proteins. 4. Aortic wall radioactivities from rat and human LDL and from human fibrinogen were significantly increased by both agents. Adrenaline at 25-41 nM increased the radioactivities by 52 and 47% for rat and human LDL respectively, and by 31% for human fibrinogen; these differences were highly significant (P < 0.01). Angiotensin II at ca. 10 nM also increased the radioactivities significantly, by 21% for human LDL and by 109% for human fibrinogen (P < 0.05). 5. The results suggest that the accumulation of LDL and of fibrinogen by rat aorta is increased by adrenaline or by angiotensin II at concentrations which raise the blood pressure progressively and significantly after 3 or 5 days respectively.

Angiotensin II↗
PubMed1995

Inhibition by nifedipine of the efflux of plasma low-density lipoprotein and albumin from the vasculature of the mouse mesentery in vivo.

Efflux and extravascular accumulation of intravenously administered fluorescent-labeled low-density lipoprotein (LDL) and albumin were measured in superfused mouse mesenteric preparation in anesthetized mice. Pretreatment of animals with nifedipine (1 and 3 mg/kg sc) significantly reduced both the extravascular accumulation of LDL (measured by fluorescence densitometry) and the efflux (measurement of the tracers in the superfusate) of both LDL and albumin. These effects may help to explain the possible anti-atherogenic effect of nifedipine.

Animals↗
PubMed1995

Effect of inhibition of nitric oxide synthesis on the uptake of LDL and fibrinogen by arterial walls and other organs of the rat.

1. The effects of administering 3 mg ml-1 NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO), on the uptake of low density lipoprotein (LDL), fibrinogen and blood pressure were determined in conscious, unrestrained, cannulated normotensive and spontaneously hypertensive (SHR) Wistar rats. 2. The uptake of LDL and fibrinogen, labelled respectively with 125I or 131I via the adduct tyramine cellobiose ([125I]TC-LDL and [131I]TC-fibrinogen), were compared in aortic walls, heart, skeletal muscle, lung, liver, kidney and adrenal during the final 24 h of 6 days' administration of L-NAME in the drinking water. 3. In control normotensive rats, the systolic blood pressure did not change significantly over 6 days, while administration of L-NAME in normotensive rats increased the blood pressure progressively and significantly to about 170 mmHg over the same period. 4. In normotensive rats L-NAME increased significantly the uptake of both LDL and fibrinogen by aortic walls and heart, but not by muscle, lung, liver, kidney and adrenal. 5. The blood pressure in SHR was about 170 mmHg before administration of L-NAME and did not increase significantly after 6 days of treatment. In these rats the uptake of LDL or of fibrinogen was increased only in the heart but not in aortic walls nor in any of the other organs. 6. In normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increases in the uptake of the atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart but not by the skeletal muscle, lung, liver, kidney and adrenal. The slightly higher blood pressure of SHR treated with L-NAME was not associated with increased uptake of LDL or fibrinogen by aorta nor by any organ except heart. Thus, while in normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increase in the uptake of atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart, in SHR which showed uptakes similar to the normotensive animals, the non-significant increase in blood pressure induced by inhibition of NO generation was not associated with increased uptake of LDL or fibrinogen in any organ except the heart.7. These results are consistent with effects, demonstrated earlier, of infusing the pressor agents noradrenaline, adrenaline and angiotensin II, which produce increases in uptake of LDL and fibrinogen by aortic wall, whereas this is not so in spontaneously hypertensive rats.

Animals↗
PubMed1994

Effect of increasing doses of angiotensin II infused into normal and hypertensive Wistar rats on low density lipoprotein and fibrinogen uptake by aortic walls.

The effect of 6 days' s.c. infusions of angiotensin II at increasing doses was determined on the uptake of rat or human low density lipoprotein (LDL) and of human fibrinogen by aorta in normal and spontaneously hypertensive rats. Rat or human LDL or human fibrinogen was injected i.v. 5 days after the start of infusion, and 24 hr later the radioactivity of aortic walls was determined. Body weight was almost constant in control rats and moderately decreased in a dose-dependent way by angiotensin II. Diastolic blood pressure decreased slightly over 6 days in control rats and increased transiently at the lowest dose of angiotensin II and progressively with two higher concentrations. All three angiotensin II concentrations significantly increased the uptake of rat and human LDL and of fibrinogen by aorta. The increase was dose related for rat LDL but not for human LDL or fibrinogen. In spontaneously hypertensive rats of the same age in which blood pressure was higher than in angiotensin II-infused rats, protein uptakes were not increased. The blood content of aortic walls was negligible and not altered by angiotensin II. Therefore, the uptake of atherogenic plasma proteins by rat aorta is increased by angiotensin II, but this effect may be independent of its pressor action.

Angiotensin II↗
PubMed1994

New determinants of the uptake of atherogenic plasma proteins by arteries.

Atherosclerotic disease begins with the accumulation of atherogenic plasma proteins, predominantly low-density lipoprotein (LDL), in susceptible arteries. One determinant of this is the LDL concentration in the blood (4). We are investigating other factors which may influence the uptake of LDL and of fibrinogen, another atherogenic plasma protein, by artery walls, as well as the mechanism(s) of this uptake. In order to model human atherogenesis as closely as possible, the experiments are mostly in vivo, using rabbits and rats. In anesthetized rabbits, intravenous infusions of histamine sufficient to produce interendothelial gaps throughout the venular systems did not increase the rate constant of the disappearance of LDL from the circulating blood. This makes it improbable that significant quantities of LDL pass out of the blood into vessel walls between endothelial cells, and it indirectly supports the evidence that LDL leaves the plasma by transcytosis through the endothelial cells. In anesthetized rabbits and in conscious rats the uptake of LDL, methylated to prevent its removal by high-affinity receptors (m-LDL), is significantly increased by noradrenaline and by adrenaline at their pathophysiological blood concentrations. In man this could help to account for the coronary risk factor status of cigarette smoking, hypertension, stress, etc. when associated with increases in circulating catecholamines. The mechanism of this effect is now under investigation.

Animals↗
PubMed1993

Testing of small connective tissue specimens for the determination of the mechanical behaviour of atherosclerotic plaques.

The tearing of the cap of atheromatous plaques is the commonest cause of thrombosis in human coronary arteries. It has been proposed that tearing arises because of structural weakening of the cap's connective tissue around the tear. To test this hypothesis we compared the mechanical properties of the intact edges of torn plaque caps and unbroken caps. Owing to limitations in plaque size, a purpose-built tensometer was developed to study stress-strain relationships of the small connective tissue specimens. The design of the tensometer is reported and was shown to detect accurately, minor differences in connective tissues and to generate complete stress-curves with computer-assisted image analysis.

Animals↗
PubMed1993

Nifedipine inhibits accumulation of LDL and cholesterol in the aorta of the normocholesterolemic rabbit.

The effect of 5 days of oral nifedipine treatment (approximately 1 mg/kg per day in drinking water) on low density lipoprotein (LDL) and cholesterol accumulation in rabbit arteries was determined. Compared with control aortas, nifedipine treatment (n = 5) significantly reduced homologous 125I-tyramine cellobiose-LDL accumulation (control versus nifedipine: 45.93 +/- 4.3 versus 20.14 +/- 3.1 ng LDL per milligram dry weight x10(-3), p = 0.001) while the reduction of human LDL accumulation (n = 5) was not significant (49.1 +/- 6.1 versus 35.5 +/- 4.1 ng LDL per milligram dry weight x10(-3)). Aortic accumulation of orally administered [3H]cholesterol was also inhibited by nifedipine (352 +/- 34 versus 257 +/- 16 ng cholesterol per milligram dry weight x10(-3), n = 10, p = 0.022). These findings suggest a possible mechanism for the antiatherosclerotic effect of nifedipine.

Animals↗
PubMed1992

Release of thromboxane A2 and beta-thromboglobulin during in-vivo plug formation following standardized skin incisions: effect of a moderate fish intake.

This paper describes a controlled study of the effects of a fish supplement on haemostasis. This was evaluated by measuring bleeding times from skin incisions, the volume of the emerging blood, the number of platelets taking part in the formation of the haemostatic plug (platelet retention), and the release of thromboxane B2 and beta-thromboglobulin in volunteers, before and after consuming a daily supplement of 100 g of fish (n = 20) or meat (n = 20) paste for 6 weeks. The fish supplement decreased the amount of thromboxane B2 released per platelet incorporated into the plug. Despite this, the skin bleeding times were hardly changed. There was also no difference in platelet retention, which was consistent with there being no difference in the release of beta-thromboglobulin. These results suggest that in the effect of marine diets on haemostasis, a reduced vascular reactivity plays a more important role than decreased plug formation.

Animals↗
PubMed1992

Collagen types I and III, collagen content, GAGs and mechanical strength of human atherosclerotic plaque caps: span-wise variations.

Measurements of total collagen, of the ratio of collagen types III/(I+III) and of sulphated glycosaminoglycans (GAGs) were compared with mechanical strength for individual ulcerated and non-ulcerated human aortic plaque caps and with intima adjacent to the plaques. The distributions of the collagen type ratio were similar for both ulcerated and non-ulcerated plaque caps but different from that of the adjacent intima. The proportions of different collagen types were not related to fracture stress and are thus unlikely to affect the potential to ulcerate. The distributions of the sulphated GAGs showed lower amounts for the plaque caps compared with the nearby intima, with the centres of ulcerated plaque caps having the lowest values. Total collagen had higher values in the peripheries of plaque caps compared with the nearby intima, but was distinctly lower in the centres of ulcerated plaque caps. Plaque caps appeared to require a higher collagen content than adjacent intima to support a given level of mechanical strength, suggesting that while collagen production had occurred in the plaque caps it was not as efficiently organized to resist fracture as a similar amount of collagen in the adjacent intima. Ulcerated plaque caps are notable for much larger transverse (centre vs. periphery) gradients of connective tissue constituents than for non-ulcerated plaque caps. The development of these transverse gradients may be a critical aspect in determining the propensity of a plaque to ulcerate.

Aortic Diseases↗
PubMed1992

Adrenaline increases the uptake of low-density lipoproteins in carotid arteries of rabbits.

The uptake of low-density lipoprotein was compared in carotid arteries of anaesthetized male New Zealand rabbits after infusing alternate carotids with adrenaline, or with saline as a control. The infusions were at approximately 2% of the carotid blood flow, the adrenaline being at approximately 10 nM in the carotid blood. Human low density lipoprotein, methylated to prevent recognition by the high affinity receptor (m-LDL), was labelled with 125I and injected intravenously. Adrenaline infusions for 2 or 4 h significantly increased m-LDL radioactivity in the carotid walls. The radioactivity of reinjected red cells labelled with 51Cr was the same in the walls of both carotids. This excluded the possibility that the excess LDL radioactivity in adrenaline infused carotids was accounted for by increased amounts of blood in the arterial wall. It also made it improbable that the excess LDL resulted from decreased elimination through a vasoconstriction effect of adrenaline on the vasa vasorum, which should have decreased the amount of radioactivity due to red cells. The results, therefore, suggest that adrenaline at its pathophysiological blood concentrations accelerates the uptake of LDL by large arteries in rabbits.

Animals↗
PubMed1992

Plaque fissure: the link between atherosclerosis and thrombosis.

The immediate cause of arterial, predominantly coronary thrombosis is almost always cracking or fissuring of the cap of an atheromatous plaque. This exposes collagen and lipids to the flowing blood and thereby initiates thrombotic platelet aggregation, almost immediately followed by coagulation. The thrombi tend to extend into the arterial lumen, causing obstruction to blood flow and clinical symptoms and signs. Evidence for this sequence of events comes, inter alia, from angiograms of patients with unstable angina and developing myocardial infarction. Direct angioscopy in life is also visualising mural thrombi over fissured plaques in atheromatous coronary arteries. We are investigating the initial development of atheromatous plaques liable to fissuring. The cap over such plaques covers a "lipid pool". We have discovered that one factor promoting the uptake of lipid, in the form of plasma low-density lipoprotein, is the concentration of circulating catecholamines (Cardona-Sanclemente LE, Gorog P, Born GVR (1992) J Physiol London, in press). We are also investigating the immediate cause(s) of plaque fissure. We have evidence for a complex interaction of different determinants, including the concentration of macrophages, presumably as foam cells, in the plaque caps (Lendon CL, Davies MJ, Born BVR, Richardson PD (1991) Atherosclerosis 87: 87).

Angina, Unstable↗
PubMed1991

Atherosclerotic plaque caps are locally weakened when macrophages density is increased.

The density of macrophages, identified by the antibody EBMII, in human aortic plaque caps was counted. A contiguous strip of cap tissue was tested mechanically. Aortic plaque caps which had undergone rupture (ulceration) at one end (n = 18) were compared with caps of intact plaques (n = 22). The caps of ruptured plaques showed a significant increase in macrophage density, an increased extensibility and decreased maximum stress (force per unit area) at fracture when compared with caps from intact plaques.

Aorta↗
PubMed1991

In vivo and in vitro effects of low molecular weight heparan sulphate on the human fibrinolytic enzyme system.

The aim of this study was to evaluate the effects of a preparation of low molecular weight heparan sulphate (LMW-HS) on the fibrinolytic system. Twenty-five healthy volunteers received LMW-HS by mouth in three separate experiments. In the first experiment, 10 volunteers received either 80 mg LMW-HS or placebo in a single-blind cross-over study; blood samples were taken before and 1, 2, 3 and 6 h after treatment. LMW-HS caused an increase in global fibrinolysis, the effect being greatest after 2-3 h and disappearing by 6 h. However, neither plasminogen activator activity nor tissue-type plasminogen activator (tPA) antigen levels were changed. In the second experiment, daily doses of 80 mg LMW-HS were administered to 10 volunteers for 7 days; this regimen did not produce a statistically significant increase in fibrinolytic activity for the whole group although some individuals did respond markedly. In the third experiment, 160 mg LMW-HS administered to five volunteers did not affect ADP- and collagen-induced platelet aggregation. In vitro, LMW-HS added to plasma at concentrations of 20 and 30 micrograms/ml, brought about a significant increase in apparent plasminogen activator activity. These results suggest that the increased fibrinolytic activity seen after LMW-HS is due to the recruitment of additional amounts of tPA in the ex vivo test system. LMW-HS had no effect on plasminogen activator inhibitor.

Adenosine Diphosphate↗